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Chen L, Ma N, Liu D, Li Y, Ci X, Wei Z. Tiliroside induces ferroptosis and suppresses tumor growth by synergistically targeting AKR1B1 and modulating iron metabolism in ovarian cancer cells. Eur J Pharmacol 2025; 997:177591. [PMID: 40187595 DOI: 10.1016/j.ejphar.2025.177591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 03/26/2025] [Accepted: 04/02/2025] [Indexed: 04/07/2025]
Abstract
AIMS Ovarian cancer (OC) is a common malignant tumor with the greatest mortality rate among gynecological tumors. Tiliroside (TIL) is a glycosidic dietary flavonoid with various pharmacological activities. The purpose of this study was to investigate the exact mechanism by which TIL eliminates OC cells. METHODS/KEY FINDINGS In vitro, TIL exerted anti-tumor activities by inducing cell death and inhibiting the invasion and migration of A2780 and OVCAR8 cells. Additionally, the suppressive effect of TIL on OC cells was mainly due to the induction of ferroptosis, as demonstrated by the fact that only ferroprostatin-1 (Fer-1) significantly inhibited the anti-tumor activity of TIL, with the accumulation of ROS, MDA, and Fe2+ and a reduction in GPX4 expression. SwissTargetPrediction, molecular docking and CETSA assay showed that the direct interaction between AKR1B1 and TIL decreased its stability and expression. Notably, AKR1B1 overexpression significantly attenuated the effects of TIL on the proliferation, invasion, migration and ferroptosis on OC cells, whereas the levels of Fe2+ remained unaffected. Interestingly, the results of the RNA sequencing (RNA-seq) analysis suggested that the regulation of iron homeostasis by TIL might be connected to ion transport. Western blotting and immunofluorescence confirmed that TIL could modulate iron metabolism by regulating iron ion transport and ferritinophagy, ultimately resulting in ferroptosis. In xenograft model mice, TIL treatment inhibited tumor growth without causing substantial tissue damage. SIGNIFICANCE Our research revealed that TIL simultaneously targets AKR1B1 and modulates iron metabolism, thereby inducing ferroptosis and improving anti-tumor efficacy. As a novel drug, TIL is promising for OC treatment.
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Affiliation(s)
- Lu Chen
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, Jilin, 130001, China; Jilin Provincial Key Laboratory of Women's Reproductive Health, Changchun, Jilin, 130001, China
| | - Ning Ma
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, Jilin, 130001, China; Jilin Provincial Key Laboratory of Women's Reproductive Health, Changchun, Jilin, 130001, China
| | - Dongzhen Liu
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, Jilin, 130001, China; Jilin Provincial Key Laboratory of Women's Reproductive Health, Changchun, Jilin, 130001, China
| | - Yuan Li
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, Jilin, 130001, China; Jilin Provincial Key Laboratory of Women's Reproductive Health, Changchun, Jilin, 130001, China
| | - Xinxin Ci
- Jilin Provincial Key Laboratory of Women's Reproductive Health, Changchun, Jilin, 130001, China; Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, 130001, China.
| | - Zhentong Wei
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, Jilin, 130001, China; Jilin Provincial Key Laboratory of Women's Reproductive Health, Changchun, Jilin, 130001, China.
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Zhang C, Zhu J, Lin H, Zhang Z, Kang B, Li F, Shan Y, Zhang Y, Xing Q, Gu J, Hu X, Cui Y, Huang J, Zhou T, Mai Y, Chen Q, Mao R, Li P, Pan G. HBO1 determines epithelial-mesenchymal transition and promotes immunotherapy resistance in ovarian cancer cells. Cell Oncol (Dordr) 2025:10.1007/s13402-025-01055-8. [PMID: 40227530 DOI: 10.1007/s13402-025-01055-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 03/12/2025] [Indexed: 04/15/2025] Open
Abstract
PURPOSE Epithelial-mesenchymal transition (EMT) plays critical roles in tumor progress and treatment resistance of ovarian cancer (OC), resulting in the most deadly gynecological cancer in women. However, the cell-intrinsic mechanism underlying EMT in OC remains less illuminated. METHOD SKOV3, the OC cell line, was treated with TGF-β to induce EMT or with SB431542, an inhibitor of the TGF-β signaling pathway, to reduce migration. The function of HBO1 in EMT was confirmed by knock-down or overexpression of HBO1 in SKOV3 cells. The role of HBO1 in cell proliferation and apoptosis of SKOV3 cells was analyzed by flow cytometry. The whole-genome transcriptome was used to compare significantly different genes in control and HBO1-KD SKOV3 cells. T-cell cytotoxicity assays were measured by an IVIS spectrum. The chromatin binding of HBO1 was investigated using CUT&Tag-seq. RESULTS Here, we show that HBO1, a MYST histone acetyltransferase (HAT), is a cell-intrinsic determinant for EMT in OC cells. HBO1 is greatly elevated during TGF-β-triggered EMT in SKOV3 OC cells as well as in later stages of clinical OC samples. HBO1 Knock-down (KD) in SKOV3 cells blocks TGF-β-triggered EMT, migration, invasion and tumor formation in vivo. Interestingly, HBO1 KD in SKOV3 cells suppresses their resistance to CAR-T cells. Mechanistically, HBO1 co-binds the gene sets responsible for EMT with SMAD4 and orchestrates a gene regulatory network critical for tumor progression in SKOV3 cells. CONCLUSION HBO1 plays an essential onco-factor to drive EMT and promote the immunotherapy resistance in ovarian cancer cells. Together, we reveal a critical role of HBO1 mediated epigenetic mechanism in OC progression, providing an insight into designing new therapy strategies.
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Affiliation(s)
- Cong Zhang
- Key Laboratory of Immune Response and Immunotherapy, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou, 511436, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Jinmin Zhu
- Key Laboratory of Immune Response and Immunotherapy, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou, 511436, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Huaisong Lin
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Chinese Academy of Sciences, Hong Kong, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Zhishuai Zhang
- Key Laboratory of Immune Response and Immunotherapy, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou, 511436, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Baoqiang Kang
- Key Laboratory of Immune Response and Immunotherapy, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou, 511436, China
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Chinese Academy of Sciences, Hong Kong, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Fei Li
- Key Laboratory of Immune Response and Immunotherapy, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou, 511436, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Yongli Shan
- Key Laboratory of Immune Response and Immunotherapy, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou, 511436, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Yanqi Zhang
- Key Laboratory of Immune Response and Immunotherapy, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou, 511436, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Qi Xing
- Key Laboratory of Immune Response and Immunotherapy, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou, 511436, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Jiaming Gu
- Key Laboratory of Immune Response and Immunotherapy, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou, 511436, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Xing Hu
- Key Laboratory of Immune Response and Immunotherapy, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou, 511436, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Yuanbin Cui
- Key Laboratory of Immune Response and Immunotherapy, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou, 511436, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Jingxi Huang
- Key Laboratory of Immune Response and Immunotherapy, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou, 511436, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Tiancheng Zhou
- Key Laboratory of Immune Response and Immunotherapy, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou, 511436, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Yuchan Mai
- Key Laboratory of Immune Response and Immunotherapy, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou, 511436, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Qianyu Chen
- Key Laboratory of Immune Response and Immunotherapy, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou, 511436, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Rui Mao
- Key Laboratory of Immune Response and Immunotherapy, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou, 511436, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Peng Li
- Key Laboratory of Immune Response and Immunotherapy, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou, 511436, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Guangjin Pan
- Key Laboratory of Immune Response and Immunotherapy, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou, 511436, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Chinese Academy of Sciences, Hong Kong, China.
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
- GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
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Lusk HJ, Haughan MA, Bergsten TM, Burdette JE, Sanchez LM. Branched-Chain Amino Acid Catabolism Promotes Ovarian Cancer Cell Proliferation via Phosphorylation of mTOR. CANCER RESEARCH COMMUNICATIONS 2025; 5:569-579. [PMID: 40066850 PMCID: PMC11973964 DOI: 10.1158/2767-9764.crc-24-0532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 01/24/2025] [Accepted: 03/06/2025] [Indexed: 03/19/2025]
Abstract
SIGNIFICANCE This study uncovers altered amino acid metabolism, specifically increased BCAA catabolism, at the interface of ovarian cancer cells and omental tissue in a coculture model of HGSOC secondary metastasis. Enhanced BCAA catabolism promotes cancer cell proliferation through mTOR signaling, presenting potential therapeutic value. These findings deepen our understanding of HGSOC pathogenesis and the metastatic tumor microenvironment, offering insights for developing new treatment strategies.
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Affiliation(s)
- Hannah J. Lusk
- Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, California
| | - Monica A. Haughan
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, Illinois
| | - Tova M. Bergsten
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, Illinois
| | - Joanna E. Burdette
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, Illinois
| | - Laura M. Sanchez
- Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, California
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4
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Hollis RL, Churchman M, Grimes GR, Meynert AM, Gautier P, McMahon L, Sherwood K, Oswald AJ, Croy I, Ferguson M, Martin CW, McGoldrick T, McPhail N, Creedon H, Barrett JC, March R, Dougherty BA, Roxburgh P, Ewing A, Herrington CS, Semple CA, Gourley C. Somatic BRCA1/2 mutations are associated with a similar survival advantage to their germline counterparts in tubo-ovarian high grade serous carcinoma. Eur J Cancer 2025; 219:115299. [PMID: 39955805 DOI: 10.1016/j.ejca.2025.115299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 02/04/2025] [Accepted: 02/08/2025] [Indexed: 02/18/2025]
Abstract
BACKGROUND Half of high grade serous tubo-ovarian carcinomas (HGSOC) demonstrate homologous recombination repair (HRR) deficiency, most commonly through germline or somatic pathogenic variants in BRCA1/2 (gBRCA1/2 or sBRCA1/2). gBRCA1/2 is associated with favourable survival, greater response rate to platinum-based chemotherapy, and marked sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. sBRCA1/2 has been assumed to confer a similar clinical phenotype; however, few studies have specifically investigated sBRCA1/2 versus gBRCA1/2 to demonstrate their equivalence. METHODS We investigated the association of gBRCA1/2, sBRCA1/2 and non-BRCA HRR gene mutations with HGSOC patient survival using two patient cohorts (cohort 1, n = 174 matched FFPE tumour and normal with panel-based sequencing; cohort 2, n = 279 matched fresh tumour and normal with whole genome sequencing). TCGA-OV samples (n = 316) were used for external validation. RESULTS Patients with HRR-mutant tumours (BRCA1, BRCA2, non-BRCA HRR-mutant) demonstrated prolonged survival across both cohorts (cohort 1: multivariable hazard ratio [multiHR] 0.53 [0.32-0.87]; cohort 2: multiHR 0.36 [0.25-0.51]). gBRCA1/2 and sBRCA1/2 were associated with a similar survival benefit compared to the HRR-wildtype group in the combined cohort (cohort 1 +2) (gBRCA1/2: multiHR 0.50 [0.34-0.71]; sBRCA1/2: multiHR 0.41 [0.25-0.68]). These findings were recapitulated using the TCGA-OV dataset (gBRCA1/2: multiHR 0.56 [0.34-0.91]; sBRCA1/2: multiHR 0.48 [0.25-0.92]). Non-BRCA HRR mutations were associated with marked survival advantage (multiHR vs HRR-wildtype 0.22 [0.11-0.45]). The survival advantage in BRCA1-mutant cases (germline or somatic) was less marked (multiHR for non-BRCA HRR-mutant vs BRCA1-mutant 0.41 [0.19-0.90]). gBRCA1/2, sBRCA1/2 and non-BRCA HRR mutations were all associated with high HRDetect scores measuring HRR deficiency (median 1.00 versus 0.56 in HRR-wildtype, P < 0.01). CONCLUSION gBRCA1/2 and sBRCA1/2 are equivalent in their association with prolonged survival. Non-BRCA HRR gene mutations may be associated with markedly favourable survival in HGSOC.
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Affiliation(s)
- Robert L Hollis
- The Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
| | - Michael Churchman
- The Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Graeme R Grimes
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Alison M Meynert
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Philippe Gautier
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Lynn McMahon
- Precision Medicine Scotland (PMS-IC), Queen Elizabeth University Hospital, Glasgow, UK
| | - Kitty Sherwood
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK; Department of Oncology, University of Oxford, Oxford, UK; Edinburgh Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Ailsa J Oswald
- The Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Ian Croy
- The Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | | | - Cameron W Martin
- The Simpson Centre for Reproductive Health, Royal Infirmary Edinburgh, Edinburgh, UK
| | | | - Neil McPhail
- Department of Oncology, Raigmore Hospital, NHS Highland, Inverness, UK
| | - Helen Creedon
- The Edinburgh Cancer Centre, Western General Hospital, NHS Lothian, Edinburgh, UK
| | - J Carl Barrett
- Translational Medicine, Oncology R&D, AstraZeneca, Waltham, MA, USA
| | - Ruth March
- Precision Medicine and Biosamples, Oncology R&D, AstraZeneca, Cambridge, UK
| | | | - Patricia Roxburgh
- Cancer Research UK Scotland Centre, School of Cancer Sciences, Glasgow, UK; Beatson West of Scotland Cancer Centre, Glasgow, UK
| | - Ailith Ewing
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK; Edinburgh Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - C Simon Herrington
- The Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Colin A Semple
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Charlie Gourley
- The Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
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Zhao X, Lai H, Li G, Qin Y, Chen R, Labrie M, Stommel JM, Mills GB, Ma D, Gao Q, Fang Y. Rictor orchestrates β-catenin/FOXO balance by maintaining redox homeostasis during development of ovarian cancer. Oncogene 2025:10.1038/s41388-025-03351-x. [PMID: 40133477 DOI: 10.1038/s41388-025-03351-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 02/14/2025] [Accepted: 03/11/2025] [Indexed: 03/27/2025]
Abstract
Rictor/mTORC2 has been demonstrated to have important roles in cancer development and progression in a number of solid and hematologic malignancies. However, little is known about the role of Rictor/mTORC2 in ovarian cancer pathophysiology. Herein, using conditional Rictor knockout mice, we were able to demonstrate that Rictor deletion disrupted glutathione metabolism through AKT/Nrf2 signaling pathway and induced intracellular oxidative stress during the malignant transformation of Kras/Pten-mutant ovarian surface epithelial cells. Elevated reactive oxygen species and activated FOXO3a in Rictor-deleted cells strikingly shifts the functional interaction of β-catenin from TCF to FOXO3a, which strongly inhibits classical Wnt/β-catenin signaling. Our findings emphasize a pivotal role for Rictor in orchestrating crosstalk between the PI3K/AKT and Wnt/β-catenin signaling in the development of ovarian cancer. Illustration of Rictor/mTORC2 in promoting tumor onset by regulating glutathione metabolism and mediating oncogenic signaling.
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Affiliation(s)
- Xuejiao Zhao
- National Clinical Research Center for Obstetrics and Gynaecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Gynaecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huiling Lai
- Department of Gynecology, the Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Guannan Li
- National Clinical Research Center for Obstetrics and Gynaecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Gynaecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Qin
- National Clinical Research Center for Obstetrics and Gynaecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Gynaecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ruqi Chen
- National Clinical Research Center for Obstetrics and Gynaecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Gynaecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Marilyne Labrie
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Jayne M Stommel
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Gordon B Mills
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA
| | - Ding Ma
- National Clinical Research Center for Obstetrics and Gynaecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Department of Gynaecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Qinglei Gao
- National Clinical Research Center for Obstetrics and Gynaecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Department of Gynaecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Yong Fang
- National Clinical Research Center for Obstetrics and Gynaecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Department of Gynaecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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6
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Jopek MA, Sieczczyński M, Pastuszak K, Łapińska-Szumczyk S, Jassem J, Żaczek AJ, Rondina MT, Supernat A. Impact of clinical factors on accuracy of ovarian cancer detection via platelet RNA profiling. Blood Adv 2025; 9:979-989. [PMID: 39715465 PMCID: PMC11907454 DOI: 10.1182/bloodadvances.2024014008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 12/05/2024] [Accepted: 12/05/2024] [Indexed: 12/25/2024] Open
Abstract
ABSTRACT Ovarian cancer (OC) presents a diagnostic challenge, often resulting in poor patient outcomes. Platelet RNA sequencing, which reflects host response to disease, shows promise for earlier OC detection. This study examines the impact of sex, age, platelet count, and the training on cancer types other than OC on classification accuracy achieved in the previous platelet-alone training data set. A total of 339 samples from healthy donors and 1396 samples from patients with cancer, spanning 18 cancer types (including 135 OC cases) were analyzed. Logistic regression was applied to verify our classifiers' performance and interpretability. Models were tested at 100% specificity and 100% sensitivity levels. Incorporating patient age as an additional feature along with gene expression increased sensitivity from 68.6% to 72.6%. Models trained on data from both sexes and on female-only data achieved a sensitivity of 68.6% and 74.5%, respectively. Training solely on OC data reduced late-stage sensitivity from 69.1% to 44.1% but increased early-stage sensitivity from 66.7% to 69.7%. This study highlights the potential of platelet RNA profiling for OC detection and the importance of clinical variables in refining classification accuracy. Incorporating age with gene expression data may enhance OC diagnostic accuracy. The inclusion of male samples deteriorates classifier performance. Data from diverse cancer types improves advanced cancer detection but negatively affects early-stage diagnosis.
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Affiliation(s)
- Maksym A. Jopek
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology of the University of Gdańsk and the Medical University of Gdańsk, Gdańsk, Poland
- Centre of Biostatistics and Bioinformatics, Medical University of Gdańsk, Gdańsk, Poland
| | - Michał Sieczczyński
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology of the University of Gdańsk and the Medical University of Gdańsk, Gdańsk, Poland
| | - Krzysztof Pastuszak
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology of the University of Gdańsk and the Medical University of Gdańsk, Gdańsk, Poland
- Centre of Biostatistics and Bioinformatics, Medical University of Gdańsk, Gdańsk, Poland
- Department of Algorithms and Systems Modelling, Faculty of Electronics, Telecommunications and Informatics, Gdańsk University of Technology, Gdańsk, Poland
| | | | - Jacek Jassem
- Department of Oncology and Radiotherapy, Medical University of Gdańsk, Gdańsk, Poland
| | - Anna J. Żaczek
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology of the University of Gdańsk and the Medical University of Gdańsk, Gdańsk, Poland
| | - Matthew T. Rondina
- Molecular Medicine Program, The University of Utah, Salt Lake City, UT
- Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, The University of Utah and Huntsman Cancer Institute, Salt Lake City, UT
- George E. Wahlen Veterans Affairs Medical Center Department of Internal Medicine and the Geriatric Research Education and Clinical Center, Salt Lake City, UT
- Department of Pathology, The University of Utah, Salt Lake City, UT
| | - Anna Supernat
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology of the University of Gdańsk and the Medical University of Gdańsk, Gdańsk, Poland
- Centre of Biostatistics and Bioinformatics, Medical University of Gdańsk, Gdańsk, Poland
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7
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Mahmoud A, Choi PH, Sukhwa C, Pintar J, Walch H, Zhao N, Bermeo J, Chung S, Raghavan M, Bapat S, Jiang Q, Karagkounis G, Meredith J, Giarrizzo M, Firat C, Cercek A, Foote MB, Schultz N, Chatila WK, Nash GM, Shia J, Sanchez-Vega F, Larson S, Dar AC, Rosen N, Ganesh K. Paired primary-metastasis patient-derived organoids and mouse models identify phenotypic evolution and druggable dependencies of peritoneal metastasis from appendiceal cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.17.638725. [PMID: 40027618 PMCID: PMC11870485 DOI: 10.1101/2025.02.17.638725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Peritoneal carcinomatosis is a common yet deadly manifestation of gastrointestinal cancers, with few effective treatments. To identify targetable determinants of peritoneal metastasis, we focused on appendiceal adenocarcinoma (AC), a gastrointestinal cancer that metastasizes almost exclusively to the peritoneum. Current treatments are extrapolated from colorectal cancer (CRC), yet AC has distinct genomic alterations, mucinous morphology and peritoneum restricted metastatic pattern. Further, no stable preclinical models of AC exist, limiting drug discovery and representing an unmet clinical need. We establish a first-in-class stable biobank of 16 long-term cultured AC patient-derived organoids (PDOs), including 3 matched, simultaneously resected primary AC-peritoneal carcinomatosis (AC-PC) pairs. By enriching for cancer cells, AC PDOs enable accurate genomic characterization relative to paucicellular AC tissue. We establish an organoid orthotopic intraperitoneal xenograft model that recapitulates diffuse peritoneal carcinomatosis and show that PC-organoids retain increased metastatic capacity, decreased growth factor dependency and sensitivity to standard of care chemotherapy relative to matched primary AC organoids. Single cell profiling of AC-PC pairs reveals dedifferentiation from mucinous differentiated states in primary AC into intestinal stem cell and fetal progenitor states in AC-PC, with upregulation of oncogenic signaling pathways. Through hypothesis-driven drug testing, we identify KRASMULTI-ON inhibitor RMC-7977 and Wnt-targeting tyrosine kinase inhibitor WNTinib as novel, clinically actionable strategies to target AC-PC more effectively.
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Affiliation(s)
- Ahmed Mahmoud
- Pharmacology Program, Weill Cornell Graduate School, New York, NY, USA
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Philip H. Choi
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Christine Sukhwa
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jura Pintar
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Henry Walch
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nan Zhao
- Program in Chemical Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jonathan Bermeo
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sebastian Chung
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Manisha Raghavan
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Program in Chemical Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Samhita Bapat
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Qingwen Jiang
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Georgios Karagkounis
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Julia Meredith
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael Giarrizzo
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Canan Firat
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA
| | - Andrea Cercek
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael B. Foote
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Walid K. Chatila
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Garrett M. Nash
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jinru Shia
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA
| | - Francisco Sanchez-Vega
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Steven Larson
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Arvin C. Dar
- Program in Chemical Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Neal Rosen
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Karuna Ganesh
- Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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8
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Kurelac I, Sollazzo M, De Luise M, Nanetti F, Lanteri L, D’Angelo L, Cavina B, Corrà S, Miglietta S, Milioni S, Luppi E, Iommarini L, Di Costanzo S, Ricciardi AM, Coluccelli S, Maloberti T, Grillini M, Coadă CA, Perrone AM, De Iaco P, de Biase D, Ragazzi M, Gasparre G, Porcelli AM. Immunomagnetic enrichment coupled to PAX8/TP53 molecular pathology approach increases sensitivity in the detection of ovarian cancer cells in ascites. Front Mol Biosci 2025; 12:1537407. [PMID: 40051502 PMCID: PMC11882402 DOI: 10.3389/fmolb.2025.1537407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Accepted: 01/27/2025] [Indexed: 03/09/2025] Open
Abstract
High-grade serous ovarian carcinoma (HGSOC) is one of the deadliest malignancies in female population and the cause of 70% of all ovarian cancer-related deaths. Among its hallmarks, the fluid accumulation in the peritoneal cavity, or ascites, is a peculiar pathological sign during late stages and in recurrent patients. Besides cancer cells, ascitic fluids contain a heterogeneous cellular composition, representing a precious source to dissect molecular mechanisms underlying invasion and metastatization or find new biomarkers to predict therapy response. However, malignant cells are often a minority population in ascites making the detection and analysis of cancer cells a challenge. Here we propose a combinatorial approach for the detection of malignant cells in OC ascites based on TP53 deep sequencing and PAX8 cytological staining. In addition, we improve the procedure by implementing a cancer cell enrichment step, increasing the sensitivity in the detection of neoplastic fraction and potentiating downstream research and diagnostics applications.
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Affiliation(s)
- Ivana Kurelac
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Manuela Sollazzo
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy
- Centre for Applied Biomedical Research, University of Bologna, Bologna, Italy
| | - Monica De Luise
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - Francesca Nanetti
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - Laura Lanteri
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - Luigi D’Angelo
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy
| | - Beatrice Cavina
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - Simona Corrà
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - Stefano Miglietta
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy
| | - Sara Milioni
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy
| | - Elena Luppi
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - Luisa Iommarini
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy
- Centre for Applied Biomedical Research, University of Bologna, Bologna, Italy
| | - Stella Di Costanzo
- Division of Gynecologic Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | | | - Sara Coluccelli
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Thais Maloberti
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Marco Grillini
- Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Camelia Alexandra Coadă
- Division of Gynecologic Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Anna Myriam Perrone
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
- Division of Gynecologic Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Pierandrea De Iaco
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
- Division of Gynecologic Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Dario de Biase
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Moira Ragazzi
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Giuseppe Gasparre
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
- Centre for Applied Biomedical Research, University of Bologna, Bologna, Italy
- Centro Studi e Ricerca sulle Neoplasie Ginecologiche, University of Bologna, Bologna, Italy
| | - Anna Maria Porcelli
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy
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9
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Chen D, Tan Y, Chen T, Wang Q, Yan Y, Zhao X, Zhang Z, Qiu J, Zhang J. Sempervirine inhibits proliferation, invasion and metastasis of ovarian cancer cells and induces ultrastructural changes in vivo. J Ovarian Res 2025; 18:17. [PMID: 39875926 PMCID: PMC11773766 DOI: 10.1186/s13048-024-01580-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Accepted: 12/11/2024] [Indexed: 01/30/2025] Open
Abstract
Ovarian cancer is one of the deadliest gynecological malignancies due to its late diagnosis and easy recurrence. Therefore, it is urgent to develop novel therapeutics for ovarian cancer treatment. In this study, we evaluated the anti-ovarian cancer effects of sempervirine in vitro and in vivo. CCK8 assays showed that sempervirine dose-dependently inhibited the proliferation of SKOV3 ovarian cancer cells. Transwell assays demonstrated that sempervirine significantly suppressed the invasion and metastasis of SKOV3 cells. Furthermore, in an orthotopic ovarian cancer mouse model, sempervirine dramatically inhibited tumor growth and induced pathological changes in tumor tissues, including poor development of tumor mucosa, collagen deposition, endoplasmic reticulum damage, mitochondrial swelling and vacuolar degeneration, which were similar to the positive control 5-Fu. Mechanistic studies revealed that sempervirine decreased the expression of proteins related to apelin signaling pathway. In conclusion, our results demonstrate the potent anti-ovarian cancer effects of sempervirine both in vitro and in vivo. Sempervirine may repress ovarian cancer by down-regulating apelin signaling pathway. Our study suggests that sempervirine is a promising therapeutic agent against ovarian cancer.
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Affiliation(s)
- Danni Chen
- Department of Obstetrics and Gynecology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Department of Obstetrics and Gynecology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China
| | - Yan Tan
- Department of Obstetrics and Gynecology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China
| | - Tingting Chen
- Department of Obstetrics and Gynecology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China
| | - Qin Wang
- Department of Obstetrics and Gynecology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China
| | - Yan Yan
- Department of Obstetrics and Gynecology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China
| | - Xiaoya Zhao
- Department of Obstetrics and Gynecology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China.
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China.
| | - Zhongxiao Zhang
- Department of Obstetrics and Gynecology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China.
| | - Jin Qiu
- Department of Obstetrics and Gynecology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China.
| | - Jian Zhang
- Department of Obstetrics and Gynecology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China.
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China.
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10
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Gonçalves ACC, Carvalho KC, Turri JAO, Simões RDS, Carvalho JP, da Silva LFF, Soares Júnior JM, Baracat EC. 7,12-Dimethylbenz(a)anthracene as a Model for Ovarian Cancer Induction in Rats. BIOLOGY 2025; 14:73. [PMID: 39857303 PMCID: PMC11762512 DOI: 10.3390/biology14010073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 12/13/2024] [Accepted: 12/23/2024] [Indexed: 01/27/2025]
Abstract
Ovarian cancer has the highest mortality rate of all gynecological cancers. Animal models using 7,12-dimethylbenz(a)anthracene (DMBA) have been developed to investigate the mechanisms of ovarian carcinogenesis. The present study is a systematic review of efforts to establish DMBA as a model for ovarian cancer induction in rat models. A total of 432 studies were retrieved from the Medline/PubMed and Embase databases. The studies using DMBA to induce ovarian cancer with isolated results were included in our analysis, and their data were meta-analyzed. The ROBINS-I tool and a meta-analysis demonstrated a low risk of bias (less than 1%) for increased effectiveness and no bias for mortality. The results were all similar: regardless of the dose, administration route, animal strain, or induction time, the induction rate of ovarian tumors was always high, reinforcing the role of DMBA as an effective inducer of ovarian carcinogenesis. We conclude that ovarian carcinogenesis can be studied using DMBA as an inducer in rat and mouse models with a long time range for tumor establishment (at least 110 days) and a high rate of mortality. CNPq (No. 304264/2021-0) and FAPESP (Protocol No. 2018/24224-9).
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Affiliation(s)
| | - Katia Candido Carvalho
- Laboratório de Ginecologia Estrutural e Molecular (LIM 58) do Departamento de Obstetrícia e Ginecologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo 17012-901, SP, Brazil; (K.C.C.); (J.A.O.T.)
| | - José Antônio Orellana Turri
- Laboratório de Ginecologia Estrutural e Molecular (LIM 58) do Departamento de Obstetrícia e Ginecologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo 17012-901, SP, Brazil; (K.C.C.); (J.A.O.T.)
| | - Ricardo dos Santos Simões
- Disciplina de Ginecologia, Departamento de Obstetrícia e Ginecologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 17012-901, SP, Brazil; (R.d.S.S.); (J.P.C.)
| | - Jesus Paula Carvalho
- Disciplina de Ginecologia, Departamento de Obstetrícia e Ginecologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 17012-901, SP, Brazil; (R.d.S.S.); (J.P.C.)
| | | | - José Maria Soares Júnior
- Laboratório de Ginecologia Estrutural e Molecular (LIM 58) do Departamento de Obstetrícia e Ginecologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo 17012-901, SP, Brazil; (K.C.C.); (J.A.O.T.)
| | - Edmund Chada Baracat
- Laboratório de Ginecologia Estrutural e Molecular (LIM 58) do Departamento de Obstetrícia e Ginecologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo 17012-901, SP, Brazil; (K.C.C.); (J.A.O.T.)
- Disciplina de Ginecologia, Departamento de Obstetrícia e Ginecologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 17012-901, SP, Brazil; (R.d.S.S.); (J.P.C.)
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11
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Lara OD, Van Oudenhove E, Pereira L, Misirlioglu S, Levine DA, Hacker KE. SPL-108 mitigates metastasis and chemoresistance in tubo-ovarian carcinoma. Transl Oncol 2025; 51:102168. [PMID: 39504709 PMCID: PMC11577183 DOI: 10.1016/j.tranon.2024.102168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 09/25/2024] [Accepted: 10/28/2024] [Indexed: 11/08/2024] Open
Abstract
BACKGROUND Overcoming the heterogeneous mechanisms of metastasis and chemoresistance will improve outcomes for women with tubo-ovarian carcinomas (TOCs). CD44 expression has been shown to be associated with poor prognosis and advanced disease in TOCs. In addition, studies have shown a link between chemoresistance and CD44 pathways. Given the therapeutic implications of targeting CD44, this manuscript examines the biologic effects of a novel CD44 modulator, SPL-108, in TOCs. MATERIALS AND METHODS We assessed the effects of SPL-108 on chemosensitivity and migration in a panel of ovarian cancer cell lines with varied CD44 and MDR1 expression. In vitro experiments (cell viability assay, Western blot analysis, Calcein AM fluorescence assay, and migration assay) were carried out to determine the functional effects of SPL-108 in TOCs. FINDINGS Ovarian cancer cell lines OVCAR5 and OVCAR8 expressed higher protein levels of CD44 as demonstrated through Western Blot analysis. SPL-108 treatment significantly decreased the number of migrating cells in OVCAR8, OVCAR5 and OVCAR3 cell lines and migratory response was independent of CD44 expression. Treatment with SPL-108 led to significant accumulation of the MDR1 substrate Calcein in OVCAR5, OVCAR8 and OVCAR3 cells lines compared to verapamil treated positive control cells. Retention of Calcein after SPL-108 treatment was seen in cell lines with high MDR1 protein expression and no Calcein retention was seen in cells lacking MDR1 expression, suggesting SPL-108 inhibits MDR1. CONCLUSIONS SPL-108 treatment has anti-metastatic properties and may play a role in chemoresistance in preclinical models of TOCs independent of CD44 expression. Ongoing in vitro and in vivo studies will help guide further clinical development of SPL-108.
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Affiliation(s)
- Olivia D Lara
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Elke Van Oudenhove
- Division of Gynecologic Oncology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA
| | - Luiza Pereira
- Division of Gynecologic Oncology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA
| | - Selim Misirlioglu
- Division of Gynecologic Oncology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA
| | - Douglas A Levine
- Division of Gynecologic Oncology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA; Merck & Co., Rahway, NJ, USA
| | - Kari E Hacker
- Division of Gynecologic Oncology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
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12
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Kumari S, Gupta S, Jamil A, Tabatabaei D, Karakashev S. Exploring Metabolic Approaches for Epithelial Ovarian Cancer Therapy. J Cell Physiol 2025; 240:e31495. [PMID: 39676338 DOI: 10.1002/jcp.31495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 10/21/2024] [Accepted: 11/18/2024] [Indexed: 12/17/2024]
Abstract
Epithelial ovarian cancer (EOC) has the highest mortality rate among malignant tumors of the female reproductive system and the lowest survival rate. This poor prognosis is due to the aggressive nature of EOC, its late-stage diagnosis, and the tumor's ability to adapt to stressors through metabolic reprogramming. EOC cells sustain their rapid proliferation by altering the uptake, utilization, and regulation of carbohydrates, lipids, and amino acids. These metabolic changes support tumor growth and contribute to metastasis, chemotherapy resistance, and immune evasion. Targeting these metabolic vulnerabilities has shown promise in preclinical studies, with some therapies advancing to clinical trials. However, challenges remain due to tumor heterogeneity, adaptive resistance mechanisms, and the influence of the tumor microenvironment. This review provides a comprehensive summary of metabolic targets for EOC treatment and offers an overview of the current landscape of clinical trials focusing on ovarian cancer metabolism. Future efforts should prioritize combination therapies that integrate metabolic inhibitors with immunotherapies or chemotherapy. Advances in precision medicine and multi-omics approaches will be crucial for identifying patient-specific metabolic dependencies and improving outcomes. By addressing these challenges, metabolism-based therapies can significantly transform the treatment of this devastating disease.
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Affiliation(s)
- Sangeeta Kumari
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Shraddha Gupta
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Aisha Jamil
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Deyana Tabatabaei
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, USA
| | - Sergey Karakashev
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
- Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
- Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
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13
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Subramani K, Huang HS, Chen PC, Ding DC, Chu TY. Ovulation sources ROS to confer mutagenic activities on the TP53 gene in the fallopian tube epithelium. Neoplasia 2025; 59:101085. [PMID: 39637685 DOI: 10.1016/j.neo.2024.101085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 11/07/2024] [Indexed: 12/07/2024]
Abstract
INTRODUCTION Epidemiological studies have implicated ovulation as a risk factor for ovarian high-grade serous carcinoma (HGSC) at the initiation stage. Precancerous lesions of HGSC commonly exhibit TP53 mutations attributed to DNA deamination and are frequently localized in the fallopian tube epithelium (FTE), a site regularly exposed to ovulatory follicular fluid (FF). This study aimed to assess the mutagenic potential of FF and investigate the expression levels and functional role of activation-induced cytidine deaminase (AID) following ovulation, along with the resulting TP53 DNA deamination. METHODS The mutagenic activity of FF toward premalignant and malignant FTE cells was determined using the hypoxanthine phosphoribosyl transferase (HPRT) mutation assay with or without AID knockdown. The sequential activation of AID, including expressional induction, nuclear localization, DNA binding, and deamination, was determined. AID inducers in FF were identified, and the times of action and signaling pathways were determined. RESULTS FF induced AID activation and de novo FTE cell mutagenesis in two waves of activity in accordance with post-ovulation FF exposure. The ERK-mediated early activity started at 2 min and peaked at 45 min, and the NF-κB-mediated late activity started at 6 h and peaked at 8.5 h after exposure. ROS, TNF-α, and estradiol, which are abundant in FF, all induced the two activities, while all activities were abolished by antioxidant cotreatment. AID physically bound to and biochemically deaminated the TP53 gene, regardless of known mutational hotspots. It did not act on other prevalent tumor-suppressor genes of HGSC. CONCLUSION This study revealed the ROS-dependent AID-mediated mutagenic activity of the ovulatory FF. The results filled up the missing link between ovulation and the initial TP53 mutation and invited a strategy of antioxidation in prevention of HGSC.
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Affiliation(s)
- Kanchana Subramani
- Center for Prevention and Therapy of Gynecological Cancers, Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, ROC; Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan, ROC
| | - Hsuan-Shun Huang
- Center for Prevention and Therapy of Gynecological Cancers, Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, ROC
| | - Pao-Chu Chen
- Department of Obstetrics & Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, ROC
| | - Dah-Ching Ding
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan, ROC; Department of Obstetrics & Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, ROC
| | - Tang-Yuan Chu
- Center for Prevention and Therapy of Gynecological Cancers, Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, ROC; Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan, ROC; Department of Obstetrics & Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, ROC.
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14
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Moffitt LR, Karimnia N, Wilson AL, Stephens AN, Ho GY, Bilandzic M. Challenges in Implementing Comprehensive Precision Medicine Screening for Ovarian Cancer. Curr Oncol 2024; 31:8023-8038. [PMID: 39727715 PMCID: PMC11674382 DOI: 10.3390/curroncol31120592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 12/13/2024] [Accepted: 12/16/2024] [Indexed: 12/28/2024] Open
Abstract
Precision medicine has revolutionised targeted cancer treatments; however, its implementation in ovarian cancer remains challenging. Diverse tumour biology and extensive heterogeneity in ovarian cancer can limit the translatability of genetic profiling and contribute to a lack of biomarkers of treatment response. This review addresses the barriers in precision medicine for ovarian cancer, including obtaining adequate and representative tissue samples for analysis, developing functional and standardised screening methods, and navigating data infrastructure and management. Ethical concerns related to patient consent, data privacy and health equity are also explored. We highlight the socio-economic complexities for precision medicine and propose strategies to overcome these challenges with an emphasis on accessibility and education amongst patients and health professionals and the development of regulatory frameworks to support clinical integration. Interdisciplinary collaboration is essential to drive progress in precision medicine to improve disease management and ovarian cancer patient outcomes.
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Affiliation(s)
- Laura R. Moffitt
- Hudson Institute of Medical Research, Clayton 3168, Australia; (L.R.M.); (N.K.); (A.L.W.); (A.N.S.)
- Department of Molecular and Translational Sciences, Monash University, Clayton 3168, Australia
| | - Nazanin Karimnia
- Hudson Institute of Medical Research, Clayton 3168, Australia; (L.R.M.); (N.K.); (A.L.W.); (A.N.S.)
- Department of Molecular and Translational Sciences, Monash University, Clayton 3168, Australia
| | - Amy L. Wilson
- Hudson Institute of Medical Research, Clayton 3168, Australia; (L.R.M.); (N.K.); (A.L.W.); (A.N.S.)
- Department of Molecular and Translational Sciences, Monash University, Clayton 3168, Australia
| | - Andrew N. Stephens
- Hudson Institute of Medical Research, Clayton 3168, Australia; (L.R.M.); (N.K.); (A.L.W.); (A.N.S.)
- Department of Molecular and Translational Sciences, Monash University, Clayton 3168, Australia
| | - Gwo-Yaw Ho
- School of Clinical Sciences, Monash University, Clayton 3168, Australia;
- Department of Oncology, Monash Health, Bentleigh 3165, Australia
| | - Maree Bilandzic
- Hudson Institute of Medical Research, Clayton 3168, Australia; (L.R.M.); (N.K.); (A.L.W.); (A.N.S.)
- Department of Molecular and Translational Sciences, Monash University, Clayton 3168, Australia
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15
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Zhang B, Guo B, Kong H, Yang L, Yan H, Liu J, Zhou Y, An R, Wang F. Decoding the Ferroptosis-Related Gene Signatures and Immune Infiltration Patterns in Ovarian Cancer: Bioinformatic Prediction Integrated with Experimental Validation. J Inflamm Res 2024; 17:10333-10346. [PMID: 39654865 PMCID: PMC11626233 DOI: 10.2147/jir.s498740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 11/27/2024] [Indexed: 12/12/2024] Open
Abstract
Background Ovarian cancer is a type of gynecological cancer with extremely high fatality rate. Ferroptosis, an iron-dependent regulated cell death, inhibits the immune infiltration of tumor cells. Therefore, it is worthwhile to explore the effects of ferroptosis-related gene signatures and immune infiltration patterns on the clinical prognosis of ovarian cancer. Methods In this study, we used the mRNA expression matrix and related medical information of those who suffer from ovarian cancer in the TCGA database. After that, we established a ferroptosis-related gene signature based on LASSO Cox regression model, and employed several specific enrichment analyses to explore the bioinformatics functions of differentially expressed genes (DEGs). Additionally, we analyzed the link between ferroptosis and immune cells by single-sample gene set enrichment analysis (ssGSEA) to create a heatmap of gene-immune cell correlation. We then examined the expression of immune checkpoints and verified the gene expression in ovarian cancer tissues by qPCR assays. Finally, we induced ferroptosis in ovarian cancer cells using drugs and analyzed their migration, invasion and gene expression. Results According to LASSO Cox regression analysis, 9 prognostic DEGs were in association with overall survival (OS), which was utilized to construct a 9-gene signature for patients. Patients were divided into two groups, in which high-risk group's OS was markedly shorter than that of low-risk group (Log-rank p<0.001). KEGG enrichment analysis showed that these DEGs were linked to human cytomegalovirus (HCMV) infection. The ssGSEA analysis revealed significant differences in immune cell type and expression between ALOX12 and GLRX5 groups (p<0.05). Heatmap showed high correlation of prognostic genes with various immune cells. qPCR assay confirmed the 9 gene expression signature in ovarian cancer tissues. The ovarian cancer cell invasion and migration were significantly inhibited after induction of ferroptosis. Conclusion We decoded the ferroptosis-related gene signatures and immune infiltration patterns that can be used to predict the prognosis of ovarian cancer patients.
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Affiliation(s)
- Beilei Zhang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, People’s Republic of China
| | - Bin Guo
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, People’s Republic of China
| | - Hancun Kong
- Department of Medical Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710004, People’s Republic of China
| | - Linwei Yang
- Department of Medical Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710004, People’s Republic of China
| | - Hui Yan
- Department of Medical Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710004, People’s Republic of China
| | - Jierui Liu
- Department of Medical Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710004, People’s Republic of China
| | - Yichen Zhou
- Department of Medical Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710004, People’s Republic of China
| | - Ruifang An
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, People’s Republic of China
| | - Fu Wang
- Department of Medical Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710004, People’s Republic of China
- Department of Biophysics, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, People’s Republic of China
- School of Pharmacy, Shaanxi University of International Trade & Commerce, Xianyang, Shaanxi, 712046, People’s Republic of China
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16
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Beevors LI, Sundar S, Foster PA. Steroid metabolism and hormonal dynamics in normal and malignant ovaries. Essays Biochem 2024; 68:491-507. [PMID: 38994724 PMCID: PMC11625866 DOI: 10.1042/ebc20240028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 06/18/2024] [Accepted: 06/24/2024] [Indexed: 07/13/2024]
Abstract
The ovaries are key steroid hormone production sites in post-pubertal females. However, current research on steroidogenic enzymes, endogenous hormone concentrations and their effects on healthy ovarian function and malignant development is limited. Here, we discuss the importance of steroid enzymes in normal and malignant ovaries, alongside hormone concentrations, receptor expression and action. Key enzymes include STS, 3β-HSD2, HSD17B1, ARK1C3, and aromatase, which influence ovarian steroidal action. Both androgen and oestrogen action, via their facilitating enzyme, drives ovarian follicle activation, development and maturation in healthy ovarian tissue. In ovarian cancer, some data suggest STS and oestrogen receptor α may be linked to aggressive forms, while various oestrogen-responsive factors may be involved in ovarian cancer metastasis. In contrast, androgen receptor expression and action vary across ovarian cancer subtypes. For future studies investigating steroidogenesis and steroidal activity in ovarian cancer, it is necessary to differentiate between disease subtypes for a comprehensive understanding.
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Affiliation(s)
- Lucy I Beevors
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, U.K
| | - Sudha Sundar
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, U.K
| | - Paul A Foster
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, U.K
- Centre for Diabetes, Endocrinology, and Metabolism, Birmingham Health Partners, Birmingham, U.K
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17
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Rižner TL, Gjorgoska M. Steroid sulfatase and sulfotransferases in the estrogen and androgen action of gynecological cancers: current status and perspectives. Essays Biochem 2024; 68:411-422. [PMID: 38994718 PMCID: PMC11625860 DOI: 10.1042/ebc20230096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 06/07/2024] [Accepted: 06/26/2024] [Indexed: 07/13/2024]
Abstract
Sulfatase (STS) and sulfotransferases (SULT) have important role in the biosynthesis and action of steroid hormones. STS catalyzes the hydrolysis of estrone-sulfate (E1-S) and dehydroepiandrosterone-sulfate (DHEA-S), while sulfotransferases catalyze the reverse reaction and require 3-phosphoadenosine-5-phosphosulfate as a sulfate donor. These enzymes control the concentration of active estrogens and androgens in peripheral tissues. Aberant expression of STS and SULT genes has been found in both, benign hormone-dependent diseases and hormone-dependent cancers. The aim of this review is to present the current knowledge on the role of STS and SULT in gynecological cancers, endometrial (EC) and ovarian cancer (OC). EC is the most common and OC the most lethal gynecological cancer. These cancers primarily affect postmenopausal women and therefore rely on the local production of steroid hormones from inactive precursors, either DHEA-S or E1-S. Following cellular uptake by organic anion transporting polypeptides (OATP) or organic anion transporters (OAT), STS and SULT regulate the formation of active estrogens and androgens, thus disturbed balance between STS and SULT can contribute to the onset and progression of cancer. The importance of these enzymes in peripheral estrogen biosynthesis has long been recognized, and this review provides new data on the important role of STS and SULT in the formation and action of androgens, their regulation and inhibition, and their potential as prognostic biomarkers.
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Affiliation(s)
- Tea Lanišnik Rižner
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Marija Gjorgoska
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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18
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He W, Zhu H, Zhang S, Shu G, Lei H, Wang M, Yin G, Ni X, Wu Q. Epigenetic editing of BRCA1 promoter increases cisplatin and olaparib sensitivity of ovarian cancer cells. Epigenetics 2024; 19:2357518. [PMID: 38796857 PMCID: PMC11135871 DOI: 10.1080/15592294.2024.2357518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 04/23/2024] [Accepted: 05/15/2024] [Indexed: 05/29/2024] Open
Abstract
Drug resistance is the primary contributor to the high mortality rate of ovarian cancer (OC). The loss of BRCA1/2 function is linked to drug sensitivity in OC cells. The aim of this study is to enhance the drug sensitivity of OC cells by inducing BRCA1 dysfunction through promoter epigenetic editing. Epigenetic regulatory regions within the BRCA1 promoter, affecting gene expression, were initially discerned through analysis of clinical samples. Subsequently, we designed and rigorously validated epigenetic editing tools. Ultimately, we evaluated the cisplatin and olaparib sensitivity of the OC cells after editing. The BRCA1 promoter contains two CpG-rich regions, with methylation of the region covering the transcription start site (TSS) strongly correlating with transcription and influencing OC development, prognosis, and homologous recombination (HR) defects. Targeting this region in OC cells using our designed epigenetic editing tools led to substantial and persistent DNA methylation changes, accompanied by significant reductions in H3K27ac histone modifications. This resulted in a notable suppression of BRCA1 expression and a decrease in HR repair capacity. Consequently, edited OC cells exhibited heightened sensitivity to cisplatin and olaparib, leading to increased apoptosis rates. Epigenetic inactivation of the BRCA1 promoter can enhance cisplatin and olaparib sensitivity of OC cells through a reduction in HR repair capacity, indicating the potential utility of epigenetic editing technology in sensitization therapy for OC.
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Affiliation(s)
- Wanhong He
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China
| | - Haijun Zhu
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China
| | - Sufen Zhang
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China
| | - Guang Shu
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Han Lei
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Maonan Wang
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Gang Yin
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Xiaohua Ni
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China
| | - Qihan Wu
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China
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19
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Naciri I, Liang M, Yang Y, Karner H, Lin B, De Lourdes Andrade Ludena M, Hanse EA, Lebron A, Razorenova OV, Nicholas D, Kong M, Sun S. Loss of XIST lncRNA unlocks stemness and cellular plasticity in ovarian cancer. Proc Natl Acad Sci U S A 2024; 121:e2418096121. [PMID: 39546568 PMCID: PMC11588085 DOI: 10.1073/pnas.2418096121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 10/16/2024] [Indexed: 11/17/2024] Open
Abstract
Plasticity, a key hallmark of cancer, enables cells to transition into different states, driving tumor heterogeneity. This cellular plasticity is associated with cancer progression, treatment resistance, and relapse. Cancer stem cells (CSCs) play a central role in this process, yet the molecular factors underlying cancer cell stemness remain poorly understood. In this study, we explored the role of XIST (X-inactive specific transcript) long noncoding RNA in ovarian cancer stemness and plasticity through in silico and in vitro analyses. We found that XIST is significantly down-regulated in ovarian tumors, with low XIST expression linked to a higher stemness index and lower overall survival. Knocking down XIST in ovarian cancer cells enhanced stemness, particularly increasing mesenchymal-like CSCs, and under hypoxic conditions, it promoted epithelial-like CSC markers. Our findings suggest that XIST loss leads to CSC enrichment and cellular plasticity in ovarian cancer, pointing to potential therapeutic targets for patients with low XIST expression.
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Affiliation(s)
- Ikrame Naciri
- Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
| | - Minzhi Liang
- Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
| | - Ying Yang
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
| | - Heather Karner
- Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
| | - Benjamin Lin
- Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
| | - Maria De Lourdes Andrade Ludena
- Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
| | - Eric A. Hanse
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
| | - Alfredo Lebron
- Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
| | - Olga V. Razorenova
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
| | - Dequina Nicholas
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
| | - Mei Kong
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
| | - Sha Sun
- Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
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20
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Wang W, Zhou Y, Wang J, Zhang S, Ozes A, Gao H, Fang F, Wang Y, Chu X, Liu Y, Wan J, Mitra AK, O’Hagan HM, Nephew KP. Targeting Ovarian Cancer Stem Cells by Dual Inhibition of the Long Noncoding RNA HOTAIR and Lysine Methyltransferase EZH2. Mol Cancer Ther 2024; 23:1666-1679. [PMID: 39039946 PMCID: PMC11534535 DOI: 10.1158/1535-7163.mct-23-0314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 02/28/2024] [Accepted: 07/15/2024] [Indexed: 07/24/2024]
Abstract
The persistence of cancer stem cells (CSC) is believed to contribute to resistance to platinum-based chemotherapy and disease relapse in ovarian cancer, the fifth leading cause of cancer-related death among US women. HOXC transcript antisense RNA (HOTAIR) is a long, noncoding RNA (lncRNA) overexpressed in high-grade serous ovarian cancer and linked to chemoresistance. However, HOTAIR impacts chromatin dynamics in ovarian CSCs. Oncogenic lncRNA's contributions to drug-resistant disease are incompletely understood. Here, we generated HOTAIR knockout (KO) high-grade serous ovarian cancer cell lines using paired CRISPR guide RNA design to investigate the function of HOTAIR. We show the loss of HOTAIR function resensitized ovarian cancer cells to platinum treatment and decreased the population of ovarian CSCs. Furthermore, HOTAIR KO inhibited the development of stemness-related phenotypes, including spheroid formation ability and expression of key stemness-associated genes ALDH1A1, NOTCH3, SOX9, and PROM1. HOTAIR KO altered the cellular transcriptome and chromatin accessibility landscape of multiple oncogenic-associated genes and pathways, including the NF-kB pathway. HOTAIR functions as an oncogene by recruiting enhancer of zeste homolog 2 (EZH2) to catalyze H3K27 trimethylation to suppress downstream tumor suppressor genes, and it was of interest to inhibit both HOTAIR and EZH2. In vivo, combining a HOTAIR inhibitor with an EZH2 inhibitor and platinum chemotherapy decreased tumor formation and increased survival. These results suggest a key role for HOTAIR in ovarian CSCs and malignant potential. Targeting HOTAIR in combination with epigenetic therapies may represent a therapeutic strategy to ameliorate ovarian cancer progression and resistance to platinum-based chemotherapy.
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Affiliation(s)
- Weini Wang
- Indiana University School of Medicine, Bloomington, IN, USA
| | - Yanchi Zhou
- Indiana University School of Medicine, Bloomington, IN, USA
| | - Ji Wang
- Indiana University School of Medicine, Bloomington, IN, USA
| | - Shu Zhang
- Indiana University School of Medicine, Bloomington, IN, USA
| | - Ali Ozes
- Altay Therapeutics, San Francisco, CA USA
| | - Hongyu Gao
- Department of Medical and Molecular Genetics, Indianapolis, IN, USA
| | - Fang Fang
- Department of Medical and Molecular Genetics, Indianapolis, IN, USA
| | - Yue Wang
- Department of Medical and Molecular Genetics, Indianapolis, IN, USA
| | - Xiaona Chu
- Genomics Core, Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, USA
| | - Yunlong Liu
- Genomics Core, Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, USA
| | - Jun Wan
- Cancer Bioinformatics Core, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, USA
| | - Anirban K. Mitra
- Indiana University School of Medicine, Bloomington, IN, USA
- Department of Medical and Molecular Genetics, Indianapolis, IN, USA
- Tumor Microenvironment and Metastasis Program, Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, USA
| | - Heather M. O’Hagan
- Indiana University School of Medicine, Bloomington, IN, USA
- Department of Medical and Molecular Genetics, Indianapolis, IN, USA
- Tumor Microenvironment and Metastasis Program, Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, USA
| | - Kenneth P. Nephew
- Indiana University School of Medicine, Bloomington, IN, USA
- Tumor Microenvironment and Metastasis Program, Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, USA
- Department of Anatomy, Cell Biology and Physiology, Indianapolis, IN, USA
- Department of Obstetrics and Gynecology, Indianapolis, IN, USA
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21
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Bates M, Mohamed BM, Lewis F, O'Toole S, O'Leary JJ. Biomarkers in high grade serous ovarian cancer. Biochim Biophys Acta Rev Cancer 2024; 1879:189224. [PMID: 39581234 DOI: 10.1016/j.bbcan.2024.189224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 11/15/2024] [Accepted: 11/15/2024] [Indexed: 11/26/2024]
Abstract
High-grade serous ovarian cancer (HGSC) is the most common subtype of ovarian cancer. HGSC patients typically present with advanced disease, which is often resistant to chemotherapy and recurs despite initial responses to therapy, resulting in the poor prognosis associated with this disease. There is a need to utilise biomarkers to manage the various aspects of HGSC patient care. In this review we discuss the current state of biomarkers in HGSC, focusing on the various available immunohistochemical (IHC) and blood-based biomarkers, which have been examined for their diagnostic, prognostic and theranostic potential in HGSC. These include various routine clinical IHC biomarkers such as p53, WT1, keratins, PAX8, Ki67 and p16 and clinical blood-borne markers and algorithms such as CA125, HE4, ROMA, RMI, ROCA, and others. We also discuss various components of the liquid biopsy as well as a number of novel IHC biomarkers and non-routine blood-borne biomarkers, which have been examined in various ovarian cancer studies. We also discuss the future of ovarian cancer biomarker research and highlight some of the challenges currently facing the field.
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Affiliation(s)
- Mark Bates
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland.
| | - Bashir M Mohamed
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland
| | - Faye Lewis
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland
| | - Sharon O'Toole
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland; Department of Obstetrics and Gynaecology, Trinity College Dublin, Dublin, Ireland
| | - John J O'Leary
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland; Department of Pathology, Coombe Women & Infants University Hospital, Dublin, Ireland
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22
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Masatti L, Marchetti M, Pirrotta S, Spagnol G, Corrà A, Ferrari J, Noventa M, Saccardi C, Calura E, Tozzi R. The unveiled mosaic of intra-tumor heterogeneity in ovarian cancer through spatial transcriptomic technologies: A systematic review. Transl Res 2024; 273:104-114. [PMID: 39111726 DOI: 10.1016/j.trsl.2024.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Revised: 07/16/2024] [Accepted: 08/01/2024] [Indexed: 08/12/2024]
Abstract
Epithelial ovarian cancer is a significant global health issue among women. Diagnosis and treatment pose challenges due to difficulties in predicting patient responses to therapy, primarily stemming from gaps in understanding tumor chemoresistance mechanisms. Recent advancements in transcriptomic technologies like single-cell RNA sequencing and spatial transcriptomics have greatly improved our understanding of ovarian cancer intratumor heterogeneity and tumor microenvironment composition. Spatial transcriptomics, in particular, comprises a plethora of technologies that enable the detection of hundreds of transcriptomes and their spatial distribution within a histological section, facilitating the study of cell types, states, and interactions within the tumor and its microenvironment. Studies investigating the spatial distribution of gene expression in ovarian cancer masses have identified specific features that impact prognosis and therapy outcomes. Emerging evidence suggests that specific spatial patterns of tumor cells and their immune and non-immune microenvironment significantly influence therapy response, as well as the behavior and progression of primary tumors and metastatic sites. The importance of spatially contextualizing ovarian cancer transcriptomes is underscored by these findings, which will advance our understanding and therapeutic approaches for this complex disease.
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Affiliation(s)
- Laura Masatti
- Department of Biology, University of Padova, Padova, Italy
| | - Matteo Marchetti
- Department of Gynecology and Obstetrics, Division of Women and Children, Padova University Hospital, Padova, Italy
| | | | - Giulia Spagnol
- Department of Gynecology and Obstetrics, Division of Women and Children, Padova University Hospital, Padova, Italy
| | - Anna Corrà
- Department of Biology, University of Padova, Padova, Italy; Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padova, Italy
| | - Jacopo Ferrari
- Department of Gynecology and Obstetrics, Division of Women and Children, Padova University Hospital, Padova, Italy
| | - Marco Noventa
- Department of Gynecology and Obstetrics, Division of Women and Children, Padova University Hospital, Padova, Italy
| | - Carlo Saccardi
- Department of Gynecology and Obstetrics, Division of Women and Children, Padova University Hospital, Padova, Italy
| | - Enrica Calura
- Department of Biology, University of Padova, Padova, Italy.
| | - Roberto Tozzi
- Department of Gynecology and Obstetrics, Division of Women and Children, Padova University Hospital, Padova, Italy
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23
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Kozłowska-Tomczyk K, Borski N, Głód P, Gogola-Mruk J, Ptak A. PGRMC1 and PAQR4 are promising molecular targets for a rare subtype of ovarian cancer. Open Life Sci 2024; 19:20220982. [PMID: 39464509 PMCID: PMC11512499 DOI: 10.1515/biol-2022-0982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 09/06/2024] [Accepted: 09/09/2024] [Indexed: 10/29/2024] Open
Abstract
The heterogeneity of ovarian cancer (OC) has made developing effective treatments difficult. Nowadays, hormone therapy plays a growing role in the treatment of OC; however, hormone modulators have had only limited success so far. To provide a more rigorous foundation for hormonal therapy for different OC subtypes, the current study used a series of bioinformatics approaches to analyse the expression profiles of genes encoding membrane progesterone (PGRMC1, progestins and the adipoQ receptor [PAQR] family), and androgen (zinc transporter member 9 [ZIP9], OXER1) receptors. Our work investigated also their prognostic value in the context of OC. We found differences in expression of ZIP9 and OXER1 between different OC subtypes, as well as between patient tumour and normal tissues. Expression of mRNA encoding PAQR7 and PAQR8 in a panel of OC cell lines was below the qPCR detection limit and was downregulated in tumour tissue samples, whereas high expression of PGRMC1 and PAQR4 mRNA was observed in rare subtypes of OC cell lines. In addition, chemical inhibition of PGRMC1 reduced the viability of rare OCs represented by COV434 cells. In conclusion, PGRMC1 and PAQR4 are promising targets for anticancer therapy, particularly for rare subtypes of OC. These findings may reflect differences in the observed responses of various OC subtypes to hormone therapy.
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Affiliation(s)
- Kamila Kozłowska-Tomczyk
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9, 30-387, Krakow, Poland
- Doctoral School of Exact and Natural Sciences, Faculty of Biology, Institute of Zoology and Biomedical Sciences, Jagiellonian University, Gronostajowa 9, 30-387, Krakow, Poland
| | - Norbert Borski
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9, 30-387, Krakow, Poland
| | - Paulina Głód
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9, 30-387, Krakow, Poland
- Doctoral School of Exact and Natural Sciences, Faculty of Biology, Institute of Zoology and Biomedical Sciences, Jagiellonian University, Gronostajowa 9, 30-387, Krakow, Poland
| | - Justyna Gogola-Mruk
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9, 30-387, Krakow, Poland
| | - Anna Ptak
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9, 30-387, Krakow, Poland
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24
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Lusk HJ, Haughan MA, Bergsten TM, Burdette JE, Sanchez LM. Branched-chain amino acid catabolism promotes ovarian cancer cell proliferation via phosphorylation of mTOR. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.15.618560. [PMID: 39464074 PMCID: PMC11507863 DOI: 10.1101/2024.10.15.618560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/29/2024]
Abstract
Ovarian cancer is the sixth leading cause of cancer-related mortality among individuals with ovaries, and high-grade serous ovarian cancer (HGSOC) is the most common and lethal subtype. Characterized by a distinct and aggressive metastatic pattern, HGSOC can originate in the fallopian tube with the transformation of fallopian tube epithelial (FTE) cells, which metastasize to the ovary and subsequently to the omentum and peritoneal cavity. The omentum is a privileged metastatic site, and the metabolic exchange underlying omental metastasis could provide enzyme or receptor targets to block spread. In this study, we adapted a mass spectrometry imaging (MSI) protocol to investigate spatial location of 3D cocultures of tumorigenic FTE cells when grown in proximity to murine omental explants as a model of early metastatic colonization. Our analysis revealed several altered metabolites in tumorigenic FTE/omentum cocultures, namely changes in branched-chain amino acids (BCAA), including valine. We quantified the heightened consumption of valine, other BCAAs, and other amino acid-derived metabolites in omental cocultures using LC-MS assays. Our analysis revealed that metabolite concentrations when monitored with MSI from cell culture media in living culture systems have notable considerations for how MSI data may produce signatures that induce ionization suppression. Supplementation with valine enhanced proliferation and mTOR signaling in tumorigenic FTE cells, suggesting the potential of BCAA's as a nutrient utilized by tumor cells during omental colonization and a possible target for metastasis.
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Affiliation(s)
- Hannah J. Lusk
- Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA, 95064
| | - Monica A. Haughan
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, IL, 60607
| | - Tova M. Bergsten
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, IL, 60607
| | - Joanna E. Burdette
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, IL, 60607
| | - Laura M. Sanchez
- Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA, 95064
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25
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Zhang Z, Liu X, Chu C, Zhang Y, Li W, Yu X, Han Q, Sun H, Zhang Y, Zhu X, Chen L, Wei R, Fan N, Zhou M, Li X. MIR937 amplification potentiates ovarian cancer progression by attenuating FBXO16 inhibition on ULK1-mediated autophagy. Cell Death Dis 2024; 15:735. [PMID: 39384743 PMCID: PMC11464496 DOI: 10.1038/s41419-024-07120-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 09/16/2024] [Accepted: 09/27/2024] [Indexed: 10/11/2024]
Abstract
High-grade serous ovarian carcinoma (HGSOC) is one of the most lethal gynecological cancer. Genetic studies have revealed gene copy number alterations (CNAs) frequently occurred in HGSOC pathogenesis, however the function and mechanism of CNAs for microRNAs are still not fully understood. Here, we show the dependence on gene copy number amplification of MIR937 that enhances cell autophagy and dictates HGSOC proliferative activity. Data mining of TCGA database revealed MIR937 amplification is correlated with increased MIR937 expression and cell proliferation of HGSOC. Deletion of MIR937 in HGSOC cells led to impaired autophagy and retarded cell proliferation, and the extent for its inhibitory effects scaled with the degree of MIR937 copy loss. Rescue assay confirmed miR-937-5p, a mature product of MIR937, was sufficient to restore its oncogenic function. Mechanistically, MIR937 amplification raised the expression of miR-937-5p, enhanced its binding to 3' UTR of FBXO16 transcript, and thereby restricting FBXO16 degradative effects on ULK1. Our results demonstrate that MIR937 amplification augments cell autophagy and proliferation, and suggest an alternative strategy of MIR937/FBXO16/ULK1 targeting for HGSOC treatment.
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Affiliation(s)
- Zhen Zhang
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
- Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xinkui Liu
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
- Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Chu Chu
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
- Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yingjie Zhang
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
- Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Wei Li
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
- Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiaoyan Yu
- Shanghai Institute of Immunology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiaoqiao Han
- Shanghai Institute of Immunology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haoyu Sun
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
- Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yunhong Zhang
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
- Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiaoxiao Zhu
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
- Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Liang Chen
- Department of Gynecologic Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Ran Wei
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
- Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, China
- School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Nannan Fan
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
- Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Miaomiao Zhou
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
- Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xia Li
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China.
- Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, China.
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26
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Zwimpfer TA, Ewald H, Bilir E, Jayawardana M, Appenzeller-Herzog C, Bizzarri N, Razumova Z, Kacperczyk-Bartnik J, Heinzelmann-Schwarz V, Friedlander M, Bowtell DD, Garsed DW. Predictive value of homologous recombination deficiency status for survival outcomes in primary tubo-ovarian high-grade serous carcinoma. Cochrane Database Syst Rev 2024; 9:CD015896. [PMID: 39312297 PMCID: PMC11418971 DOI: 10.1002/14651858.cd015896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
OBJECTIVES This is a protocol for a Cochrane Review (prognosis). The objectives are as follows: To evaluate the predictive value of the prognostic factor HRD status, as determined by various clinically validated HRD assays at the time of staging laparotomy, compared to BRCA1/2 mutation status for progression-free survival and overall survival in patients with tubo-ovarian high-grade serous carcinoma treated in the first-line setting with a combination of surgery and platinum-based chemotherapy and/or maintenance with PARP inhibitors.
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Affiliation(s)
- Tibor A Zwimpfer
- Peter MacCallum Cancer Centre, Melbourne, Australia
- Gynaecological Cancer Centre, University Hospital Basel, Basel, Switzerland
| | - Hannah Ewald
- University Medical Library, University of Basel, Basel, Switzerland
| | - Esra Bilir
- Department of Global Health, Koç University Graduate School of Health Sciences, Istanbul, Turkey
- Department of Gynecologic Oncology, Koc University School of Medicine, Istanbul, Turkey
- Department of Obstetrics and Gynecology, University Hospitals Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Madawa Jayawardana
- Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia
| | | | - Nicolò Bizzarri
- UOC Ginecologia Oncologica, Dipartimento per la Salute della Donna e del Bambino e della Salute Pubblica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
| | - Zoia Razumova
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | | | | | | | - David Dl Bowtell
- Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia
| | - Dale W Garsed
- Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia
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27
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Ghiasi M, Chang C, Shafrir AL, Vitonis AF, Sasamoto N, Vazquez AI, DiVasta AD, Upson K, Sieberg CB, Terry KL, Holzman CB, Missmer SA. Subgroups of pelvic pain are differentially associated with endometriosis and inflammatory comorbidities: a latent class analysis. Pain 2024; 165:2119-2129. [PMID: 38563996 PMCID: PMC11333181 DOI: 10.1097/j.pain.0000000000003218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 01/15/2024] [Indexed: 04/04/2024]
Abstract
ABSTRACT Chronic pelvic pain is heterogeneous with potentially clinically informative subgroups. We aimed to identify subgroups of pelvic pain based on symptom patterns and investigate their associations with inflammatory and chronic pain-related comorbidities. Latent class analysis (LCA) identified subgroups of participants (n = 1255) from the Adolescence to Adulthood (A2A) cohort. Six participant characteristics were included in the LCA: severity, frequency, and impact on daily activities of both menstruation-associated (cyclic) and non-menstruation-associated (acyclic) pelvic pain. Three-step LCA quantified associations between LC subgroups, demographic and clinical variables, and 18 comorbidities (10 with prevalence ≥10%). Five subgroups were identified: none or minimal (23%), moderate cyclic only (28%), severe cyclic only (20%), moderate or severe acyclic plus moderate cyclic (9%), and severe acyclic plus severe cyclic (21%). Endometriosis prevalence within these 5 LCA-pelvic pain-defined subgroups ranged in size from 4% in "none or minimal pelvic pain" to 24%, 72%, 70%, and 94%, respectively, in the 4 pain subgroups, with statistically significant odds of membership only for the latter 3 subgroups. Migraines were associated with significant odds of membership in all 4 pelvic pain subgroups relative to those with no pelvic pain (adjusted odds ratios = 2.92-7.78), whereas back, joint, or leg pain each had significantly greater odds of membership in the latter 3 subgroups. Asthma or allergies had three times the odds of membership in the most severe pain group. Subgroups with elevated levels of cyclic or acyclic pain are associated with greater frequency of chronic overlapping pain conditions, suggesting an important role for central inflammatory and immunological mechanisms.
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Affiliation(s)
- Marzieh Ghiasi
- Department of Epidemiology and Biostatistics, College of Human Medicine, Michigan State University, East Lansing, Michigan
| | - Chi Chang
- Department of Epidemiology and Biostatistics, College of Human Medicine, Michigan State University, East Lansing, Michigan
- Office of Medical Education Research and Development, Michigan State University, East Lansing, Michigan
| | - Amy L. Shafrir
- Division of Adolescent and Young Adult Medicine, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts
- Boston Center for Endometriosis, Boston Children’s Hospital and Brigham and Women’s Hospital, Boston, Massachusetts, USA 02115
| | - Allison F. Vitonis
- Boston Center for Endometriosis, Boston Children’s Hospital and Brigham and Women’s Hospital, Boston, Massachusetts, USA 02115
- Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women’s Hospital and Harvard Medical School; Boston, Massachusetts
| | - Naoko Sasamoto
- Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women’s Hospital and Harvard Medical School; Boston, Massachusetts
| | - Ana I. Vazquez
- Department of Epidemiology and Biostatistics, College of Human Medicine, Michigan State University, East Lansing, Michigan
- Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, Michigan
| | - Amy D. DiVasta
- Division of Adolescent and Young Adult Medicine, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts
- Boston Center for Endometriosis, Boston Children’s Hospital and Brigham and Women’s Hospital, Boston, Massachusetts, USA 02115
| | - Kristen Upson
- Department of Epidemiology and Biostatistics, College of Human Medicine, Michigan State University, East Lansing, Michigan
| | - Christine B. Sieberg
- Biobehavioral Pain Innovations Lab, Department of Psychiatry & Behavioral Sciences, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts
- Pain & Affective Neuroscience Center, Department of Anesthesiology, Critical Care, & Pain Medicine, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts
- Department of Psychiatry, Harvard Medical School, Boston, Massachusetts
| | - Kathryn L. Terry
- Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women’s Hospital and Harvard Medical School; Boston, Massachusetts
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Claudia B. Holzman
- Department of Epidemiology and Biostatistics, College of Human Medicine, Michigan State University, East Lansing, Michigan
| | - Stacey A. Missmer
- Division of Adolescent and Young Adult Medicine, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts
- Boston Center for Endometriosis, Boston Children’s Hospital and Brigham and Women’s Hospital, Boston, Massachusetts, USA 02115
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, Michigan
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28
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Ju HY, Youn SY, Kang J, Whang MY, Choi YJ, Han MR. Integrated analysis of spatial transcriptomics and CT phenotypes for unveiling the novel molecular characteristics of recurrent and non-recurrent high-grade serous ovarian cancer. Biomark Res 2024; 12:80. [PMID: 39135097 PMCID: PMC11318304 DOI: 10.1186/s40364-024-00632-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 08/02/2024] [Indexed: 08/15/2024] Open
Abstract
BACKGROUND High-grade serous ovarian cancer (HGSOC), which is known for its heterogeneity, high recurrence rate, and metastasis, is often diagnosed after being dispersed in several sites, with about 80% of patients experiencing recurrence. Despite a better understanding of its metastatic nature, the survival rates of patients with HGSOC remain poor. METHODS Our study utilized spatial transcriptomics (ST) to interpret the tumor microenvironment and computed tomography (CT) to examine spatial characteristics in eight patients with HGSOC divided into recurrent (R) and challenging-to-collect non-recurrent (NR) groups. RESULTS By integrating ST data with public single-cell RNA sequencing data, bulk RNA sequencing data, and CT data, we identified specific cell population enrichments and differentially expressed genes that correlate with CT phenotypes. Importantly, we elucidated that tumor necrosis factor-α signaling via NF-κB, oxidative phosphorylation, G2/M checkpoint, E2F targets, and MYC targets served as an indicator of recurrence (poor prognostic markers), and these pathways were significantly enriched in both the R group and certain CT phenotypes. In addition, we identified numerous prognostic markers indicative of nonrecurrence (good prognostic markers). Downregulated expression of PTGDS was linked to a higher number of seeding sites (≥ 3) in both internal HGSOC samples and public HGSOC TCIA and TCGA samples. Additionally, lower PTGDS expression in the tumor and stromal regions was observed in the R group than in the NR group based on our ST data. Chemotaxis-related markers (CXCL14 and NTN4) and markers associated with immune modulation (DAPL1 and RNASE1) were also found to be good prognostic markers in our ST and radiogenomics analyses. CONCLUSIONS This study demonstrates the potential of radiogenomics, combining CT and ST, for identifying diagnostic and therapeutic targets for HGSOC, marking a step towards personalized medicine.
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Affiliation(s)
- Hye-Yeon Ju
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, 22012, Korea
| | - Seo Yeon Youn
- Department of Radiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
| | - Jun Kang
- Department of Hospital Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
| | - Min Yeop Whang
- Department of Obstetrics and Gynecology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
| | - Youn Jin Choi
- Department of Obstetrics and Gynecology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea.
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea.
| | - Mi-Ryung Han
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, 22012, Korea.
- Institute for New Drug Development, College of Life Science and Bioengineering, Incheon National University, Incheon, 22012, Korea.
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29
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Liu JC, Liu FH, Zhang DY, Wang XY, Wu L, Li YZ, Xu HL, Wei YF, Huang DH, Li XY, Xiao Q, Xie MM, Liu PC, Gao S, Liu C, Liu N, Gong TT, Wu QJ. Association between pre- and post-diagnosis healthy eating index 2020 and ovarian cancer survival: evidence from a prospective cohort study. Food Funct 2024; 15:8408-8417. [PMID: 39040017 DOI: 10.1039/d4fo02417f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/24/2024]
Abstract
Background: Previous studies on the association between diet quality and ovarian cancer (OC) survival are limited and inconsistent. We evaluated the relationship between pre- and post-diagnosis diet quality based on the Healthy Eating Index-2020 (HEI-2020), as well as their changes and OC survival. Methods: This prospective cohort study involved 1082 patients with OC aged 18-79 years, enrolled between 2015 and 2022. Detailed dietary intake before and after diagnosis was recorded using a validated food frequency questionnaire. Deaths were ascertained until February 16th, 2023 via medical records and active follow-up. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Results: We included 549 OC cases with a median follow-up of 44.9 months, representing 206 total deaths. Higher HEI scores were associated with better OS (pre-diagnosis: HRT3 vs. T1 0.66, 95%CI: 0.46-0.93, HR1-SD 0.84, 95%CI: 0.73-0.96; post-diagnosis: HRT3 vs. T1 0.68, 95%CI: 0.49-0.96, HR1-SD 0.80, 95%CI: 0.69-0.92). Compared to the stable group, the group with decreased HEI scores (>3%) from pre- to post-diagnosis had worse OS (HR 1.93, 95%CI: 1.26-2.97). Conclusion: High pre- and post-diagnosis diet quality was associated with improved OC survival, whereas deterioration in diet quality after diagnosis was associated with decreased OC survival.
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Affiliation(s)
- Jia-Cheng Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Fang-Hua Liu
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China.
- Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - De-Yu Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Xiao-Ying Wang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Lang Wu
- Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA
| | - Yi-Zi Li
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China.
- Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - He-Li Xu
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China.
- Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yi-Fan Wei
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China.
- Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Dong-Hui Huang
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China.
- Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiao-Ying Li
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China.
- Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Qian Xiao
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
- Hospital Management Office, Shengjing Hospital of China Medical University, Shenyang, China
| | - Meng-Meng Xie
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Pei-Chen Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Song Gao
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Chuan Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Ning Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Ting-Ting Gong
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Qi-Jun Wu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China.
- Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
- NHC Key Laboratory of Advanced Reproductive Medicine and Fertility (China Medical University), National Health Commission, Shenyang, China
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Adilbayeva A, Kunz J. Pathogenesis of Endometriosis and Endometriosis-Associated Cancers. Int J Mol Sci 2024; 25:7624. [PMID: 39062866 PMCID: PMC11277188 DOI: 10.3390/ijms25147624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 07/03/2024] [Accepted: 07/08/2024] [Indexed: 07/28/2024] Open
Abstract
Endometriosis is a hormone-dependent, chronic inflammatory condition that affects 5-10% of reproductive-aged women. It is a complex disorder characterized by the growth of endometrial-like tissue outside the uterus, which can cause chronic pelvic pain and infertility. Despite its prevalence, the underlying molecular mechanisms of this disease remain poorly understood. Current treatment options are limited and focus mainly on suppressing lesion activity rather than eliminating it entirely. Although endometriosis is generally considered a benign condition, substantial evidence suggests that it increases the risk of developing specific subtypes of ovarian cancer. The discovery of cancer driver mutations in endometriotic lesions indicates that endometriosis may share molecular pathways with cancer. Moreover, the application of single-cell and spatial genomics, along with the development of organoid models, has started to illuminate the molecular mechanisms underlying disease etiology. This review aims to summarize the key genetic mutations and alterations that drive the development and progression of endometriosis to malignancy. We also review the significant recent advances in the understanding of the molecular basis of the disorder, as well as novel approaches and in vitro models that offer new avenues for improving our understanding of disease pathology and for developing new targeted therapies.
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Affiliation(s)
| | - Jeannette Kunz
- Department of Biomedical Sciences, School of Medicine, Nazarbayev University, 5/1 Kerey and Zhanibek Khans St, Astana 020000, Kazakhstan;
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31
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Borho L, Bao R, Elishaev E, Dinkins KD, O'Brien EE, Berger J, Boisen M, Comerci J, Courtney-Brooks M, Edwards RP, Garrett AA, Kelley JL, Lesnock J, Mahdi HS, Olawaiye A, Rush S, Sukumvanich P, Taylor S, Arend RC, Norian L, Modugno F. Association of allostatic load with overall survival in epithelial ovarian cancer. Gynecol Oncol 2024; 186:204-210. [PMID: 38843663 PMCID: PMC11216875 DOI: 10.1016/j.ygyno.2024.05.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/20/2024] [Accepted: 05/28/2024] [Indexed: 07/03/2024]
Abstract
OBJECTIVE Elevated allostatic load (AL), an integrated, cumulative marker of physiologic damage due to socioenvironmental stress, is associated with increased mortality in patients with breast, lung, and other cancers. The relationship between allostatic load and mortality in ovarian cancer patients remains unknown. We examined the relationship between allostatic load and overall survival in ovarian cancer patients. METHODS This cross-sectional study used data from 201 patients enrolled in a prospective observational ovarian cancer cohort study at a National Cancer Institute-designated Comprehensive Cancer Center from October 2012 through June 2022. All patients underwent debulking surgery and completed a full course of standard-of-care platinum-based chemotherapy. Follow-up was completed through January 2024. Allostatic load was calculated as a summary score by assigning one point to the worst sample quartile for each of ten biomarkers measured within 45 days before the ovarian cancer diagnosis. High allostatic load was defined as having an allostatic load in the top quartile of the summary score. A Cox proportional hazard model with robust variance tested the association between allostatic load and overall survival. RESULTS There were no associations between allostatic load and ovarian cancer clinical characteristics. After accounting for demographic, clinical, and treatment factors, high allostatic load was associated with a significant increase in mortality (hazard ratio 2.17 [95%CI, 1.13-4.15]; P = 0.02). CONCLUSION Higher allostatic load is associated with worse survival among ovarian cancer patients. Allostatic load could help identify patients at risk for poorer outcomes who may benefit from greater socioenvironmental support during treatment.
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Affiliation(s)
- Lauren Borho
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee-Womens Research Institute and Foundation, Pittsburgh, PA, United States of America
| | - Riyue Bao
- Department of Hematology/Oncology, University of Pittsburgh School of Medicine and Hillman Cancer Center, Pittsburgh, PA, United States of America
| | - Esther Elishaev
- Department of Pathology, University of Pittsburgh School of Medicine and Magee-Womens Research Institute and Foundation, Pittsburgh, PA, United States of America
| | - Kaitlyn D Dinkins
- Department of Obstetrics and Gynecology, University of Alabama at Birmingham School of Medicine and O'Neal Comprehensive Cancer Center, Birmingham, AL, United States of America
| | - Emily E O'Brien
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee-Womens Research Institute and Foundation, Pittsburgh, PA, United States of America
| | - Jessica Berger
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee-Womens Research Institute and Foundation, Pittsburgh, PA, United States of America
| | - Michelle Boisen
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee-Womens Research Institute and Foundation, Pittsburgh, PA, United States of America
| | - John Comerci
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee-Womens Research Institute and Foundation, Pittsburgh, PA, United States of America
| | - Madeleine Courtney-Brooks
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee-Womens Research Institute and Foundation, Pittsburgh, PA, United States of America
| | - Robert P Edwards
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee-Womens Research Institute and Foundation, Pittsburgh, PA, United States of America
| | - Alison Aunkst Garrett
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee-Womens Research Institute and Foundation, Pittsburgh, PA, United States of America
| | - Joseph L Kelley
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee-Womens Research Institute and Foundation, Pittsburgh, PA, United States of America
| | - Jamie Lesnock
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee-Womens Research Institute and Foundation, Pittsburgh, PA, United States of America
| | - Haider S Mahdi
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee-Womens Research Institute and Foundation, Pittsburgh, PA, United States of America
| | - Alexander Olawaiye
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee-Womens Research Institute and Foundation, Pittsburgh, PA, United States of America
| | - Shannon Rush
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee-Womens Research Institute and Foundation, Pittsburgh, PA, United States of America
| | - Paniti Sukumvanich
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee-Womens Research Institute and Foundation, Pittsburgh, PA, United States of America
| | - Sarah Taylor
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee-Womens Research Institute and Foundation, Pittsburgh, PA, United States of America
| | - Rebecca C Arend
- Department of Obstetrics and Gynecology, University of Alabama at Birmingham School of Medicine and O'Neal Comprehensive Cancer Center, Birmingham, AL, United States of America
| | - Lyse Norian
- Department of Nutrition Sciences, University of Alabama at Birmingham School of Health Professions, Nutrition Obesity Research Center, O'Neal Comprehensive Cancer Center, Birmingham, AL, United States of America
| | - Francesmary Modugno
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee-Womens Research Institute and Foundation, Pittsburgh, PA, United States of America; Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, United States of America; Women's Cancer Research Center, Magee-Womens Research Institute and Foundation and Hillman Cancer Center, Pittsburgh, PA, United States of America
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Han YL, Fang Z, Gao ZJ, Li WG, Yang J. Comprehensive single-cell and bulk RNA-seq analyses reveal a novel CD8 + T cell-associated prognostic signature in ovarian cancer. Aging (Albany NY) 2024; 16:10636-10656. [PMID: 38925650 PMCID: PMC11236322 DOI: 10.18632/aging.205966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 05/03/2024] [Indexed: 06/28/2024]
Abstract
CD8+ T cells play pivotal roles in combating intracellular pathogens and eliminating malignant cells in cancer. However, the prognostic role of CD8+ T cells in ovarian carcinoma is insufficiently exploited. Herein, through univariate Cox regression along with least absolute shrinkage and selection operator (LASSO) regression analyses, we developed a novel prognostic model based on CD8+ T cell markers identified by single-cell sequencing (scRNA-seq) analyses. Patient grouping by the median risk score reveals an excellent prognostic efficacy of this model in both training and validation cohorts. Of note, patients classified as low-risk group exhibit a dramatically improved prognosis. In addition, higher enrichment level of immune-related pathways and increased infiltration level of multiple immune cells are found in patients with lower risk score. Importantly, low-risk patients also exhibited higher response rate to immunotherapies. Summarily, this developed CD8+ T cell-associated prognostic model serves as an excellent predictor for clinical outcomes and aids in guiding therapeutic strategy choices for ovarian cancer patients.
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Affiliation(s)
- Yi-Ling Han
- Center for Reproductive Medicine, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhou Fang
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Zhi-Jie Gao
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Wen-Ge Li
- Department of Oncology, Shanghai Artemed Hospital, Shanghai, China
| | - Jing Yang
- Center for Reproductive Medicine, Renmin Hospital of Wuhan University, Wuhan, China
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Wang F, Zhou C, Zhu Y, Keshavarzi M. The microRNA Let-7 and its exosomal form: Epigenetic regulators of gynecological cancers. Cell Biol Toxicol 2024; 40:42. [PMID: 38836981 PMCID: PMC11153289 DOI: 10.1007/s10565-024-09884-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 05/15/2024] [Indexed: 06/06/2024]
Abstract
Many types of gynecological cancer (GC) are often silent until they reach an advanced stage, and are therefore often diagnosed too late for effective treatment. Hence, there is a real need for more efficient diagnosis and treatment for patients with GC. During recent years, researchers have increasingly studied the impact of microRNAs cancer development, leading to a number of applications in detection and treatment. MicroRNAs are a particular group of tiny RNA molecules that regulate regular gene expression by affecting the translation process. The downregulation of numerous miRNAs has been observed in human malignancies. Let-7 is an example of a miRNA that controls cellular processes as well as signaling cascades to affect post-transcriptional gene expression. Recent research supports the hypothesis that enhancing let-7 expression in those cancers where it is downregulated may be a potential treatment option. Exosomes are tiny vesicles that move through body fluids and can include components like miRNAs (including let-7) that are important for communication between cells. Studies proved that exosomes are able to enhance tumor growth, angiogenesis, chemoresistance, metastasis, and immune evasion, thus suggesting their importance in GC management.
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Affiliation(s)
- Fei Wang
- Haiyan People's Hospital, Zhejiang Province, Jiaxing, 314300, Zhejiang, China
| | - Chundi Zhou
- Haiyan People's Hospital, Zhejiang Province, Jiaxing, 314300, Zhejiang, China
| | - Yanping Zhu
- Haiyan People's Hospital, Zhejiang Province, Jiaxing, 314300, Zhejiang, China.
| | - Maryam Keshavarzi
- School of Medicine, Tehran University of Medical Sciences, Tehran, Tehran, Iran.
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Stiegeler N, Garsed DW, Au-Yeung G, Bowtell DDL, Heinzelmann-Schwarz V, Zwimpfer TA. Homologous recombination proficient subtypes of high-grade serous ovarian cancer: treatment options for a poor prognosis group. Front Oncol 2024; 14:1387281. [PMID: 38894867 PMCID: PMC11183307 DOI: 10.3389/fonc.2024.1387281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 05/15/2024] [Indexed: 06/21/2024] Open
Abstract
Approximately 50% of tubo-ovarian high-grade serous carcinomas (HGSCs) have functional homologous recombination-mediated (HR) DNA repair, so-called HR-proficient tumors, which are often associated with primary platinum resistance (relapse within six months after completion of first-line therapy), minimal benefit from poly(ADP-ribose) polymerase (PARP) inhibitors, and shorter survival. HR-proficient tumors comprise multiple molecular subtypes including cases with CCNE1 amplification, AKT2 amplification or CDK12 alteration, and are often characterized as "cold" tumors with fewer infiltrating lymphocytes and decreased expression of PD-1/PD-L1. Several new treatment approaches aim to manipulate these negative prognostic features and render HR-proficient tumors more susceptible to treatment. Alterations in multiple different molecules and pathways in the DNA damage response are driving new drug development to target HR-proficient cancer cells, such as inhibitors of the CDK or P13K/AKT pathways, as well as ATR inhibitors. Treatment combinations with chemotherapy or PARP inhibitors and agents targeting DNA replication stress have shown promising preclinical and clinical results. New approaches in immunotherapy are also being explored, including vaccines or antibody drug conjugates. Many approaches are still in the early stages of development and further clinical trials will determine their clinical relevance. There is a need to include HR-proficient tumors in ovarian cancer trials and to analyze them in a more targeted manner to provide further evidence for their specific therapy, as this will be crucial in improving the overall prognosis of HGSC and ovarian cancer in general.
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Affiliation(s)
| | - Dale W. Garsed
- Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
| | - George Au-Yeung
- Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
| | - David D. L. Bowtell
- Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
| | | | - Tibor A. Zwimpfer
- Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Department of Gynecological Oncology, University Hospital Basel, Basel, Switzerland
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Abstract
All cancers arise from normal cells whose progeny acquire the cancer-initiating mutations and epigenetic modifications leading to frank tumorigenesis. The identity of those "cells-of-origin" has historically been a source of controversy across tumor types, as it has not been possible to witness the dynamic events giving rise to human tumors. Genetically engineered mouse models (GEMMs) of cancer provide an invaluable substitute, enabling researchers to interrogate the competence of various naive cellular compartments to initiate tumors in vivo. Researchers using these models have relied on lineage-specific promoters, knowledge of preneoplastic disease states in humans, and technical advances allowing more precise manipulations of the mouse germline. These approaches have given rise to the emerging view that multiple lineages within a given organ may generate tumors with similar histopathology. Here, we review some of the key studies leading to this conclusion in solid tumors and highlight the biological and clinical ramifications.
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Affiliation(s)
- Jason R Pitarresi
- Division of Hematology and Oncology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01655, USA
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01655, USA
| | - Ben Z Stanger
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA
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Matsuo K, Chen L, Klar M, Roman LD, Sood AK, Gershenson DM, Wright JD. Primary Cytoreduction and Survival for Patients With Less-Common Epithelial Ovarian Cancer. JAMA Netw Open 2024; 7:e2417775. [PMID: 38900429 PMCID: PMC11190790 DOI: 10.1001/jamanetworkopen.2024.17775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 04/17/2024] [Indexed: 06/21/2024] Open
Abstract
This cohort study examines the association between primary cytoreduction status and survival for patients with less-common, advanced-stage epithelial ovarian carcinoma.
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Affiliation(s)
- Koji Matsuo
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
| | - Ling Chen
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, New York
| | - Maximilian Klar
- Department of Obstetrics and Gynecology, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany
| | - Lynda D. Roman
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
| | - Anil K. Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston
| | - David M. Gershenson
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston
| | - Jason D. Wright
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, New York
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Wu F, Xu J, Jin X, Zhu Y, Gao W, Liu M, Zhang Y, Qian W, Huang X, Zhao D, Feng G, Hou S, Xi X. TRIM8 promotes ovarian cancer proliferation and migration by targeting VDAC2 for ubiquitination and degradation. Cancer Med 2024; 13:e7396. [PMID: 38881325 PMCID: PMC11180974 DOI: 10.1002/cam4.7396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 03/21/2024] [Accepted: 06/02/2024] [Indexed: 06/18/2024] Open
Abstract
BACKGROUND Ovarian cancer is a common gynecological tumor with high malignant potential and poor prognosis. TRIM8, is involved in the development of various tumors, but its precise regulatory role in ovarian cancer is still unknown. AIMS The aim of this study was to explore the specific mechanism by which TRIM8 regulates ovarian cancer. MATERIALS AND METHODS We used bioinformatics analysis to screen for high expression of TRIM8 in ovarian cancer. The expression of TRIM8 in healthy and cancerous ovarian tissues was assessed by immunofluorescence. TRIM8 was silenced or overexpressed in ovarian cancer cell lines, with cell proliferation and migration evaluated by CCK8, transwell and clonal formation assays. The effect of TRIM8 on ovarian cancer cells in vivo was assessed by subcutaneous tumor formation experiments in nude mice. The potential interacting protein VDAC2 was identified by mass spectrometry. The mechanism underlying TRIM8 regulation of VDAC2 was evaluated by co-immunoprecipitation and western blotting. RESULTS TRIM8 was overexpressed in ovarian cancer. TRIM8 promoted the proliferation and migration of ovarian cancer cells in vitro and the growth of subcutaneous tumors in mice in vivo. TRIM8 interacted with VDAC2, weakened the stability of the protein, and promoted its polyubiquitination and subsequent degradation. Knockdown of VDAC2 increased the resistance of ovarian cancer cells to iron death, whereas overexpression of VDAC2 attenuated ovarian cancer progression induced by TRIM8 overexpression. DISCUSSION TRIM8 promotes ovarian cancer proliferation and migration by targeting VDAC2 for ubiquitination and degradation, these finding may provide new targets for the treatment of ovarian cancer. CONCLUSION TRIM8 degraded VDAC2 through the ubiquitination pathway, increased the resistance of ovarian cancer cells to iron death, and promoted the proliferation and migration of ovarian cancer.
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Affiliation(s)
- Fei Wu
- Department of Obstetrics and GynecologyThe Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou Municipal HospitalSuzhouJiangsuChina
| | - Jiaqi Xu
- Department of Obstetrics and GynecologyThe Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou Municipal HospitalSuzhouJiangsuChina
| | - Xin Jin
- Department of Obstetrics and GynecologyThe Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou Municipal HospitalSuzhouJiangsuChina
| | - Yue Zhu
- Department of Breast and Thyroid SurgeryThe Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou Municipal HospitalSuzhouJiangsuChina
| | - Wenxin Gao
- Department of Histology and Embryology, School of Basic Medical SciencesNanjing Medical UniversityNanjingChina
| | - Meng Liu
- Department of Obstetrics and GynecologyThe Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou Municipal HospitalSuzhouJiangsuChina
| | - Yan Zhang
- Department of Obstetrics and GynecologyThe Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou Municipal HospitalSuzhouJiangsuChina
| | - Weifeng Qian
- Department of Breast and Thyroid SurgeryThe Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou Municipal HospitalSuzhouJiangsuChina
| | - Xiaoyan Huang
- Department of Histology and Embryology, School of Basic Medical SciencesNanjing Medical UniversityNanjingChina
| | - Dan Zhao
- Reproductive Medicine CenterThe Fourth Affiliated Hospital of Jiangsu UniversityZhenjiangChina
- Institute of Reproductive Sciences, Jiangsu UniversityZhenjiangChina
| | - Guannan Feng
- Department of Obstetrics and GynecologyThe Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou Municipal HospitalSuzhouJiangsuChina
| | - Shunyu Hou
- Department of Obstetrics and GynecologyThe Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou Municipal HospitalSuzhouJiangsuChina
| | - Xiaoxue Xi
- Department of Obstetrics and GynecologyThe Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou Municipal HospitalSuzhouJiangsuChina
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Atwani R, Nagare RP, Rogers A, Prasad M, Lazar V, Sandusky G, Tong Y, Pin F, Condello S. Integrin-linked kinase-frizzled 7 interaction maintains cancer stem cells to drive platinum resistance in ovarian cancer. J Exp Clin Cancer Res 2024; 43:156. [PMID: 38822429 PMCID: PMC11143768 DOI: 10.1186/s13046-024-03083-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 05/27/2024] [Indexed: 06/03/2024] Open
Abstract
BACKGROUND Platinum-based chemotherapy regimens are a mainstay in the management of ovarian cancer (OC), but emergence of chemoresistance poses a significant clinical challenge. The persistence of ovarian cancer stem cells (OCSCs) at the end of primary treatment contributes to disease recurrence. Here, we hypothesized that the extracellular matrix protects CSCs during chemotherapy and supports their tumorigenic functions by activating integrin-linked kinase (ILK), a key enzyme in drug resistance. METHODS TCGA datasets and OC models were investigated using an integrated proteomic and gene expression analysis and examined ILK for correlations with chemoresistance pathways and clinical outcomes. Canonical Wnt pathway components, pro-survival signaling, and stemness were examined using OC models. To investigate the role of ILK in the OCSC-phenotype, a novel pharmacological inhibitor of ILK in combination with carboplatin was utilized in vitro and in vivo OC models. RESULTS In response to increased fibronectin secretion and integrin β1 clustering, aberrant ILK activation supported the OCSC phenotype, contributing to OC spheroid proliferation and reduced response to platinum treatment. Complexes formed by ILK with the Wnt receptor frizzled 7 (Fzd7) were detected in tumors and correlated with metastatic progression. Moreover, TCGA datasets confirmed that combined expression of ILK and Fzd7 in high grade serous ovarian tumors is correlated with reduced response to chemotherapy and poor patient outcomes. Mechanistically, interaction of ILK with Fzd7 increased the response to Wnt ligands, thereby amplifying the stemness-associated Wnt/β-catenin signaling. Notably, preclinical studies showed that the novel ILK inhibitor compound 22 (cpd-22) alone disrupted ILK interaction with Fzd7 and CSC proliferation as spheroids. Furthermore, when combined with carboplatin, this disruption led to sustained AKT inhibition, apoptotic damage in OCSCs and reduced tumorigenicity in mice. CONCLUSIONS This "outside-in" signaling mechanism is potentially actionable, and combined targeting of ILK-Fzd7 may lead to new therapeutic approaches to eradicate OCSCs and improve patient outcomes.
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Affiliation(s)
- Rula Atwani
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA
| | - Rohit Pravin Nagare
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA
| | - Amber Rogers
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA
- Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Mayuri Prasad
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA
| | - Virginie Lazar
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA
| | - George Sandusky
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Yan Tong
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA
- Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Fabrizio Pin
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Salvatore Condello
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA.
- Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
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Bhavsar D, Raguraman R, Kim D, Ren X, Munshi A, Moore K, Sikavitsas V, Ramesh R. Exosomes in diagnostic and therapeutic applications of ovarian cancer. J Ovarian Res 2024; 17:113. [PMID: 38796525 PMCID: PMC11127348 DOI: 10.1186/s13048-024-01417-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 04/16/2024] [Indexed: 05/28/2024] Open
Abstract
Ovarian cancer accounts for more deaths than any other female reproductive tract cancer. The major reasons for the high mortality rates include delayed diagnoses and drug resistance. Hence, improved diagnostic and therapeutic options for ovarian cancer are a pressing need. Extracellular vesicles (EVs), that include exosomes provide hope in both diagnostic and therapeutic aspects. They are natural lipid nanovesicles secreted by all cell types and carry molecules that reflect the status of the parent cell. This facilitates their potential use as biomarkers for an early diagnosis. Additionally, EVs can be loaded with exogenous cargo, and have features such as high stability and favorable pharmacokinetic properties. This makes them ideal for tumor-targeted delivery of biological moieties. The International Society of Extracellular Vesicles (ISEV) based on the Minimal Information for Studies on Extracellular Vesicles (MISEV) recommends the usage of the term "small extracellular vesicles (sEVs)" that includes exosomes for particles that are 30-200 nm in size. However, majority of the studies reported in the literature and relevant to this review have used the term "exosomes". Therefore, this review will use the term "exosomes" interchangeably with sEVs for consistency with the literature and avoid confusion to the readers. This review, initially summarizes the different isolation and detection techniques developed to study ovarian cancer-derived exosomes and the potential use of these exosomes as biomarkers for the early diagnosis of this devastating disease. It addresses the role of exosome contents in the pathogenesis of ovarian cancer, discusses strategies to limit exosome-mediated ovarian cancer progression, and provides options to use exosomes for tumor-targeted therapy in ovarian cancer. Finally, it states future research directions and recommends essential research needed to successfully transition exosomes from the laboratory to the gynecologic-oncology clinic.
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Affiliation(s)
- Dhaval Bhavsar
- Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE, 10th Street, Oklahoma City, OK, 73104, USA
- OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 800 NE, 10th Street, Oklahoma City, OK, 73104, USA
| | - Rajeswari Raguraman
- Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE, 10th Street, Oklahoma City, OK, 73104, USA
- OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 800 NE, 10th Street, Oklahoma City, OK, 73104, USA
| | - Dongin Kim
- Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, 1110 N, Stonewall Ave, Oklahoma City, OK, 73104, USA
- OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 800 NE, 10th Street, Oklahoma City, OK, 73104, USA
| | - Xiaoyu Ren
- Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, 1110 N, Stonewall Ave, Oklahoma City, OK, 73104, USA
| | - Anupama Munshi
- Department of Radiation Oncology, University of Oklahoma Health Sciences Center, 975 NE, 10th Street, Oklahoma City, OK, 73104, USA
- OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 800 NE, 10th Street, Oklahoma City, OK, 73104, USA
| | - Kathleen Moore
- Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, 800 NE, 10th Street, Oklahoma City, OK, 73104, USA
- OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 800 NE, 10th Street, Oklahoma City, OK, 73104, USA
| | - Vassilios Sikavitsas
- OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 800 NE, 10th Street, Oklahoma City, OK, 73104, USA
- Department of Chemical, Biological and Materials Engineering, Oklahoma University, Norman, OK, 73019, USA
| | - Rajagopal Ramesh
- Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE, 10th Street, Oklahoma City, OK, 73104, USA.
- OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 800 NE, 10th Street, Oklahoma City, OK, 73104, USA.
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Ye J, Zhang X, Xie JX, Hou Y, Fan WM, Wang XQ, Zhang LW, Yang XM, Li J, Fei H. RACGAP1 knockdown synergizes and enhances the effects of chemotherapeutics on ovarian cancer. Am J Transl Res 2024; 16:2132-2146. [PMID: 38883382 PMCID: PMC11170603 DOI: 10.62347/qnzu1402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 05/06/2024] [Indexed: 06/18/2024]
Abstract
Among the three most prevalent cancers affecting the female reproductive system, ovarian cancer (OV) ranks as the second most frequently diagnosed. It is important to investigate the genomic complexity of OV to develop diagnostic and therapeutic strategies. Through the utilization of bioinformatics analysis, it was determined that RacGTPase Activating Protein 1 (RACGAP1) holds significant significance in the field of OV chemotherapeutics, an aspect that has not been thoroughly explored in prior investigations. In our study, a notable increase in RACGAP1 expression was detected in ovarian cancer, demonstrating a robust association with clinicopathological features and patient prognosis. In vivo and in vitro testing revealed that RACGAP1 acts synergistically with chemotherapeutics to enhance their effects on ovarian cancer. Furthermore, an interaction between RACGAP1 and the subunit G2 of the condensin II complex, known as non-SMC condensin II complex subunit G2 (NCAPG2), has been identified. Our findings may provide new insight for improving therapeutic strategies for OV.
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Affiliation(s)
- Jun Ye
- Department of Obstetrics and Gynecology, The Fifth People's Hospital of Shanghai, Fudan University Shanghai, China
| | - Xiang Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, China
| | - Jia-Xuan Xie
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, China
| | - Yue Hou
- Department of Obstetrics and Gynecology, The Fifth People's Hospital of Shanghai, Fudan University Shanghai, China
| | - Wei-Min Fan
- Department of Obstetrics and Gynecology, The Fifth People's Hospital of Shanghai, Fudan University Shanghai, China
| | - Xiao-Qin Wang
- Department of Obstetrics and Gynecology, The Fifth People's Hospital of Shanghai, Fudan University Shanghai, China
| | - Li-Wen Zhang
- Department of Obstetrics and Gynecology, The Fifth People's Hospital of Shanghai, Fudan University Shanghai, China
| | - Xiao-Mei Yang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, China
| | - Jun Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, China
| | - He Fei
- Department of Obstetrics and Gynecology, The Fifth People's Hospital of Shanghai, Fudan University Shanghai, China
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41
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Zhang Q, Guo F, Liu H, Hong L. Enhancing wound healing and overcoming cisplatin resistance in ovarian cancer. Int Wound J 2024; 21:e14569. [PMID: 38158767 PMCID: PMC10961880 DOI: 10.1111/iwj.14569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 12/04/2023] [Accepted: 12/04/2023] [Indexed: 01/03/2024] Open
Abstract
Ovarian cancer (OC) poses significant oncological challenges, notably impaired wound healing in the context of cisplatin (DDP) resistance. This study investigates the role of miR-200b in OC, emphasizing its impact on wound healing processes through DNMT3A/TGF-β1 pathway. The primary aim was to explore how miR-200b regulates autophagy and its consequential effects on wound healing in OC, alongside its influence on cisplatin resistance. Utilizing DDP-sensitive (A2780) and resistant (A2780/DDP) OC cell lines, along with human fibroblast cultures, the study employed an array of in vitro techniques. These included cell transfection with miR-200b mimic or inhibitor, chromatin immunoprecipitation (ChIP), dual-luciferase reporter (DLR) assays, quantitative PCR, Western blotting, MTT and particularly, wound healing assays. The research highlighted the role of miR-200b in wound healing within OC. Inhibition of miR-200b in A2780 cells and its mimic in A2780/DDP cells affected cell viability, indicating the link with DDP resistance. Crucially, miR-200b mimic significantly delayed fibroblast-mediated wound closure in assays, underscoring its impact on wound healing. Bioinformatics analysis and subsequent DLR assays confirmed miR-200b's interaction with DNMT3A, affecting TGF-β1 expression, the key factor in wound repair. Further, ChIP, quantitative PCR and Western blot analyses validated the interaction and expression changes in DNMT3A and TGF-β1. The study demonstrated that miR-200b played a pivotal role in OC by modulating autophagy, which in turn significantly affected wound healing through the DNMT3A/TGF-β1 pathway.
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Affiliation(s)
- Qifan Zhang
- Department of Obstetrics and GynecologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Fengqin Guo
- Department of Obstetrics and GynecologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Hua Liu
- Department of Obstetrics and GynecologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Li Hong
- Department of Obstetrics and GynecologyRenmin Hospital of Wuhan UniversityWuhanChina
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Anitha K, Chenchula S, Surendran V, Shvetank B, Ravula P, Milan R, Chikatipalli R, R P. Advancing cancer theranostics through biomimetics: A comprehensive review. Heliyon 2024; 10:e27692. [PMID: 38496894 PMCID: PMC10944277 DOI: 10.1016/j.heliyon.2024.e27692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 03/02/2024] [Accepted: 03/05/2024] [Indexed: 03/19/2024] Open
Abstract
Nanotheranostics, especially those employing biomimetic approaches, are of substantial interest for molecular imaging and cancer therapy. The incorporation of diagnostics and therapeutics, known as cancer theranostics, represents a promising strategy in modern oncology. Biomimetics, inspired by nature, offers a multidisciplinary avenue with potential in advancing cancer theranostics. This review comprehensively analyses recent progress in biomimetics-based cancer theranostics, emphasizing its role in overcoming current treatment challenges, with a focus on breast, prostate, and skin cancers. Biomimetic approaches have been explored to address multidrug resistance (MDR), emphasizing their role in immunotherapy and photothermal therapy. The specific areas covered include biomimetic drug delivery systems bypassing MDR mechanisms, biomimetic platforms for immune checkpoint blockade, immune cell modulation, and photothermal tumor ablation. Pretargeting techniques enhancing radiotherapeutic agent uptake are discussed, along with a comprehensive review of clinical trials of global nanotheranostics. This review delves into biomimetic materials, nanotechnology, and bioinspired strategies for cancer imaging, diagnosis, and targeted drug delivery. These include imaging probes, contrast agents, and biosensors for enhanced specificity and sensitivity. Biomimetic strategies for targeted drug delivery involve the design of nanoparticles, liposomes, and hydrogels for site-specific delivery and improved therapeutic efficacy. Overall, this current review provides valuable information for investigators, clinicians, and biomedical engineers, offering insights into the latest biomimetics applications in cancer theranostics. Leveraging biomimetics aims to revolutionize cancer diagnosis, treatment, and patient outcomes.
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Affiliation(s)
- Kuttiappan Anitha
- Department of Pharmacology, School of Pharmacy and Technology Management (SPTM), SVKM's Narsee Monjee Institute of Management Studies (NMIMS) Deemed-to-University, Shirpur, 425405, India
| | - Santenna Chenchula
- Department of Clinical Pharmacology, All India Institute of Medical Sciences (AIIMS), Bhopal, 462020, Madhya Pradesh, India
| | - Vijayaraj Surendran
- Dr Kalam College of Pharmacy, Thanjavur District, Tamil Nadu, 614 623, India
| | - Bhatt Shvetank
- School of Health Sciences and Technology, Dr Vishwanath Karad MIT World Peace University, Pune, 411038, Maharashtra, India
| | - Parameswar Ravula
- Amity Institute of Pharmacy, Amity University Madhya Pradesh (AUMP), Gwalior, 474005, Madhya Pradesh, India
| | - Rhythm Milan
- Amity Institute of Pharmacy, Amity University Madhya Pradesh (AUMP), Gwalior, 474005, Madhya Pradesh, India
| | - Radhika Chikatipalli
- Sri Venkateshwara College of Pharmacy, Chittoor District, Andhra Pradesh, 517520, India
| | - Padmavathi R
- SVS Medical College, Mahbubnagar, Telangana, India
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Atwani R, Rogers A, Nagare R, Prasad M, Lazar V, Sandusky G, Pin F, Condello S. Integrin-linked kinase-frizzled 7 interaction maintains cancer stem cells to drive platinum resistance in ovarian cancer. RESEARCH SQUARE 2024:rs.3.rs-4086737. [PMID: 38559125 PMCID: PMC10980163 DOI: 10.21203/rs.3.rs-4086737/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Background Platinum-based chemotherapy regimens are a mainstay in the management of ovarian cancer (OC), but emergence of chemoresistance poses a significant clinical challenge. The persistence of ovarian cancer stem cells (OCSCs) at the end of primary treatment contributes to disease recurrence. Here, we hypothesized that the extracellular matrix protects CSCs during chemotherapy and supports their tumorigenic functions by activating integrin-linked kinase (ILK), a key enzyme in drug resistance. Methods TCGA datasets and OC models were investigated using an integrated proteomic and gene expression analysis and examined ILK for correlations with chemoresistance pathways and clinical outcomes. Canonical Wnt pathway components, pro-survival signaling, and stemness were examined using OC models. To investigate the role of ILK in the OCSC-phenotype, a novel pharmacological inhibitor of ILK in combination with carboplatin was utilized in vitro and in vivo OC models. Results In response to increased fibronectin (FN) secretion and integrin β1 clustering, aberrant ILK activation supported the OCSC phenotype, contributing to OC spheroid proliferation and reduced response to platinum treatment. Complexes formed by ILK with the Wnt receptor frizzled 7 (Fzd7) were detected in tumors and showed a strong correlation with metastatic progression. Moreover, TCGA datasets confirmed that combined expression of ILK and Fzd7 in high grade serous ovarian tumors is correlated with reduced response to chemotherapy and poor patient outcomes. Mechanistically, interaction of ILK with Fzd7 increased the response to Wnt ligands, thereby amplifying the stemness-associated Wnt/β-catenin signaling. Notably, preclinical studies showed that the novel ILK inhibitor compound 22 (cpd-22) alone disrupted ILK interaction with Fzd7 and CSC proliferation as spheroids. Furthermore, when combined with carboplatin, this disruption led to sustained AKT inhibition, apoptotic damage in OCSCs and reduced tumorigenicity in mice. Conclusions This "outside-in" signaling mechanism is potentially actionable, and combined targeting of ILK-Fzd7 may represent a new therapeutic strategy to eradicate OCSCs and improve patient outcomes.
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Wu X, Zhong Y, Zhang H, Li M. MiR-5590-3p inhibits the proliferation and invasion of ovarian cancer cells through mediating the Wnt/β-catenin signaling pathway by targeting TNIK. Histol Histopathol 2024; 39:345-355. [PMID: 37318197 DOI: 10.14670/hh-18-636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
MicroRNAs (miRNAs) are crucial regulatory molecules involved in diverse biological processes and human diseases, including ovarian cancer (OC). miR-5590-3p has been involved in multiple malignant solid tumors, but its exact role in the progression of OC is largely unknown. This study mainly focuses on how miR-5590-3p works in OC and illuminating the underlying mechanism. We found that miR-5590-3p was significantly downregulated in human OC cell lines and patient tissues. Cell counting 8 (CCK-8) and Transwell assays proved that overexpression or inhibition of miR-5590-3p suppressed or promoted cell proliferation and cell invasion. Subsequently, TNIK was identified as a target of miR-5590-3p. Silence of TNIK by small interfering RNA (siRNA) reversed the increasing effect of miR-5590-3p inhibition on cell proliferation and invasion in OC cell lines. Furthermore, our results showed that the Wnt/β-catenin pathway was inhibited by its specific inhibitor XAV-939, but miR-5590-3p inhibitor and adenoviral TNIK overexpression vector (Ad-TNIK) reactivated the activation of Wnt/β-catenin signaling and increased cell malignancy. Lastly, tumorigenicity assay demonstrated that inhibition of miR-5590-3p increased tumor volume and weight in vivo. In conclusion, miR-5590-3p may function as a cancer suppressor gene in OC progression through the Wnt/β-catenin signaling by transcriptionally suppressing TNIK expression, which provides a potential therapeutic approach for ovarian cancer treatment.
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Affiliation(s)
- Xiaoling Wu
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
| | - Youwen Zhong
- School of Economics and Finance, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Hua Zhang
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Mu Li
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
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45
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Xue W, Yang L, Chen C, Ashrafizadeh M, Tian Y, Sun R. Wnt/β-catenin-driven EMT regulation in human cancers. Cell Mol Life Sci 2024; 81:79. [PMID: 38334836 PMCID: PMC10857981 DOI: 10.1007/s00018-023-05099-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/09/2023] [Accepted: 12/20/2023] [Indexed: 02/10/2024]
Abstract
Metastasis accounts for 90% of cancer-related deaths among the patients. The transformation of epithelial cells into mesenchymal cells with molecular alterations can occur during epithelial-mesenchymal transition (EMT). The EMT mechanism accelerates the cancer metastasis and drug resistance ability in human cancers. Among the different regulators of EMT, Wnt/β-catenin axis has been emerged as a versatile modulator. Wnt is in active form in physiological condition due to the function of GSK-3β that destructs β-catenin, while ligand-receptor interaction impairs GSK-3β function to increase β-catenin stability and promote its nuclear transfer. Regarding the oncogenic function of Wnt/β-catenin, its upregulation occurs in human cancers and it can accelerate EMT-mediated metastasis and drug resistance. The stimulation of Wnt by binding Wnt ligands into Frizzled receptors can enhance β-catenin accumulation in cytoplasm that stimulates EMT and related genes upon nuclear translocation. Wnt/β-catenin/EMT axis has been implicated in augmenting metastasis of both solid and hematological tumors. The Wnt/EMT-mediated cancer metastasis promotes the malignant behavior of tumor cells, causing therapy resistance. The Wnt/β-catenin/EMT axis can be modulated by upstream mediators in which non-coding RNAs are main regulators. Moreover, pharmacological intervention, mainly using phytochemicals, suppresses Wnt/EMT axis in metastasis suppression.
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Affiliation(s)
- Wenhua Xue
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Lin Yang
- Department of Hepatobiliary Surgery, Xianyang Central Hospital, Xianyang, 712000, Shaanxi, China
| | - Chengxin Chen
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Milad Ashrafizadeh
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Yu Tian
- School of Public Health, Benedictine University, Lisle, USA.
| | - Ranran Sun
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
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Collier AB, Viswanadhapalli S, Gopalam R, Lee TK, Kassees K, Parra K, Sharma G, Reese TC, Liu X, Yang X, Ebrahimi B, Pratap UP, Mahajan M, Arnold WC, Baker A, Chen CY, Elmore ST, Subbarayalu P, Sareddy GR, Valente PT, Kost ER, Ahn JM, Vadlamudi RK. Novel LIPA-Targeted Therapy for Treating Ovarian Cancer. Cancers (Basel) 2024; 16:500. [PMID: 38339252 PMCID: PMC10854701 DOI: 10.3390/cancers16030500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 01/18/2024] [Accepted: 01/19/2024] [Indexed: 02/12/2024] Open
Abstract
Ovarian cancer (OCa) is the most lethal form of gynecologic cancer, and the tumor heterogeneities at the molecular, cellular, and tissue levels fuel tumor resistance to standard therapies and pose a substantial clinical challenge. Here, we tested the hypothesis that the heightened basal endoplasmic reticulum stress (ERS) observed in OCa represents an exploitable vulnerability and may overcome tumor heterogeneity. Our recent studies identified LIPA as a novel target to induce ERS in cancer cells using the small molecule ERX-41. However, the role of LIPA and theutility of ERX-41 to treat OCa remain unknown. Expression analysis using the TNMplot web tool, TCGA data sets, and immunohistochemistry analysis using a tumor tissue array showed that LIPA is highly expressed in OCa tissues, compared to normal tissues. ERX-41 treatment significantly reduced the cell viability and colony formation ability and promoted the apoptosis of OCa cells. Mechanistic studies revealed a robust and consistent induction of ERS markers, including CHOP, elF2α, PERK, and ATF4, upon ERX-41 treatment. In xenograft and PDX studies, ERX-41 treatment resulted in a significant reduction in tumor growth. Collectively, our results suggest that ERX-41 is a novel therapeutic agent that targets the LIPA with a unique mechanism of ERS induction, which could be exploited to treat heterogeneity in OCa.
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Affiliation(s)
- Alexia B. Collier
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (A.B.C.); (S.V.); (R.G.); (X.Y.); (B.E.); (U.P.P.); (M.M.); (W.C.A.); (A.B.); (G.R.S.); (P.T.V.); (E.R.K.)
| | - Suryavathi Viswanadhapalli
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (A.B.C.); (S.V.); (R.G.); (X.Y.); (B.E.); (U.P.P.); (M.M.); (W.C.A.); (A.B.); (G.R.S.); (P.T.V.); (E.R.K.)
- Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Rahul Gopalam
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (A.B.C.); (S.V.); (R.G.); (X.Y.); (B.E.); (U.P.P.); (M.M.); (W.C.A.); (A.B.); (G.R.S.); (P.T.V.); (E.R.K.)
| | - Tae-Kyung Lee
- Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX 75080, USA; (T.-K.L.); (K.K.); (C.-Y.C.); (S.T.E.); (J.-M.A.)
| | - Kara Kassees
- Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX 75080, USA; (T.-K.L.); (K.K.); (C.-Y.C.); (S.T.E.); (J.-M.A.)
| | - Karla Parra
- Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; (K.P.); (G.S.); (T.C.R.); (X.L.)
| | - Gaurav Sharma
- Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; (K.P.); (G.S.); (T.C.R.); (X.L.)
| | - Tanner C. Reese
- Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; (K.P.); (G.S.); (T.C.R.); (X.L.)
| | - Xihui Liu
- Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; (K.P.); (G.S.); (T.C.R.); (X.L.)
| | - Xue Yang
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (A.B.C.); (S.V.); (R.G.); (X.Y.); (B.E.); (U.P.P.); (M.M.); (W.C.A.); (A.B.); (G.R.S.); (P.T.V.); (E.R.K.)
| | - Behnam Ebrahimi
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (A.B.C.); (S.V.); (R.G.); (X.Y.); (B.E.); (U.P.P.); (M.M.); (W.C.A.); (A.B.); (G.R.S.); (P.T.V.); (E.R.K.)
| | - Uday P. Pratap
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (A.B.C.); (S.V.); (R.G.); (X.Y.); (B.E.); (U.P.P.); (M.M.); (W.C.A.); (A.B.); (G.R.S.); (P.T.V.); (E.R.K.)
| | - Megharani Mahajan
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (A.B.C.); (S.V.); (R.G.); (X.Y.); (B.E.); (U.P.P.); (M.M.); (W.C.A.); (A.B.); (G.R.S.); (P.T.V.); (E.R.K.)
| | - William C. Arnold
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (A.B.C.); (S.V.); (R.G.); (X.Y.); (B.E.); (U.P.P.); (M.M.); (W.C.A.); (A.B.); (G.R.S.); (P.T.V.); (E.R.K.)
| | - Adriana Baker
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (A.B.C.); (S.V.); (R.G.); (X.Y.); (B.E.); (U.P.P.); (M.M.); (W.C.A.); (A.B.); (G.R.S.); (P.T.V.); (E.R.K.)
| | - Chia-Yuan Chen
- Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX 75080, USA; (T.-K.L.); (K.K.); (C.-Y.C.); (S.T.E.); (J.-M.A.)
| | - Scott Terry Elmore
- Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX 75080, USA; (T.-K.L.); (K.K.); (C.-Y.C.); (S.T.E.); (J.-M.A.)
| | - Panneerdoss Subbarayalu
- Greehey Children’s Cancer Research Institute, Department of Cell Systems & Anatomy, University of Texas Health San Antonio, San Antonio, TX 78229, USA;
| | - Gangadhara R. Sareddy
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (A.B.C.); (S.V.); (R.G.); (X.Y.); (B.E.); (U.P.P.); (M.M.); (W.C.A.); (A.B.); (G.R.S.); (P.T.V.); (E.R.K.)
- Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Philip T. Valente
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (A.B.C.); (S.V.); (R.G.); (X.Y.); (B.E.); (U.P.P.); (M.M.); (W.C.A.); (A.B.); (G.R.S.); (P.T.V.); (E.R.K.)
| | - Edward R. Kost
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (A.B.C.); (S.V.); (R.G.); (X.Y.); (B.E.); (U.P.P.); (M.M.); (W.C.A.); (A.B.); (G.R.S.); (P.T.V.); (E.R.K.)
| | - Jung-Mo Ahn
- Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX 75080, USA; (T.-K.L.); (K.K.); (C.-Y.C.); (S.T.E.); (J.-M.A.)
| | - Ratna K. Vadlamudi
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (A.B.C.); (S.V.); (R.G.); (X.Y.); (B.E.); (U.P.P.); (M.M.); (W.C.A.); (A.B.); (G.R.S.); (P.T.V.); (E.R.K.)
- Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX 78229, USA
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Fang Y, Xiao X, Wang J, Dasari S, Pepin D, Nephew KP, Zamarin D, Mitra AK. Cancer associated fibroblasts serve as an ovarian cancer stem cell niche through noncanonical Wnt5a signaling. NPJ Precis Oncol 2024; 8:7. [PMID: 38191909 PMCID: PMC10774407 DOI: 10.1038/s41698-023-00495-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 12/05/2023] [Indexed: 01/10/2024] Open
Abstract
Frequent relapse and chemoresistance cause poor outcome in ovarian cancer (OC) and cancer stem cells (CSCs) are important contributors. While most studies focus exclusively on CSCs, the role of the microenvironment in providing optimal conditions to maintain their tumor-initiating potential remains poorly understood. Cancer associated fibroblasts (CAFs) are a major constituent of the OC tumor microenvironment and we show that CAFs and CSCs are enriched following chemotherapy in patient tumors. CAFs significantly increase OC cell resistance to carboplatin. Using heterotypic CAF-OC cocultures and in vivo limiting dilution assay, we confirm that the CAFs act by enriching the CSC population. CAFs increase the symmetric division of CSCs as well as the dedifferentiation of bulk OC cells into CSCs. The effect of CAFs is limited to OC cells in their immediate neighborhood, which can be prevented by inhibiting Wnt. Analysis of single cell RNA-seq data from OC patients reveal Wnt5a as the highest expressed Wnt in CAFs and that certain subpopulations of CAFs express higher levels of Wnt5a. Our findings demonstrate that Wnt5a from CAFs activate a noncanonical Wnt signaling pathway involving the ROR2/PKC/CREB1 axis in the neighboring CSCs. While canonical Wnt signaling is found to be predominant in interactions between cancer cells in patients, non-canonical Wnt pathway is activated by the CAF-OC crosstalk. Treatment with a Wnt5a inhibitor sensitizes tumors to carboplatin in vivo. Together, our results demonstrate a novel mechanism of CSC maintenance by signals from the microenvironmental CAFs, which can be targeted to treat OC chemoresistance and relapse.
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Affiliation(s)
- Yiming Fang
- Indiana University School of Medicine-Bloomington, Indiana University, Bloomington, IN, USA
- Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Xue Xiao
- Indiana University School of Medicine-Bloomington, Indiana University, Bloomington, IN, USA
- Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Ji Wang
- Indiana University School of Medicine-Bloomington, Indiana University, Bloomington, IN, USA
- Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Subramanyam Dasari
- Indiana University School of Medicine-Bloomington, Indiana University, Bloomington, IN, USA
- Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
| | - David Pepin
- Pediatric Surgical Research Laboratories, Massachusetts General Hospital; Department of Surgery, Harvard Medical School, Boston, MA, USA
| | - Kenneth P Nephew
- Indiana University School of Medicine-Bloomington, Indiana University, Bloomington, IN, USA
- Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Dmitriy Zamarin
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Anirban K Mitra
- Indiana University School of Medicine-Bloomington, Indiana University, Bloomington, IN, USA.
- Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
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48
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Li H, Lin R, Zhang Y, Zhu Y, Huang S, Lan J, Lu N, Xie C, He S, Zhang W. N6-methyladenosine-modified circPLPP4 sustains cisplatin resistance in ovarian cancer cells via PIK3R1 upregulation. Mol Cancer 2024; 23:5. [PMID: 38184597 PMCID: PMC10770956 DOI: 10.1186/s12943-023-01917-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 12/15/2023] [Indexed: 01/08/2024] Open
Abstract
BACKGROUND Cisplatin (CDDP) is the first-line chemotherapeutic strategy to treat patients with ovarian cancer (OC). The development of CDDP resistance remains an unsurmountable obstacle in OC treatment and frequently induces tumor recurrence. Circular RNAs (circRNAs) are noncoding RNAs with important functions in cancer progression. Whether circRNAs function in CDDP resistance of OC is unclear. METHODS Platinum-resistant circRNAs were screened via circRNA deep sequencing and examined using in situ hybridization (ISH) in OC. The role of circPLPP4 in CDDP resistance was assessed by clone formation and Annexin V assays in vitro, and by OC patient-derived xenografts and intraperitoneal tumor models in vivo. The mechanism underlying circPLPP4-mediated activation of miR-136/PIK3R1 signaling was examined by luciferase reporter assay, RNA pull-down, RIP, MeRIP and ISH. RESULTS circPLPP4 was remarkably upregulated in platinum resistant OC. circPLPP4 overexpression significantly enhanced, whereas circPLPP4 silencing reduced, OC cell chemoresistance. Mechanistically, circPLPP4 acts as a microRNA sponge to sequester miR-136, thus competitively upregulating PIK3R1 expression and conferring CDDP resistance. The increased circPLPP4 level in CDDP-resistant cells was caused by increased RNA stability, mediated by increased N6-methyladenosine (m6A) modification of circPLPP4. In vivo delivery of an antisense oligonucleotide targeting circPLPP4 significantly enhanced CDDP efficacy in a tumor model. CONCLUSIONS Our study reveals a plausible mechanism by which the m6A -induced circPLPP4/ miR-136/ PIK3R1 axis mediated CDDP resistance in OC, suggesting that circPLPP4 may serve as a promising therapeutic target against CDDP resistant OC. A circPLPP4-targeted drug in combination with CDDP might represent a rational regimen in OC.
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Affiliation(s)
- Han Li
- Department of Gynecology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Run Lin
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China
| | - Yanna Zhang
- Department of Gynecology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, China
| | - Yanni Zhu
- Department of Gynecology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Shuting Huang
- Department of Gynecology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Jing Lan
- Department of Gynecology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Nian Lu
- Department of Radiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, China
| | - Chuanmiao Xie
- Department of Radiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, China.
| | - Shanyang He
- Department of Gynecology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China.
| | - Weijing Zhang
- Department of Gynecology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, China.
- Department of Radiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, China.
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49
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Wang Y, Duval AJ, Adli M, Matei D. Biology-driven therapy advances in high-grade serous ovarian cancer. J Clin Invest 2024; 134:e174013. [PMID: 38165032 PMCID: PMC10760962 DOI: 10.1172/jci174013] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2024] Open
Abstract
Following a period of slow progress, the completion of genome sequencing and the paradigm shift relative to the cell of origin for high grade serous ovarian cancer (HGSOC) led to a new perspective on the biology and therapeutic solutions for this deadly cancer. Experimental models were revisited to address old questions, and improved tools were generated. Additional pathways emerging as drivers of ovarian tumorigenesis and key dependencies for therapeutic targeting, in particular, VEGF-driven angiogenesis and homologous recombination deficiency, were discovered. Molecular profiling of histological subtypes of ovarian cancer defined distinct genetic events for each entity, enabling the first attempts toward personalized treatment. Armed with this knowledge, HGSOC treatment was revised to include new agents. Among them, PARP inhibitors (PARPis) were shown to induce unprecedented improvement in clinical benefit for selected subsets of patients. Research on mechanisms of resistance to PARPis is beginning to discover vulnerabilities and point to new treatment possibilities. This Review highlights these advances, the remaining challenges, and unsolved problems in the field.
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Affiliation(s)
- Yinu Wang
- Department of Obstetrics and Gynecology and
| | - Alexander James Duval
- Department of Obstetrics and Gynecology and
- Driskill Graduate Program, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Mazhar Adli
- Department of Obstetrics and Gynecology and
- Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, USA
| | - Daniela Matei
- Department of Obstetrics and Gynecology and
- Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, USA
- Jesse Brown Veteran Affairs Medical Center, Chicago, Illinois, USA
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50
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Wu M, Xie J, Xing Y, Zhang L, Chen H, Tang B, Zhou M, Lv S, Huang D, Jian S, Zhou C, Liu M, Guo W, Chen Y, Yi Z. Selectively targeting BCL6 using a small molecule inhibitor is a potential therapeutic strategy for ovarian cancer. Int J Biol Sci 2024; 20:486-501. [PMID: 38169532 PMCID: PMC10758095 DOI: 10.7150/ijbs.86303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 11/15/2023] [Indexed: 01/05/2024] Open
Abstract
Ovarian cancer is one of the tumors with the highest fatality rate among gynecological tumors. The current 5-year survival rate of ovarian cancer is <35%. Therefore, more novel alternative strategies and drugs are needed to treat ovarian cancer. The transcription factor B-cell lymphoma 6 (BCL6) is critically associated with poor prognosis and cisplatin resistance in ovarian cancer treatment. Therefore, BCL6 may be an attractive therapeutic target for ovarian cancer. However, the role of targeting BCL6 in ovarian cancer remains elusive. Here, we developed a novel BCL6 small molecule inhibitor, WK369, which exhibits excellent anti-ovarian cancer bioactivity, induces cell cycle arrest and causes apoptosis. WK369 effectively inhibits the growth and metastasis of ovarian cancer without obvious toxicity in vitro and in vivo. meanwhile, WK369 can prolong the survival of ovarian cancer-bearing mice. It is worth noting that WK369 also has significant anti-tumor effects on cisplatin-resistant ovarian cancer cell lines. Mechanistic studies have shown that WK369 can directly bind to the BCL6-BTB domain and block the interaction between BCL6 and SMRT, leading to the reactivation of p53, ATR and CDKN1A. BCL6-AKT, BCL6-MEK/ERK crosstalk is suppressed. As a first attempt, our study demonstrates that targeting BCL6 may be an effective approach to treat ovarian cancer and that WK369 has the potential to be used as a candidate therapeutic agent for ovarian cancer.
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Affiliation(s)
- Min Wu
- East China Normal University, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, 500 Dong Chuan Rd, Shanghai 200241, China
| | - Jiuqing Xie
- East China Normal University, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, 500 Dong Chuan Rd, Shanghai 200241, China
| | - Yajing Xing
- East China Normal University, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, 500 Dong Chuan Rd, Shanghai 200241, China
| | - Lin Zhang
- East China Normal University, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, 500 Dong Chuan Rd, Shanghai 200241, China
| | - Huang Chen
- East China Normal University, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, 500 Dong Chuan Rd, Shanghai 200241, China
| | - Bin Tang
- Department of Gynecology, The Second People's Hospital of Wuhu, Wuhu, Anhui 241000, China
| | - Miaoran Zhou
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Shiyi Lv
- East China Normal University, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, 500 Dong Chuan Rd, Shanghai 200241, China
| | - Dongxia Huang
- East China Normal University, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, 500 Dong Chuan Rd, Shanghai 200241, China
| | - Shuyi Jian
- East China Normal University, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, 500 Dong Chuan Rd, Shanghai 200241, China
| | - Cili Zhou
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Mingyao Liu
- East China Normal University, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, 500 Dong Chuan Rd, Shanghai 200241, China
| | - Weikai Guo
- East China Normal University, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, 500 Dong Chuan Rd, Shanghai 200241, China
- The Jointed National Laboratory of Antibody Drug Engineering, Henan University, Kaifeng, 475004, China
| | - Yihua Chen
- East China Normal University, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, 500 Dong Chuan Rd, Shanghai 200241, China
| | - Zhengfang Yi
- East China Normal University, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, 500 Dong Chuan Rd, Shanghai 200241, China
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