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Ito Y, Sakumoto J, Hirabayashi H, Haruna S, Konno W, Nakajima I, Ishida K, Haruyama Y, Sairenchi T, Nishihara E, Fukata S, Hishinuma A, Kogai T. Assessing the potential of high-mobility group AT-hook 2 immunohistochemical staining as a prognostic marker of metastatic recurrence in follicular thyroid cancer: a retrospective cohort study. Endocr J 2025; 72:535-543. [PMID: 39971318 PMCID: PMC12086272 DOI: 10.1507/endocrj.ej24-0557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 01/05/2025] [Indexed: 02/21/2025] Open
Abstract
High-mobility group AT-hook 2 (HMGA2) is a nuclear protein involved in the differentiation and proliferation of epithelial-derived tumors and also considered to be involved in the growth and differentiation of various malignant tumors, including thyroid cancer. Immunohistochemistry (IHC) for HMGA2 has been reported to show diffuse positivity in several follicular thyroid carcinoma (FTC) cases. This study aimed to investigate whether positive immunohistochemical staining for HMGA2 in primary tumors can be used to predict the prognosis and detect prognostic factors in malignant thyroid tumors associated with metastatic recurrence in FTC. Formalin-fixed, paraffin-embedded (FFPE) resected specimens used for the IHC for HMGA2. The association of positive HMGA2 staining with metastasis and recurrence, along with the potential of HMGA2 as a prognostic marker of metastatic recurrence, was statistically determined. HMGA2 staining was positive in most malignant tissues, whereas benign tissues were unstained. HMGA2 staining of the marginal and invasive regions was observed in FTC tissues. The association of HMGA2 staining with metastasis and recurrence was significant (p = 0.018). Kaplan-Meier curves showed an association of negative HMGA2 staining with metastasis and disease-free survival (p = 0.090). Tumor size (>4 cm) and wide invasion were also significant factors (p = 0.043, p < 0.001). The risk ratio without HMGA2 was significantly reduced by 30% compared to that with HMGA2. In primary tumors, positive HMGA2 staining can be used to predict prognosis in malignant thyroid tumors associated with metastatic recurrence in FTC and negative HMGA2 staining may indicate longer disease-free survival after surgery.
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Affiliation(s)
- Yuka Ito
- Department of Genetic Diagnosis and Laboratory Medicine, Dokkyo Medical University, Tochigi 321-0293, Japan
| | - Junko Sakumoto
- Department of Genetic Diagnosis and Laboratory Medicine, Dokkyo Medical University, Tochigi 321-0293, Japan
| | - Hideki Hirabayashi
- Department of Otorhinolaryngology, Head and Neck Surgery, Dokkyo Medical University, Tochigi 321-0293, Japan
| | - Shinichi Haruna
- Department of Otorhinolaryngology, Head and Neck Surgery, Dokkyo Medical University, Tochigi 321-0293, Japan
| | - Wataru Konno
- Department of Otorhinolaryngology, Head and Neck Surgery, Dokkyo Medical University, Tochigi 321-0293, Japan
| | - Itsuo Nakajima
- Department of Otorhinolaryngology, Head and Neck Surgery, Dokkyo Medical University, Tochigi 321-0293, Japan
| | - Kazuyuki Ishida
- Department of Diagnostic Pathology, Dokkyo Medical University, Tochigi 321-0293, Japan
| | - Yasuo Haruyama
- Department of Public Health, Dokkyo Medical University, Tochigi 321-0293, Japan
| | - Toshimi Sairenchi
- Medical Science of Nursing, Dokkyo Medical University School of Nursing, Tochigi 321-0293, Japan
| | | | | | | | - Takahiko Kogai
- Department of Genetic Diagnosis and Laboratory Medicine, Dokkyo Medical University, Tochigi 321-0293, Japan
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Resar LMS, Luo LZ. High Mobility Group A1 Chromatin Keys: Unlocking the Genome During MPN Progression. Int J Mol Sci 2025; 26:2125. [PMID: 40076747 PMCID: PMC11899949 DOI: 10.3390/ijms26052125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 02/11/2025] [Accepted: 02/18/2025] [Indexed: 03/14/2025] Open
Abstract
Patients with chronic, indolent myeloproliferative neoplasms (MPNs) are at risk for transformation to highly lethal leukemia, although targetable mechanisms driving progression remain elusive. We discovered that the High Mobility Group A1 (HMGA1) gene is up-regulated with MPN progression in patients and required for evolution into myelofibrosis (MF) or acute myeloid leukemia (AML) in preclinical models. HMGA1 encodes the HMGA1 epigenetic regulators that modulate the chromatin state during embryogenesis and tissue regeneration. While HMGA1 is silenced in most differentiated cells, it becomes aberrantly re-expressed in JAK2 mutant (JAK2-V617F) MPN, with the highest levels after transformation to secondary MF or AML. Here, we review recent work highlighting HMGA1 function in MPN progression. Though underlying mechanisms continue to emerge, increasing evidence suggests that HMGA1 functions as a "chromatin key" required to "unlock" regions of the genome involved in clonal expansion and progression in MPN. Together, these findings illuminate HMGA1 as a driver of MPN progression and a promising therapeutic target.
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Affiliation(s)
- Linda M. S. Resar
- Departments of Medicine (Hematology), Oncology, Pathology and Institute for Cellular Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA;
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Zhang L, Xu YM, Bian MM, Yan HZ, Gao JX, Bao QH, Chen YQ, Ding SQ, Wang R, Zhang N, Hu JG, Lü HZ. Ezrin, a novel marker of ependymal cells, can be used to demonstrate their proliferation regulation after spinal cord injury in mice. Neurobiol Dis 2024; 203:106746. [PMID: 39603280 DOI: 10.1016/j.nbd.2024.106746] [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: 01/20/2024] [Revised: 11/01/2024] [Accepted: 11/21/2024] [Indexed: 11/29/2024] Open
Abstract
Ependymal cells (EpCs), as a potential stem cell niche, have gained interest for their potential in vivo stem cell therapy for spinal cord injury (SCI). Heterogeneity of spinal EpCs may contribute to differences in the ability of spinal EpCs to proliferate, differentiate and transition after injury, while there is limited understanding of the regulation of these events. Our research found that ezrin (Ezr) was expressed highly in EpCs of the spinal cord, and its upregulation rapidly occurred after injury (6 h). It remained consistently highly expressed in proliferating EpCs, this occurs before pathological accumulation of it occurs in other glial and immune-related cells. Differential expression of Ezr, Arg3, Pvalb, Ccnd1, and Gmpr characterized distinct responses of EpCs to injury activity. Also, we uncovered the dynamic regulatory behavior of immature EpCs after injury. In contrast to constitutive expression in parenchymal tissues, injury factors upregulated guanosine monophosphate reductase (Gmpr) in arrested EpCs, unveiling a distinctive mechanism to regulate proliferation in EpCs following spinal cord injury.
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Affiliation(s)
- Lin Zhang
- Clinical Laboratory, the First Affiliated Hospital of Bengbu Medical University, Anhui 233004, PR China; Anhui Key Laboratory of Tissue Transplantation, the First Affiliated Hospital of Bengbu Medical University, Anhui 233004, PR China; School of life Science, Bengbu Medical University, Anhui 233030, PR China
| | - Yao-Mei Xu
- Clinical Laboratory, the First Affiliated Hospital of Bengbu Medical University, Anhui 233004, PR China; Anhui Key Laboratory of Tissue Transplantation, the First Affiliated Hospital of Bengbu Medical University, Anhui 233004, PR China
| | - Ming-Ming Bian
- Clinical Laboratory, the First Affiliated Hospital of Bengbu Medical University, Anhui 233004, PR China; Anhui Key Laboratory of Tissue Transplantation, the First Affiliated Hospital of Bengbu Medical University, Anhui 233004, PR China
| | - Hua-Zheng Yan
- Clinical Laboratory, the First Affiliated Hospital of Bengbu Medical University, Anhui 233004, PR China; Anhui Key Laboratory of Tissue Transplantation, the First Affiliated Hospital of Bengbu Medical University, Anhui 233004, PR China
| | - Jian-Xiong Gao
- Clinical Laboratory, the First Affiliated Hospital of Bengbu Medical University, Anhui 233004, PR China; Anhui Key Laboratory of Tissue Transplantation, the First Affiliated Hospital of Bengbu Medical University, Anhui 233004, PR China
| | - Qian-Hui Bao
- Clinical Laboratory, the First Affiliated Hospital of Bengbu Medical University, Anhui 233004, PR China; Anhui Key Laboratory of Tissue Transplantation, the First Affiliated Hospital of Bengbu Medical University, Anhui 233004, PR China
| | - Yu-Qing Chen
- Clinical Laboratory, the First Affiliated Hospital of Bengbu Medical University, Anhui 233004, PR China; Anhui Key Laboratory of Tissue Transplantation, the First Affiliated Hospital of Bengbu Medical University, Anhui 233004, PR China
| | - Shu-Qin Ding
- Clinical Laboratory, the First Affiliated Hospital of Bengbu Medical University, Anhui 233004, PR China
| | - Rui Wang
- Anhui Key Laboratory of Tissue Transplantation, the First Affiliated Hospital of Bengbu Medical University, Anhui 233004, PR China
| | - Nan Zhang
- Anhui Key Laboratory of Tissue Transplantation, the First Affiliated Hospital of Bengbu Medical University, Anhui 233004, PR China
| | - Jian-Guo Hu
- Clinical Laboratory, the First Affiliated Hospital of Bengbu Medical University, Anhui 233004, PR China; Anhui Key Laboratory of Tissue Transplantation, the First Affiliated Hospital of Bengbu Medical University, Anhui 233004, PR China; Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-related Diseases,Bengbu Medical University, Anhui 233030, PR China
| | - He-Zuo Lü
- Clinical Laboratory, the First Affiliated Hospital of Bengbu Medical University, Anhui 233004, PR China; Anhui Key Laboratory of Tissue Transplantation, the First Affiliated Hospital of Bengbu Medical University, Anhui 233004, PR China; Anhui Province Key Laboratory of Immunology in Chronic Diseases,Bengbu Medical University, Anhui 233030, PR China; Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-related Diseases,Bengbu Medical University, Anhui 233030, PR China.
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Sun Q, Lei X, Yang X. CircRNAs as upstream regulators of miRNA//HMGA2 axis in human cancer. Pharmacol Ther 2024; 263:108711. [PMID: 39222752 DOI: 10.1016/j.pharmthera.2024.108711] [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: 05/22/2024] [Revised: 07/21/2024] [Accepted: 08/30/2024] [Indexed: 09/04/2024]
Abstract
High mobility group protein A2 (HMGA2) is widely recognized as a chromatin-binding protein, whose overexpression is observed in nearly all human cancers. It exerts its oncogenic effects by influencing various cellular processes such as the epithelial-mesenchymal transition, cell differentiation, and DNA damage repair. MicroRNA (miRNA) serves as a pivotal gene expression regulator, concurrently modulating multiple genes implicated in cancer progression, including HMGA2. It also serves as a significant biomarker for cancer. Circular RNA (circRNA) plays a crucial role in gene regulation primarily by sequestering miRNAs and impeding their ability to enhance the expression of other genes, including HMGA2. Increasingly, studies have underscored the vital role of miRNA/HMGA2 interactions in cancer. Given the significance of circRNA as an upstream regulatory mediator and the complexity of regulatory mechanisms, we hereby present a comprehensive overview of the pivotal role of circRNAs as upstream regulators of the miRNA//HMGA2 axis in human cancers. This insight may herald a novel direction for future cancer research.
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Affiliation(s)
- Qiqi Sun
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, Hunan 421001, China
| | - Xiaoyong Lei
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, Hunan 421001, China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, 28 Western Changsheng Road, Hengyang, Hunan 421001, China
| | - Xiaoyan Yang
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, Hunan 421001, China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, 28 Western Changsheng Road, Hengyang, Hunan 421001, China.
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Lim C, Seo D. Assessment of the carcinogenic potential of particulate matter generated from 3D printing devices in Balb/c 3T3-1-1 cells. Sci Rep 2024; 14:23981. [PMID: 39402095 PMCID: PMC11473660 DOI: 10.1038/s41598-024-75491-1] [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: 04/24/2024] [Accepted: 10/07/2024] [Indexed: 10/17/2024] Open
Abstract
Recently, there have been reports of sarcoma occurring in a Korean science teachers who used a 3D printer with acrylonitrile butadiene styrene (ABS) and polylactic acid (PLA) filaments for educational purposes. However, limited toxicological research data on 3D printing make it challenging to confirm a causal relationship between 3D printing and cancer. Therefore, occupational accidents involving teachers who have developed sarcoma have not been officially recognized. To address this gap, we aimed to evaluate the carcinogenic potential of particulate matter produced from ABS and PLA filaments commonly used in 3D printing. We created a generator mimicking 3D printing to generate particulate matter, which was used as an experimental material. The collected particulate matter was exposed to an in vitro system to investigate genetic damage, effects on cell transformation, and changes in carcinogenesis-related genes. Various assays, such as the comet assay, cell transformation assays, microarray analysis, and glucose consumption measurement, were employed. Cytotoxicity tests performed to determine the exposure concentration for the comet assay showed that cell viability was 83.6, 62.6, 42.0, and 10.2% for ABS at exposure concentrations of 50, 100, 200, and 400 µg/mL, respectively. PLA showed 91.7, 80.3, 65.1, and 60.8% viability at exposure concentrations of 50, 100, 200, and 400 µg/mL, respectively. Therefore, 50 µg/mL was set as the highest concentration for both ABS and PLA, and 25 and 12.5 µg/mL were set as the medium and low concentrations, respectively. The comet assay showed no changes in genetic damage caused by the particulate matter. Cytotoxicity results performed to establish exposure concentrations in the transformation assay showed that ABS showed cell viability of 88.0, 77.4, 84.7, and 85.5% at concentrations of 1.25, 2.5, 5, and 10 µg/mL, respectively, but few cells survived at concentrations above 20 µg/mL. PLA showed minimal cytotoxicity up to a concentration of 20 µg/ml. Therefore, in the cell transformation assay, a concentration of 10 µg/mL for ABS and 20 µg/mL for PLA was set as the highest exposure concentration, followed by medium and low exposure concentrations with a common ratio of 2. In cell transformation assays, only one transformed focus each was observed for both ABS and PLA particulate matter-exposed cells. The microarray assay revealed changes in gene expression, with a 41.7% change at 10 µg/mL for ABS and an 18.6% change at 20 µg/mL for PLA compared to the positive control group. Analysis of carcinogenesis-related gene expression changes on days 1, 7, and 25 of the promotion phase revealed that in cells exposed to 5 µg/mL of ABS, RBM3 gene expression increased by 3.66, 3.26, and 3.74 times, respectively, while MPP6 gene expression decreased by 0.33, 0.28, and 0.38 times, respectively, compared to the negative control group. Additionally, the measurement of glucose consumption showed that it increased in cells exposed to ABS and PLA particulate matter. Our findings suggest that the carcinogenic potential of ABS- and PLA-derived particulate matter in 3D printing cannot be completely ruled out. Therefore, further research in other test systems and analysis of additional parameters related to carcinogenesis, are deemed necessary to evaluate the carcinogenic risk of 3D printers using these materials.
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Affiliation(s)
- CheolHong Lim
- Inhalation Toxicity Research Center, Occupational Safety and Health Research Institute, Korea Occupational Safety and Health Agency, 30, Expro-ro 339 beon-gil, Yuseong-gu, Daejeon, Republic of Korea
| | - DongSeok Seo
- Inhalation Toxicity Research Center, Occupational Safety and Health Research Institute, Korea Occupational Safety and Health Agency, 30, Expro-ro 339 beon-gil, Yuseong-gu, Daejeon, Republic of Korea.
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Zhao S, Zhang Y, Bao S, Jiang L, Li Q, Kong Y, Cao J. A novel HMGA2/MPC-1/mTOR signaling pathway promotes cell growth via facilitating Cr (VI)-induced glycolysis. Chem Biol Interact 2024; 399:111141. [PMID: 38992767 DOI: 10.1016/j.cbi.2024.111141] [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: 03/15/2024] [Revised: 06/25/2024] [Accepted: 07/08/2024] [Indexed: 07/13/2024]
Abstract
Mitochondrial Pyruvate Carrier 1 (MPC1) is localized on mitochondrial outer membrane to mediate the transport of pyruvate from cytosol to mitochondria. It is also well known to act as a tumor suppressor. Hexavalent chromium (Cr (VI)) contamination poses a global challenge due to its high toxicity and carcinogenesis. This research was intended to probe the potential mechanism of MPC1 in the effect of Cr (VI)-induced carcinogenesis. First, Cr (VI)-treatments decreased the expression of MPC1 in vitro and in vivo. Overexpression of MPC1 inhibited Cr (VI)-induced glycolysis and migration in A549 cells. Then, high mobility group A2 (HMGA2) protein strongly suppressed the transcription of MPC1 by binding to its promoter, and HMGA2/MPC1 axis played an important role in oxidative phosphorylation (OXPHOS), glycolysis and cell migration. Furthermore, endoplasmic reticulum (ER) stress made a great effect on the interaction between HMGA2 and MPC1. Finally, the mammalian target of the rapamycin (mTOR) was determined to mediate MPC1-regulated OXPHOS, aerobic glycolysis and cell migration. Collectively, our data revealed a novel HMGA2/MPC-1/mTOR signaling pathway to promote cell growth via facilitating the metabolism reprogramming from OXPHOS to aerobic glycolysis, which might be a potential therapy for cancers.
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Affiliation(s)
- Siyang Zhao
- Department of Occupational and Environmental Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian, 116044, China; Institute of Plant Resources, Dalian Minzu University, No.18 Liaohe West Road, Dalian, 116600, China
| | - Yahui Zhang
- Department of Occupational and Environmental Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian, 116044, China
| | - Shibo Bao
- Department of Occupational and Environmental Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian, 116044, China
| | - Liping Jiang
- Department of Occupational and Environmental Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian, 116044, China
| | - Qiujuan Li
- Department of Occupational and Environmental Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian, 116044, China
| | - Ying Kong
- Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, 116044, China.
| | - Jun Cao
- Department of Occupational and Environmental Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian, 116044, China.
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Khazem F, Zetoune AB. Decoding high mobility group A2 protein expression regulation and implications in human cancers. Discov Oncol 2024; 15:322. [PMID: 39085703 PMCID: PMC11291832 DOI: 10.1007/s12672-024-01202-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 07/29/2024] [Indexed: 08/02/2024] Open
Abstract
High Mobility Group A2 (HMGA2) oncofetal proteins are a distinct category of Transcription Factors (TFs) known as "architectural factors" due to their lack of direct transcriptional activity. Instead, they modulate the three-dimensional structure of chromatin by binding to AT-rich regions in the minor grooves of DNA through their AT-hooks. This binding allows HMGA2 to interact with other proteins and different regions of DNA, thereby regulating the expression of numerous genes involved in carcinogenesis. Consequently, multiple mechanisms exist to finely control HMGA2 protein expression at various transcriptional levels, ensuring precise concentration adjustments to maintain cellular homeostasis. During embryonic development, HMGA2 protein is highly expressed but becomes absent in adult tissues. However, recent studies have revealed its re-elevation in various cancer types. Extensive research has demonstrated the involvement of HMGA2 protein in carcinogenesis at multiple levels. It intervenes in crucial processes such as cell cycle regulation, apoptosis, angiogenesis, epithelial-to-mesenchymal transition, cancer cell stemness, and DNA damage repair mechanisms, ultimately promoting cancer cell survival. This comprehensive review provides insights into the HMGA2 protein, spanning from the genetic regulation to functional protein behavior. It highlights the significant mechanisms governing HMGA2 gene expression and elucidates the molecular roles of HMGA2 in the carcinogenesis process.
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Affiliation(s)
- Farah Khazem
- Department of Biochemistry and Microbiology, Faculty of Pharmacy, Damascus University, Damascus, Syria.
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Liadi YM, Campbell T, Hwang BJ, Elliott B, Odero-Marah V. High Mobility Group AT-hook 2: A Biomarker Associated with Resistance to Enzalutamide in Prostate Cancer Cells. Cancers (Basel) 2024; 16:2631. [PMID: 39123360 PMCID: PMC11311100 DOI: 10.3390/cancers16152631] [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: 06/20/2024] [Revised: 07/18/2024] [Accepted: 07/22/2024] [Indexed: 08/12/2024] Open
Abstract
Metastatic prostate cancer (mPCa) is a leading cause of mortality, partly due to its resistance to anti-androgens like enzalutamide. Snail can promote this resistance by increasing full-length AR and AR-V7. High Mobility Group AT-hook 2 (HMGA2), a DNA-binding protein upstream of Snail, is crucial in proliferation and epithelial-mesenchymal transition (EMT). This study examines HMGA2's role in enzalutamide resistance. LNCaP and 22Rv1 cells overexpressing wild-type HMGA2, but not truncated HMGA2, showed EMT. Both variants led to a decreased sensitivity to enzalutamide but not alisertib compared to Neo control cells. The overexpression of HMGA2 did not alter AR expression. Enzalutamide-resistant C4-2B cells (C4-2B MDVR) had higher HMGA2 and AR/AR variant expression than enzalutamide-sensitive C4-2B cells but remained sensitive to alisertib. The HMGA2 knockdown in C4-2B MDVR cells increased sensitivity to both enzalutamide and alisertib without changing AR expression. A clinical analysis via cBioPortal revealed HMGA2 alterations in 3% and AR alterations in 59% of patients. The HMGA2 changes were linked to treatments like enzalutamide, abiraterone, or alisertib, with amplifications more prevalent in bone, lymph node, and liver metastases. Conclusively, HMGA2 is a potential biomarker for enzalutamide resistance in mPCa, independent of Snail and AR signaling, and alisertib may be an effective treatment for mPCa that expresses HMGA2.
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Affiliation(s)
- Yusuf Mansur Liadi
- Center for Urban Health Disparities Research and Innovation, Department of Biology, Morgan State University, Baltimore, MD 21251, USA; (Y.M.L.); (B.-J.H.); (B.E.)
- Department of Biology, Umaru Musa Yar’adua University, Katsina 820102, Nigeria
| | - Taaliah Campbell
- Center for Cancer Research and Therapeutic Development, Department of Biological Sciences, Clark Atlanta University, Atlanta, GA 30314, USA;
| | - Bor-Jang Hwang
- Center for Urban Health Disparities Research and Innovation, Department of Biology, Morgan State University, Baltimore, MD 21251, USA; (Y.M.L.); (B.-J.H.); (B.E.)
| | - Bethtrice Elliott
- Center for Urban Health Disparities Research and Innovation, Department of Biology, Morgan State University, Baltimore, MD 21251, USA; (Y.M.L.); (B.-J.H.); (B.E.)
| | - Valerie Odero-Marah
- Center for Urban Health Disparities Research and Innovation, Department of Biology, Morgan State University, Baltimore, MD 21251, USA; (Y.M.L.); (B.-J.H.); (B.E.)
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Ma D, Chen J, Shi Y, Gao H, Wei Z, Fan J, Wang L. Dysregulation of TCONS_00006091 contributes to the elevated risk of oral squamous cell carcinoma by upregulating SNAI1, IRS and HMGA2. Sci Rep 2024; 14:9616. [PMID: 38671227 PMCID: PMC11053020 DOI: 10.1038/s41598-024-60310-4] [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: 12/25/2023] [Accepted: 04/21/2024] [Indexed: 04/28/2024] Open
Abstract
In this study, we aimed to study the role of TCONS_00006091 in the pathogenesis of oral squamous cellular carcinoma (OSCC) transformed from oral lichen planus (OLP). This study recruited 108 OSCC patients which transformed from OLP as the OSCC group and 102 OLP patients with no sign of OSCC as the Control group. ROC curves were plotted to measure the diagnostic values of TCONS_00006091, miR-153, miR-370 and let-7g, and the changes in gene expressions were measured by RT-qPCR. Sequence analysis and luciferase assays were performed to analyze the molecular relationships among these genes. Cell proliferation and apoptosis were observed via MTT and FCM. TCONS_00006091 exhibited a better diagnosis value for OSCC transformed from OLP. OSCC group showed increased TCONS_00006091 expression and decreased expressions of miR-153, miR-370 and let-7g. The levels of SNAI1, IRS and HMGA2 was all significantly increased in OSCC patients. And TCONS_00006091 was found to sponge miR-153, miR-370 and let-7g, while these miRNAs were respectively found to targe SNAI1, IRS and HMGA2. The elevated TCONS_00006091 suppressed the expressions of miR-153, miR-370 and let-7g, leading to the increased expression of SNAI1, IRS and HMGA2. Also, promoted cell proliferation and suppressed apoptosis were observed upon the over-expression of TCONS_00006091. This study demonstrated that the expressions of miR-153, miR-370 and let-7g were down-regulated by the highly expressed TCONS_00006091 in OSCC patients, which accordingly up-regulated the expressions of SNAI1, IRS and HMGA2, resulting in the promoted cell proliferation and suppressed cell apoptosis.
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Affiliation(s)
- Danhua Ma
- Department of Stomatology, Ningbo No. 2 Hospital, No. 41 Northwest Street, Ningbo, 315010, Zhejiang, China
| | - Jijun Chen
- Department of Stomatology, Ningbo No. 2 Hospital, No. 41 Northwest Street, Ningbo, 315010, Zhejiang, China
| | - Yuyuan Shi
- Department of Stomatology, Ningbo No. 2 Hospital, No. 41 Northwest Street, Ningbo, 315010, Zhejiang, China
| | - Hongyan Gao
- Department of Stomatology, Ningbo No. 2 Hospital, No. 41 Northwest Street, Ningbo, 315010, Zhejiang, China
| | - Zhen Wei
- Department of Stomatology, Ningbo No. 2 Hospital, No. 41 Northwest Street, Ningbo, 315010, Zhejiang, China
| | - Jiayan Fan
- Department of Stomatology, Ningbo No. 2 Hospital, No. 41 Northwest Street, Ningbo, 315010, Zhejiang, China
| | - Liang Wang
- Department of Stomatology, Ningbo No. 2 Hospital, No. 41 Northwest Street, Ningbo, 315010, Zhejiang, China.
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Luo Z, Zheng Q, Ye S, Li Y, Chen J, Fan C, Chen J, Lei Y, Liao Q, Xi Y. HMGA2 alleviates ferroptosis by promoting GPX4 expression in pancreatic cancer cells. Cell Death Dis 2024; 15:220. [PMID: 38493165 PMCID: PMC10944463 DOI: 10.1038/s41419-024-06592-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 03/02/2024] [Accepted: 03/05/2024] [Indexed: 03/18/2024]
Abstract
Pancreatic cancer is one of the most malignant tumor types and is characterized by high metastasis ability and a low survival rate. As a chromatin-binding protein, HMGA2 is widely overexpressed and considered an oncogene with various undefined regulatory mechanisms. Herein, we demonstrated that HMGA2 is highly expressed in pancreatic cancer tissues, mainly distributed in epithelial cells, and represents a subtype of high epithelial-mesenchymal transition. Deletion of HMGA2 inhibits tumor malignancy through cell proliferation, metastasis, and xenograft tumor growth in vivo. Moreover, HMGA2 enhanced the cellular redox status by inhibiting reactive oxygen species and promoting glutathione production. Importantly, ferroptotic cell death was significantly ameliorated in cells overexpressing HMGA2. Conversely, HMGA2 deletion exacerbated ferroptosis. Mechanistically, HMGA2 activated GPX4 expression through transcriptional and translational regulation. HMGA2 binds and promotes cis-element modification in the promoter region of the GPX4 gene by enhancing enhancer activity through increased H3K4 methylation and H3K27 acetylation. Furthermore, HMGA2 stimulated GPX4 protein synthesis via the mTORC1-4EBP1 and -S6K signaling axes. The overexpression of HMGA2 alleviated the decrease in GPX4 protein levels resulting from the pharmacologic inhibition of mTORC1. Conversely, compared with the control, HMGA2 deletion more strongly reduced the phosphorylation of 4EBP1 and S6K. A strong positive correlation between HMGA2 and GPX4 expression was confirmed using immunohistochemical staining. We also demonstrated that HMGA2 mitigated the sensitivity of cancer cells to combination treatment with a ferroptosis inducer and mTORC1 inhibition or gemcitabine. In summary, our results revealed a regulatory mechanism by which HMGA2 coordinates GPX4 expression and underscores the potential value of targeting HMGA2 in cancer treatment.
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Affiliation(s)
- Ziyang Luo
- Department of Biochemistry and Molecular Biology and Zhejiang Key Laboratory of Pathophysiology, School of Basic Medical Sciences, Health Science Center, Ningbo University, Ningbo, 315211, China
| | - Qingfang Zheng
- Department of Biochemistry and Molecular Biology and Zhejiang Key Laboratory of Pathophysiology, School of Basic Medical Sciences, Health Science Center, Ningbo University, Ningbo, 315211, China
| | - Shazhou Ye
- Department of Biochemistry and Molecular Biology and Zhejiang Key Laboratory of Pathophysiology, School of Basic Medical Sciences, Health Science Center, Ningbo University, Ningbo, 315211, China
| | - Yanguo Li
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, 315211, China
| | - Jiayi Chen
- Department of Biochemistry and Molecular Biology and Zhejiang Key Laboratory of Pathophysiology, School of Basic Medical Sciences, Health Science Center, Ningbo University, Ningbo, 315211, China
| | - Chengjiang Fan
- Department of Biochemistry and Molecular Biology and Zhejiang Key Laboratory of Pathophysiology, School of Basic Medical Sciences, Health Science Center, Ningbo University, Ningbo, 315211, China
| | - Jianing Chen
- Department of Biochemistry and Molecular Biology and Zhejiang Key Laboratory of Pathophysiology, School of Basic Medical Sciences, Health Science Center, Ningbo University, Ningbo, 315211, China
| | - Yuxin Lei
- Department of Biochemistry and Molecular Biology and Zhejiang Key Laboratory of Pathophysiology, School of Basic Medical Sciences, Health Science Center, Ningbo University, Ningbo, 315211, China
| | - Qi Liao
- Department of Biochemistry and Molecular Biology and Zhejiang Key Laboratory of Pathophysiology, School of Basic Medical Sciences, Health Science Center, Ningbo University, Ningbo, 315211, China.
| | - Yang Xi
- Department of Biochemistry and Molecular Biology and Zhejiang Key Laboratory of Pathophysiology, School of Basic Medical Sciences, Health Science Center, Ningbo University, Ningbo, 315211, China.
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11
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Ma Q, Ye S, Liu H, Zhao Y, Mao Y, Zhang W. HMGA2 promotes cancer metastasis by regulating epithelial-mesenchymal transition. Front Oncol 2024; 14:1320887. [PMID: 38361784 PMCID: PMC10867147 DOI: 10.3389/fonc.2024.1320887] [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: 10/13/2023] [Accepted: 01/09/2024] [Indexed: 02/17/2024] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a complex physiological process that transforms polarized epithelial cells into moving mesenchymal cells. Dysfunction of EMT promotes the invasion and metastasis of cancer. The architectural transcription factor high mobility group AT-hook 2 (HMGA2) is highly overexpressed in various types of cancer (e.g., colorectal cancer, liver cancer, breast cancer, uterine leiomyomas) and significantly correlated with poor survival rates. Evidence indicated that HMGA2 overexpression markedly decreased the expression of epithelial marker E-cadherin (CDH1) and increased that of vimentin (VIM), Snail, N-cadherin (CDH2), and zinc finger E-box binding homeobox 1 (ZEB1) by targeting the transforming growth factor beta/SMAD (TGFβ/SMAD), mitogen-activated protein kinase (MAPK), and WNT/beta-catenin (WNT/β-catenin) signaling pathways. Furthermore, a new class of non-coding RNAs (miRNAs, circular RNAs, and long non-coding RNAs) plays an essential role in the process of HMGA2-induced metastasis and invasion of cancer by accelerating the EMT process. In this review, we discuss alterations in the expression of HMGA2 in various types of cancer. Furthermore, we highlight the role of HMGA2-induced EMT in promoting tumor growth, migration, and invasion. More importantly, we discuss extensively the mechanism through which HMGA2 regulates the EMT process and invasion in most cancers, including signaling pathways and the interacting RNA signaling axis. Thus, the elucidation of molecular mechanisms that underlie the effects of HMGA2 on cancer invasion and patient survival by mediating EMT may offer new therapeutic methods for preventing cancer progression.
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Affiliation(s)
- Qing Ma
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
| | - Sisi Ye
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
| | - Hong Liu
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
| | - Yu Zhao
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
| | - Yan Mao
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
| | - Wei Zhang
- Emergency Department of West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
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12
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Ouyang X, Li K, Wang J, Zhu W, Yi Q, Zhong J. HMGA2 promotes nasopharyngeal carcinoma progression and is associated with tumor resistance and poor prognosis. Front Oncol 2024; 13:1271080. [PMID: 38304037 PMCID: PMC10830841 DOI: 10.3389/fonc.2023.1271080] [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: 08/01/2023] [Accepted: 12/27/2023] [Indexed: 02/03/2024] Open
Abstract
Nasopharyngeal carcinoma (NPC), as one of the most prevalent malignancies in the head and neck region, still lacks a complete understanding of its pathogenesis. Presently, radiotherapy, concurrent chemoradiotherapy, and targeted therapy stand as the primary modalities for treating NPC. With advancements in medicine, the cure rates for nasopharyngeal carcinoma have been steadily increasing. Nevertheless, recurrence and metastasis persist as the primary reasons for treatment failure. Consequently, a profound exploration of the molecular mechanisms underlying the occurrence and progression of nasopharyngeal carcinoma, along with the exploration of corresponding therapeutic approaches, becomes particularly imperative in the quest for comprehensive solutions to combat this disease. High mobility group AT-hook 2 (HMGA2) is a pivotal protein capable of altering chromatin structure, regulating gene expression, and influencing transcriptional activity. In the realm of cancer research, HMGA2 exhibits widespread dysregulation, playing a crucial role in nearly all malignant tumors. It is implicated in various tumorigenic processes, including cell cycle regulation, cell proliferation, epithelial-mesenchymal transition, angiogenesis, tumor invasion, metastasis, and drug resistance. Additionally, HMGA2 serves as a molecular marker and an independent prognostic factor in certain malignancies. Recent studies have increasingly unveiled the critical role of HMGA2 in nasopharyngeal carcinoma (NPC), particularly in promoting malignant progression, correlating with tumor resistance, and serving as an independent adverse prognostic factor. This review focuses on elucidating the oncogenic role of HMGA2 in NPC, suggesting its potential association with chemotherapy resistance in NPC, and proposing its candidacy as an independent factor in nasopharyngeal carcinoma prognosis assessment.
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Affiliation(s)
| | - Kangxin Li
- Gannan Medical University, Ganzhou, Jiangxi, China
| | - Jiaqi Wang
- Gannan Medical University, Ganzhou, Jiangxi, China
| | - Weijian Zhu
- Gannan Medical University, Ganzhou, Jiangxi, China
| | - Qiang Yi
- Gannan Medical University, Ganzhou, Jiangxi, China
| | - Jinghua Zhong
- Department of Oncology, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
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13
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Maharati A, Tolue Ghasaban F, Akhlaghipour I, Taghehchian N, Zangouei AS, Moghbeli M. MicroRNA-495: a therapeutic and diagnostic tumor marker. J Mol Histol 2023; 54:559-578. [PMID: 37759132 DOI: 10.1007/s10735-023-10159-0] [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: 10/11/2022] [Accepted: 09/18/2023] [Indexed: 09/29/2023]
Abstract
Therapeutic and diagnostic progresses have significantly reduced the mortality rate among cancer patients during the last decade. However, there is still a high rate of mortality among cancer patients. One of the important reasons involved in the high mortality rate is the late diagnosis in advanced tumor stages that causes the failure of therapeutic strategies in these patients. Therefore, investigating the molecular mechanisms involved in tumor progression has an important role in introducing the efficient early detection markers. MicroRNAs (miRNAs) as stable factors in body fluids are always considered as non-invasive diagnostic and prognostic markers. In the present review, we investigated the role of miR-495 in tumor progression. It has been reported that miR-495 has mainly a tumor suppressor function through the regulation of transcription factors and tyrosine kinases as well as cellular processes such as multidrug resistance, chromatin remodeling, and signaling pathways. This review can be an effective step towards introducing the miR-495 as a non-invasive diagnostic/prognostic marker as well as a suitable target in tumor therapy.
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Affiliation(s)
- Amirhosein Maharati
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Faezeh Tolue Ghasaban
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Iman Akhlaghipour
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Negin Taghehchian
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Sadra Zangouei
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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14
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Wang J, Wong CH, Zhu Y, Yao X, Ng KKC, Zhou C, To KF, Chen Y. Identification of GRIN2D as a novel therapeutic target in pancreatic ductal adenocarcinoma. Biomark Res 2023; 11:74. [PMID: 37553583 PMCID: PMC10410818 DOI: 10.1186/s40364-023-00514-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Accepted: 07/26/2023] [Indexed: 08/10/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a dismal prognosis, and despite significant advances in our understanding of its genetic drivers, like KRAS, TP53, CDKN2A, and SMAD4, effective therapies remain limited. Here, we identified a new therapeutic target GRIN2D and then explored its functions and mechanisms in PDAC progression. METHODS We performed a genome-wide RNAi screen in a PDAC xenograft model and identified GRIN2D, which encodes the GluN2D subunit of N-methyl-D-aspartate receptors (NMDARs), as a potential oncogene. Western blot, immunohistochemistry, and analysis on Gene Expression Omnibus were used for detecting the expression of GRIN2D in PDAC. Cellular experiments were conducted for exploring the functions of GRIN2D in vitro while subcutaneous and orthotopic injections were used in in vivo study. To clarify the mechanism, we used RNA sequencing and cellular experiments to identify the related signaling pathway. Cellular assays, RT-qPCR, and western blot helped identify the impacts of the NMDAR antagonist memantine. RESULTS We demonstrated that GRIN2D was highly expressed in PDAC cells, and further promoted oncogenic functions. Mechanistically, transcriptome profiling identified GRIN2D-regulated genes in PDAC cells. We found that GRIN2D promoted PDAC progression by activating the p38 MAPK signaling pathway and transcription factor CREB, which in turn promoted the expression of HMGA2 and IL20RB. The upregulated GRIN2D could effectively promote tumor growth and liver metastasis in PDAC. We also investigated the therapeutic potential of NMDAR antagonism in PDAC and found that memantine reduced the expression of GRIN2D and inhibited PDAC progression. CONCLUSION Our results suggested that NMDA receptor GRIN2D plays important oncogenic roles in PDAC and represents a novel therapeutic target.
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Affiliation(s)
- Jiatong Wang
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin NT, Hong Kong
| | - Chi Hin Wong
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin NT, Hong Kong
| | - Yinxin Zhu
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin NT, Hong Kong
| | - Xiaoqiang Yao
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin NT, Hong Kong
| | - Kelvin K C Ng
- Department of Surgery, The Chinese University of Hong Kong, Shatin NT, Hong Kong
| | - Chengzhi Zhou
- State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Yangchao Chen
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin NT, Hong Kong.
- Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
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15
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Zhu C, Liu P, Li C, Zhang Y, Yin J, Hou L, Zheng G, Liu X. Near-Death Cells Cause Chemotherapy-Induced Metastasis via ATF4-Mediated NF-κB Signaling Activation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2205835. [PMID: 36739602 PMCID: PMC10074103 DOI: 10.1002/advs.202205835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 01/11/2023] [Indexed: 06/18/2023]
Abstract
Cytotoxic chemotherapy is a primary treatment modality for many patients with advanced cancer. Increasing preclinical and clinical observations indicate that chemotherapy can exacerbate tumor metastasis. However, the underlying mechanism remains unclear. Here, it is attempted to identify the mechanisms underlying chemotherapy-induced cancer recurrence and metastasis. It is revealed that a small subpopulation of "near-death cells" (NDCs) with compromised plasma membranes can reverse the death process to enhance survival and repopulation after exposure to lethal doses of cytotoxins. Moreover, these NDCs acquire enhanced tumorigenic and metastatic capabilities, but maintain chemosensitivity in multiple models. Mechanistically, cytotoxin exposure induces activating transcription factor 4 (ATF4)-dependent nonclassical NF-κB signaling activation; ultimately, this results in nuclear translocation of p52 and RelB in NDCs. Deletion of ATF4 in parental cancer cells significantly reduces colony formation and metastasis of NDCs, whereas overexpression of ATF4 activates the nonclassical NF-κB signaling pathway to promote chemotherapy-induced metastasis of NDCs. Overall, these results provide novel mechanistic insights into the chemotherapy-induced metastasis and indicate the pivotal role of NDCs in mediating tumor relapse after cytotoxic therapy. This study also suggests that targeting ATF4 may be an effective approach in improving the efficacy of chemotherapy.
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Affiliation(s)
- Chenchen Zhu
- Department of BiochemistrySchool of MedicineShenzhen Campus of Sun Yat‐sen UniversityShenzhenGuangdong510275China
| | - Pei Liu
- Department of BiochemistrySchool of MedicineShenzhen Campus of Sun Yat‐sen UniversityShenzhenGuangdong510275China
| | - Chuan‐Yuan Li
- Department of DermatologyDuke University Medical CenterDurhamNC27710USA
| | - Yuli Zhang
- Department of BiochemistrySchool of MedicineShenzhen Campus of Sun Yat‐sen UniversityShenzhenGuangdong510275China
| | - Jiang Yin
- Cancer Research Institute and Cancer HospitalGuangzhou Medical UniversityGuangzhouGuangdong510180China
| | - Linlin Hou
- Department of BiochemistrySchool of MedicineShenzhen Campus of Sun Yat‐sen UniversityShenzhenGuangdong510275China
| | - Guopei Zheng
- Cancer Research Institute and Cancer HospitalGuangzhou Medical UniversityGuangzhouGuangdong510180China
| | - Xinjian Liu
- Department of BiochemistrySchool of MedicineShenzhen Campus of Sun Yat‐sen UniversityShenzhenGuangdong510275China
- Bebetter Med Inc.GuangzhouGuangdong510525China
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Xun M, Zhang J, Wu M, Chen Y. Long non-coding RNAs: The growth controller of vascular smooth muscle cells in cardiovascular diseases. Int J Biochem Cell Biol 2023; 157:106392. [PMID: 36828237 DOI: 10.1016/j.biocel.2023.106392] [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: 10/05/2022] [Revised: 02/13/2023] [Accepted: 02/19/2023] [Indexed: 02/25/2023]
Abstract
The active proliferation and migration of vascular smooth muscle cells supports the healing of vessel damage while their abnormal aggression or destitution contribute to the aberrant intima-medial structure and function in various cardiovascular diseases, so the understanding of the proliferation disorders of vascular smooth muscle cell and the related mechanism is the basis of effective intervention and control for cardiovascular diseases. Recently, long non-coding RNAs have stood out as upstream switchers for multiple proliferative signaling pathways and molecules, and many of them have been shown to conduce to the dysregulated proliferation and apoptosis of vascular smooth muscle cells under various pathogenic stimuli. This article discusses the long non-coding RNAs disclosed and linked to atherosclerosis, pulmonary hypertension, and aneurysms, and focuses upon their modulation of vascular smooth muscle cell population affecting three deadly cardiovascular diseases.
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Affiliation(s)
- Min Xun
- Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, University of South China, Hengyang 421001, China
| | - Jie Zhang
- Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, University of South China, Hengyang 421001, China
| | - Meichun Wu
- Hengyang Medical School, University of South China, Hengyang 421001, China; School of Nursing, University of South China, Hengyang 421001, China
| | - Yuping Chen
- Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, University of South China, Hengyang 421001, China; Hengyang Medical School, University of South China, Hengyang 421001, China.
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17
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The Role of Proteomics and Phosphoproteomics in the Discovery of Therapeutic Targets and Biomarkers in Acquired EGFR-TKI-Resistant Non-Small Cell Lung Cancer. Int J Mol Sci 2023; 24:ijms24054827. [PMID: 36902280 PMCID: PMC10003401 DOI: 10.3390/ijms24054827] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 02/25/2023] [Accepted: 02/26/2023] [Indexed: 03/06/2023] Open
Abstract
The discovery of potent EGFR-tyrosine kinase inhibitors (EGFR-TKIs) has revolutionized the treatment of EGFR-mutated lung cancer. Despite the fact that EGFR-TKIs have yielded several significant benefits for lung cancer patients, the emergence of resistance to EGFR-TKIs has been a substantial impediment to improving treatment outcomes. Understanding the molecular mechanisms underlying resistance is crucial for the development of new treatments and biomarkers for disease progression. Together with the advancement in proteome and phosphoproteome analysis, a diverse set of key signaling pathways have been successfully identified that provide insight for the discovery of possible therapeutically targeted proteins. In this review, we highlight the proteome and phosphoproteomic analyses of non-small cell lung cancer (NSCLC) as well as the proteome analysis of biofluid specimens that associate with acquired resistance in response to different generations of EGFR-TKI. Furthermore, we present an overview of the targeted proteins and potential drugs that have been tested in clinical studies and discuss the challenges of implementing this discovery in future NSCLC treatment.
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18
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Gaudreau-Lapierre A, Klonisch T, Nicolas H, Thanasupawat T, Trinkle-Mulcahy L, Hombach-Klonisch S. Nuclear High Mobility Group A2 (HMGA2) Interactome Revealed by Biotin Proximity Labeling. Int J Mol Sci 2023; 24:ijms24044246. [PMID: 36835656 PMCID: PMC9966875 DOI: 10.3390/ijms24044246] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/10/2023] [Accepted: 02/13/2023] [Indexed: 02/23/2023] Open
Abstract
The non-histone chromatin binding protein High Mobility Group AT-hook protein 2 (HMGA2) has important functions in chromatin remodeling, and genome maintenance and protection. Expression of HMGA2 is highest in embryonic stem cells, declines during cell differentiation and cell aging, but it is re-expressed in some cancers, where high HMGA2 expression frequently coincides with a poor prognosis. The nuclear functions of HMGA2 cannot be explained by binding to chromatin alone but involve complex interactions with other proteins that are incompletely understood. The present study used biotin proximity labeling, followed by proteomic analysis, to identify the nuclear interaction partners of HMGA2. We tested two different biotin ligase HMGA2 constructs (BioID2 and miniTurbo) with similar results, and identified known and new HMGA2 interaction partners, with functionalities mainly in chromatin biology. These HMGA2 biotin ligase fusion constructs offer exciting new possibilities for interactome discovery research, enabling the monitoring of nuclear HMGA2 interactomes during drug treatments.
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Affiliation(s)
- Antoine Gaudreau-Lapierre
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| | - Thomas Klonisch
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, College of Medicine, University of Manitoba, CancerCare Manitoba, Winnipeg, MB R3T 2N2, Canada
- Department of Pathology, Rady Faculty of Health Sciences, College of Medicine, University of Manitoba, CancerCare Manitoba, Winnipeg, MB R3T 2N2, Canada
- Department of Medical Microbiology & Infectious Diseases, Rady Faculty of Health Sciences, College of Medicine, University of Manitoba, CancerCare Manitoba, Winnipeg, MB R3T 2N2, Canada
- Research Institute in Oncology and Hematology (RIOH), CancerCare Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Hannah Nicolas
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| | - Thatchawan Thanasupawat
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, College of Medicine, University of Manitoba, CancerCare Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Laura Trinkle-Mulcahy
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| | - Sabine Hombach-Klonisch
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, College of Medicine, University of Manitoba, CancerCare Manitoba, Winnipeg, MB R3T 2N2, Canada
- Department of Pathology, Rady Faculty of Health Sciences, College of Medicine, University of Manitoba, CancerCare Manitoba, Winnipeg, MB R3T 2N2, Canada
- Correspondence: ; Tel.: +1-204-789-3982; Fax: +1-204-789-3920
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Rastad H, Samimisedeh P, Alan MS, Afshar EJ, Ghalami J, Hashemnejad M, Alan MS. The role of lncRNA CERS6-AS1 in cancer and its molecular mechanisms: A systematic review and meta-analysis. Pathol Res Pract 2023; 241:154245. [PMID: 36580796 DOI: 10.1016/j.prp.2022.154245] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 11/23/2022] [Accepted: 11/24/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND LncRNAs have the potential to play a regulatory role in different processes of cancer development and progression. We conducted a systematic review and meta-analysis of evidence on the clinical significance and prognostic value of lncRNA CERS6-AS1 in cancer. METHODS This systematic review was conducted following PRISMA guidelines. Medline and Embase databases were searched using the relevant key terms covering lncRNA CERS6-AS1 and cancer. We pooled the estimated effect sizes and their 95 % confidence interval (CI) using random-effects models in STATA 16.0 (StataCorp, College Station, TX, USA). RESULTS Eleven articles on pancreatic, colorectal, gastric, papillary thyroid, breast, and hepatocellular cancers fulfilled our eligibility criteria. Studies consistently found that lncRNA CERS6-AS1 expression is upregulated in all assessed cancers. Based on our meta-analysis, its aberrant expression was directly associated with unfavorable clinical outcomes, including higher stage (pooled Odds ratios (95 % CI): 3.15 (2.01-4.93; I2 = 0.0 %), tumor size (1.97 (1.27-3.05; I2 = 37.8 %), lymph node metastasis (6.48 (4.01-10.45; I2 = 0.40 %), and poor survival (Pooled log-rank test P-value < 0.001) in patients. Regarding potential mechanisms, functional studies revealed that LncRNA CERS6-AS1 is involved in cancer growth mainly by sponging miRNAs and regulating their downstream targets. CONCLUSION Available evidence suggests that LncRNA CERS6-AS1 is upregulated in different cancers and has an oncogenic role. LncRNA CERS6-AS1 expression level might predict cancer prognosis, highlighting its potential application as a prognostic biomarker for cancer.
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Affiliation(s)
- Hadith Rastad
- Cardiovascular Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Parham Samimisedeh
- Cardiovascular Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Mahin Seifi Alan
- Cardiovascular Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Elmira Jafari Afshar
- Cardiovascular Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Jamileh Ghalami
- Cardiovascular Research Center, Alborz University of Medical Sciences, Karaj, Iran; The Clinical Research Development units of Kamali Hospital, Alborz University of Medical Sciences, Karaj, Iran
| | - Maryam Hashemnejad
- Cardiovascular Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Mahnaz Seifi Alan
- Cardiovascular Research Center, Alborz University of Medical Sciences, Karaj, Iran.
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20
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Jagosky MH, Anderson CJ, Symanowski JT, Steuerwald NM, Farhangfar CJ, Baldrige EA, Benbow JH, Livingston MB, Patt JC, Ahrens WA, Kneisl JS, Kim ES. Genomic alterations and clinical outcomes in patients with dedifferentiated liposarcoma. Cancer Med 2022; 12:7029-7038. [PMID: 36464833 PMCID: PMC10067084 DOI: 10.1002/cam4.5502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 10/20/2022] [Accepted: 11/19/2022] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Patients with unresectable dedifferentiated liposarcoma (DDLPS) have poor overall outcomes. Few genomic alterations have been identified with limited therapeutic options. EXPERIMENTAL DESIGN Patients treated at Levine Cancer Institute with DDLPS were identified. Next generation sequencing (NGS), immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH) testing were performed on tumor tissue collected at diagnosis or recurrence/progression. Confirmation of genomic alterations was performed by orthologous methods and correlated with clinical outcomes. Univariate Cox regression was used to identify genomic alterations associated with clinical outcomes. RESULTS Thirty-eight DDLPS patients with adequate tissue for genomic profiling and clinical data were identified. Patient characteristics included: median age at diagnosis (66 years), race (84.2% Caucasian), and median follow-up time for the entire cohort was 12.1 years with a range from approximately 3.5 months to 14.1 years. Genes involved in cell cycle regulation, including MDM2 (74%) CDK4 (65%), and CDKN2A (23%), were amplified along with WNT/Notch pathway markers: HMGA2, LGR5, MCL1, and CALR (19%-29%). While common gene mutations were identified, PDE4DIP and FOXO3 were also mutated in 47% and 34% of patients, respectively, neither of which have been previously reported. FOXO3 was associated with improved overall survival (OS) (HR 0.37; p = 0.043) along with MAML2 (HR 0.30; p = 0.040). Mutations that portended worse prognosis included RECQL4 (disease-specific survival HR 4.67; p = 0.007), MN1 (OS HR = 3.38; p = 0.013), NOTCH1 (OS HR 2.28, p = 0.086), and CNTRL (OS HR 2.42; p = 0.090). CONCLUSIONS This is one of the largest retrospective reports analyzing genomic aberrations in relation to clinical outcomes for patients with DDLPS. Our results suggest therapies targeting abnormalities should be explored and confirmation of prognostic markers is needed. Dedifferentiated liposarcoma is one of the most common subtypes of soft tissue sarcoma yet little is known of its molecular aberrations and possible impact on outcomes. The work presented here is an evaluation of genetic abnormalities among a population of patients with dedifferentiated liposarcoma and how they corresponded with survival and risk of metastases. There were notable gene mutations and amplifications commonly found, some of which had interesting prognostic implications.
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Affiliation(s)
- Megan H. Jagosky
- Department of Solid Tumor Oncology, Levine Cancer Institute, Carolinas Medical Center, Atrium Health Charlotte North Carolina USA
| | - Colin J. Anderson
- Department of Orthopedic Oncology, Musculoskeletal Institute, Atrium Health Charlotte North Carolina USA
| | - James T. Symanowski
- Department of Biostatistics, Levine Cancer Institute, Carolinas Medical Center Atrium Health Charlotte North Carolina USA
| | - Nury M. Steuerwald
- The Molecular Biology and Genomics Laboratory, Levine Cancer Institute, Carolinas Medical Center, Atrium Health Charlotte North Carolina USA
| | - Carol J. Farhangfar
- LCI Translational Research, Levine Cancer Institute, Carolinas Medical Center, Atrium Health Charlotte North Carolina USA
| | - Emily A. Baldrige
- LCI Research Support, Clinical Trials Office, Levine Cancer Institute, Carolinas Medical Center, Atrium Health Charlotte North Carolina USA
| | | | - Michael B. Livingston
- Department of Solid Tumor Oncology, Levine Cancer Institute, Carolinas Medical Center, Atrium Health Charlotte North Carolina USA
| | - Joshua C. Patt
- Department of Orthopedic Oncology, Musculoskeletal Institute, Atrium Health Charlotte North Carolina USA
| | - Will A. Ahrens
- Department of Pathology Levine Cancer Institute, Carolinas Medical Center, Atrium Health Charlotte North Carolina USA
| | - Jeffrey S. Kneisl
- Department of Orthopedic Oncology, Musculoskeletal Institute, Atrium Health Charlotte North Carolina USA
| | - Edward S. Kim
- City of Hope Comprehensive Cancer Center Duarte California USA
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21
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Ho GY, Kyran EL, Bedo J, Wakefield MJ, Ennis DP, Mirza HB, Vandenberg CJ, Lieschke E, Farrell A, Hadla A, Lim R, Dall G, Vince JE, Chua NK, Kondrashova O, Upstill-Goddard R, Bailey UM, Dowson S, Roxburgh P, Glasspool RM, Bryson G, Biankin AV, for the Scottish Genomes Partnership, Cooke SL, Ratnayake G, McNally O, Traficante N, for the Australian Ovarian Cancer Study12,13, DeFazio A, Weroha SJ, Bowtell DD, McNeish IA, Papenfuss AT, Scott CL, Barker HE. Epithelial-to-Mesenchymal Transition Supports Ovarian Carcinosarcoma Tumorigenesis and Confers Sensitivity to Microtubule Targeting with Eribulin. Cancer Res 2022; 82:4457-4473. [PMID: 36206301 PMCID: PMC9716257 DOI: 10.1158/0008-5472.can-21-4012] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 06/15/2022] [Accepted: 10/04/2022] [Indexed: 01/24/2023]
Abstract
Ovarian carcinosarcoma (OCS) is an aggressive and rare tumor type with limited treatment options. OCS is hypothesized to develop via the combination theory, with a single progenitor resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). In this study, we analyzed DNA variants from isolated carcinoma and sarcoma components to show that OCS from 18 women is monoclonal. RNA sequencing indicated that the carcinoma components were more mesenchymal when compared with pure epithelial ovarian carcinomas, supporting the conversion theory and suggesting that EMT is important in the formation of these tumors. Preclinical OCS models were used to test the efficacy of microtubule-targeting drugs, including eribulin, which has previously been shown to reverse EMT characteristics in breast cancers and induce differentiation in sarcomas. Vinorelbine and eribulin more effectively inhibited OCS growth than standard-of-care platinum-based chemotherapy, and treatment with eribulin reduced mesenchymal characteristics and N-MYC expression in OCS patient-derived xenografts. Eribulin treatment resulted in an accumulation of intracellular cholesterol in OCS cells, which triggered a downregulation of the mevalonate pathway and prevented further cholesterol biosynthesis. Finally, eribulin increased expression of genes related to immune activation and increased the intratumoral accumulation of CD8+ T cells, supporting exploration of immunotherapy combinations in the clinic. Together, these data indicate that EMT plays a key role in OCS tumorigenesis and support the conversion theory for OCS histogenesis. Targeting EMT using eribulin could help improve OCS patient outcomes. SIGNIFICANCE Genomic analyses and preclinical models of ovarian carcinosarcoma support the conversion theory for disease development and indicate that microtubule inhibitors could be used to suppress EMT and stimulate antitumor immunity.
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Affiliation(s)
- Gwo Yaw Ho
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
- The Royal Women's Hospital, Parkville, Victoria, Australia
| | - Elizabeth L. Kyran
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
- Cancer Research UK Cambridge Institute, Cambridge, United Kingdom
| | - Justin Bedo
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- School of Computing and Information Systems, the University of Melbourne, Parkville, Victoria, Australia
| | - Matthew J. Wakefield
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, Australia
| | - Darren P. Ennis
- Division of Cancer and Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, United Kingdom
- Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Hasan B. Mirza
- Division of Cancer and Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Cassandra J. Vandenberg
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
| | - Elizabeth Lieschke
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
| | - Andrew Farrell
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
| | - Anthony Hadla
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
| | - Ratana Lim
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
| | - Genevieve Dall
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
| | - James E. Vince
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
| | - Ngee Kiat Chua
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
| | - Olga Kondrashova
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
| | - Rosanna Upstill-Goddard
- Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Ulla-Maja Bailey
- Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Suzanne Dowson
- Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Patricia Roxburgh
- Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom
- Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
| | - Rosalind M. Glasspool
- Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom
- Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
| | - Gareth Bryson
- Department of Pathology, Queen Elizabeth University Hospital, Glasgow, United Kingdom
| | - Andrew V. Biankin
- Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom
| | | | - Susanna L. Cooke
- Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom
| | | | - Orla McNally
- The Royal Women's Hospital, Parkville, Victoria, Australia
- Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, Australia
- Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
| | - Nadia Traficante
- Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
- Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | | | - Anna DeFazio
- Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, Australia
- The Daffodil Centre, The University of Sydney, A Joint Venture with Cancer Council NSW, Sydney, Australia
- Department of Gynaecological Oncology, Westmead Hospital, Sydney, Australia
| | - S. John Weroha
- Department of Oncology, Mayo Clinic, Rochester, Minnesota
| | - David D. Bowtell
- Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
- Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Iain A. McNeish
- Division of Cancer and Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, United Kingdom
- Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom
- Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
| | - Anthony T. Papenfuss
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
- Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Clare L. Scott
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
- The Royal Women's Hospital, Parkville, Victoria, Australia
- Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, Australia
- Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
| | - Holly E. Barker
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
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22
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Liu X, Qin H, Li Z, Lv Y, Feng S, Zhuang W, Quan X, Guo C, Chen C, Zhang H. Inspiratory hyperoxia suppresses lung cancer metastasis through a MYC/SLC1A5-dependent metabolic pathway. Eur Respir J 2022; 60:13993003.00062-2022. [PMID: 35680143 PMCID: PMC9712851 DOI: 10.1183/13993003.00062-2022] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 05/18/2022] [Indexed: 12/14/2022]
Abstract
The lack of knowledge about the effect of inspiratory hyperoxia on the lung-specific tumour microenvironment and progression of lung cancer has attracted considerable attention. This study proposes that inspiratory hyperoxia has special significance for the malignant phenotype of lung cancer cells. The effects of different oxygenation parameters on the proliferation, apoptosis, invasion and migration of lung cancer cells were systematically evaluated in vitro and in vivo Our results reveal that inspiratory hyperoxia treatment (60% oxygen, 6 h·day-1) not only has no tumour progression-promoting effects, but also suppresses lung cancer metastasis and promotes long-term survival. In addition, we combined transcriptome, proteome and metabolome analysis and found that hyperoxia treatment induced significant intracellular metabolic changes in lung cancer cells. Overall, we established that MYC/SLC1A5-induced metabolic reprogramming and glutamine addiction is a new mechanism that drives lung cancer metastasis, which can be significantly suppressed by inspiratory hyperoxia treatment. These findings are relevant to the debate on the perils, promises and antitumour effect of inspiratory hyperoxia, especially for patients with lung cancer.
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Affiliation(s)
- Xiucheng Liu
- Thoracic Surgery Laboratory, Xuzhou Medical University, Xuzhou, China,Department of Thoracic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China,Shanghai Engineering Research Center of Lung Transplantation, Shanghai, China,Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China,Xiucheng Liu, Hao Qin and Zheng Li contributed equally to this work
| | - Hao Qin
- Department of Thoracic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China,Xiucheng Liu, Hao Qin and Zheng Li contributed equally to this work
| | - Zheng Li
- Department of Thoracic Surgery, Huadong Hospital Affiliated to FuDan University, Shanghai, China,Xiucheng Liu, Hao Qin and Zheng Li contributed equally to this work
| | - Yin Lv
- Department of Thoracic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Shoujie Feng
- Department of Thoracic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Wei Zhuang
- Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Xiaoyu Quan
- Department of Thoracic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Chen Guo
- Department of Thoracic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Chang Chen
- Shanghai Engineering Research Center of Lung Transplantation, Shanghai, China,Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China,Hao Zhang and Chang Chen contributed equally to this article as lead authors and co-corresponding authors
| | - Hao Zhang
- Thoracic Surgery Laboratory, Xuzhou Medical University, Xuzhou, China,Department of Thoracic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China,Hao Zhang and Chang Chen contributed equally to this article as lead authors and co-corresponding authors,Corresponding author: Hao Zhang ()
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23
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Yang C, Yang Y, Wang W, Zhou W, Zhang X, Xiao Y, Zhang H. CEP55 3'-UTR promotes epithelial-mesenchymal transition and enhances tumorigenicity of bladder cancer cells by acting as a ceRNA regulating miR-497-5p. Cell Oncol (Dordr) 2022; 45:1217-1236. [PMID: 36374443 DOI: 10.1007/s13402-022-00712-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/25/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Centrosomal protein 55 (CEP55) is implicated in the tumorigenesis of bladder cancer (BC) but the detailed molecular mechanisms are unknown. We aim to develop a potential competing endogenous RNA (ceRNA) network related with CEP55 in BC. METHODS We first extracted the expression profiles of RNAs from The Cancer Genome Atlas (TCGA) database and used bioinformatic analysis to establish ceRNAs in BC. Real-time quantity PCR (RT-qPCR) and immunohistochemical analysis were performed to measure CEP55 expression in different bladder cell lines and different grades of cancer. Bioinformatics analysis and luciferase assays were conducted to predict potential binding sites among miR-497-5p, CEP55, parathyroid hormone like hormone (PTHLH) and high mobility group A2 (HMGA2). Tumor xenograft model was used to show the effect of CEP55 3'-UTR on cisplatin therapy. Bioinformatics analysis, luciferase assays, and 5' rapid amplification of cDNA ends (5'RACE) were to explore the function of CEP55 3'-untranslated region (3'-UTR) on targeting miR-497-5p. Western blot and immunofluorescence assays were to detect the epithelial-mesenchymal transition (EMT) induction of CEP55 3'-UTR. RESULTS CEP55 expression as well as the expression levels of the oncogenic proteins PTHLH and HMGA2 were upregulated in BC cells while miR-497-5p was downregulated. Low miR-497-5p expression and high CEP55 and HMGA2 expression levels were associated with more advanced tumor clinical stage and pathological grade. Overexpression of the CEP55 3'-UTR promoted the proliferation, migration, and invasion of the EJ cell line in vitro and accelerated EJ-derived tumor growth in nude mice, while inhibition of the CEP55 3'-UTR suppressed all of these oncogenic processes. In addition, CEP55 3'-UTR upregulation reduced the cisplatin sensitivity of BC cell lines and xenograft tumors. Bioinformatics analysis, luciferase assays, and 5'RACE suggested that the CEP55 3'-UTR functions as a ceRNA targeting miR-497-5p, leading to miR-497-5p downregulation and disinhibition of PTHLH and HMGA2 expression. Further, CEP55 downregulated miR-497-5p transcription by promoting NF-[Formula: see text]B signaling. In turn, CEP55 3'-UTR ultimately promotes EMT and tumorigenesis by activating P38MAPK and ERK 1/2 pathways. CONCLUSIONS These results suggest that a ceRNA regulatory network involving CEP55 upregulates PTHLH and HMGA2 expression by suppressing endogenous miR-497-5p. We unveiled a novel mechanism of BC metastasis, and could become novel therapeutics targets in BC.
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Affiliation(s)
- Chenglin Yang
- Department of Urology, General Hospital of Southern Theater Command, Liuhua Road No.111, Guangzhou, 510010, China
| | - Yue Yang
- Department of Urology, General Hospital of Southern Theater Command, Liuhua Road No.111, Guangzhou, 510010, China.,The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Wei Wang
- Department of Urology, General Hospital of Southern Theater Command, Liuhua Road No.111, Guangzhou, 510010, China. .,The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China.
| | - Wuer Zhou
- Department of Urology, General Hospital of Southern Theater Command, Liuhua Road No.111, Guangzhou, 510010, China
| | - Xiaoming Zhang
- Department of Urology, General Hospital of Southern Theater Command, Liuhua Road No.111, Guangzhou, 510010, China
| | - Yuansong Xiao
- Department of Urology, General Hospital of Southern Theater Command, Liuhua Road No.111, Guangzhou, 510010, China
| | - Huifen Zhang
- Department of Urology, General Hospital of Southern Theater Command, Liuhua Road No.111, Guangzhou, 510010, China
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24
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Wang ZH, Liu LP, Zheng YW. Melanocyte stem cells in skin diseases and their potential in cell-based therapy. Histol Histopathol 2022; 37:937-953. [PMID: 35553404 DOI: 10.14670/hh-18-470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Melanocytes have a complex function and play an important role in a variety of regulatory mechanisms in the human system. Melanocyte stem cells (MelSCs) serve as a reservoir to replenish the melanocytes by regenerating new ones, and they are capable of self-renewal and differentiation to maintain their homeostasis, repair, and regeneration in tissues. The numerical decrease and functional impairment of MelSCs may be closely related to the development and treatment response of many skin diseases. However, the current knowledge about MelSCs mainly comes from studies in mice, and little is known about human MelSC markers; especially, their markers are still unclear or lack consensus. This leads to uncertainty in clinical findings, which further limits our comprehensive understanding of pigmentary disorders and also hinders the progress of new treatments. Thus, in this review article, combined with our previous and current work, we summarize and update the recent advances in MelSC research, including the molecular markers of human MelSCs and their niche, as well as the association of MelSCs with skin diseases, including vitiligo, hair greying, and melanoma. Due to the limited tools available to explore the identified characteristics of human MelSCs, pluripotent stem cells can provide a new research model for further study, especially combined with CRISPR/Cas9 technology. The visualization of human MelSCs' development and differentiation can help to identify their molecular characteristics and understand their cellular fate dynamically, which will allow us not only to further explore their roles in associated diseases, but also to achieve MelSC-based cellular therapy.
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Affiliation(s)
- Zi-Han Wang
- Institute of Regenerative Medicine, and Department of Dermatology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Li-Ping Liu
- Institute of Regenerative Medicine, and Department of Dermatology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, China.
| | - Yun-Wen Zheng
- Institute of Regenerative Medicine, and Department of Dermatology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, China
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, and School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, Guangdong, China
- School of Medicine, Yokohama City University, Yokohama, Kanagawa, Japan
- Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Department of Medical and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan.
- Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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25
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Xiong G, Ouyang S, Xie N, Xie J, Wang W, Yi C, Zhang M, Xu X, Chen D, Wang C. FOSL1 promotes tumor growth and invasion in ameloblastoma. Front Oncol 2022; 12:900108. [PMID: 36185257 PMCID: PMC9521732 DOI: 10.3389/fonc.2022.900108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 08/19/2022] [Indexed: 12/03/2022] Open
Abstract
Background FOSL1, a key component of the Activating protein-1 (AP-1) transcriptional complex, plays an important role in cancer cell migration, invasion, and proliferation. However, the impact of FOSL1 in ameloblastoma (AM) has not been clarified. Herein, we aimed to assess the expression of FOSL1 and investigate its functional role in AM. Methods The expression of FOSL1 was examined based on an immunohistochemistry analysis of 96 AM samples. Cell proliferation, migration, invasion, and tumorigenesis were assessed using Cell Counting Kit-8 (CCK-8), colony formation, Transwell, and sphere formation assays. RNA sequencing (RNA-seq) was employed to investigate the molecular alterations of AM cells upon FOSL depletion. Microarrays of AMs were downloaded from the Gene Expression Omnibus (GEO) database for bioinformatics analysis. In addition, patient-derived AM organoids were used to evaluate the therapeutic value of the AP-1 inhibitor. Results FOSL1 was detected in the nuclei of AMs and upregulated in conventional AMs compared to unicystic AMs and normal oral epithelium. Compared with primary AM, FOSL1 expression was significantly increased in recurrent AM. Genetic knockdown of FOSL1 suppressed the proliferation, migration, invasion, and sphere formation of AMs. Similar results were also observed by pharmacological inhibition of AP-1 activity. Moreover, the AP-1 inhibitor T5224 impeded the growth of organoids derived from AM patients. Mechanistically, our Ingenuity Pathway Analysis (IPA) and gene set enrichment analysis (GSEA) results revealed that depletion of FOSL1 inactivated kinetochore metaphase signaling and the epithelial–mesenchymal transition pathway and then impaired the aggressiveness of AM cells accordingly. Conclusion FOSL1 promotes tumor recurrence and invasive growth in AM by modulating kinetochore metaphase signaling and the epithelial–mesenchymal transition pathway; thus, it represents a promising therapeutic target for AM treatment.
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Affiliation(s)
- Gan Xiong
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yatsen University, Guangzhou, China
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Shengqi Ouyang
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yatsen University, Guangzhou, China
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Nan Xie
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yatsen University, Guangzhou, China
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Jiaxiang Xie
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yatsen University, Guangzhou, China
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Wenjin Wang
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yatsen University, Guangzhou, China
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Chen Yi
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yatsen University, Guangzhou, China
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Ming Zhang
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yatsen University, Guangzhou, China
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Xiuyun Xu
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yatsen University, Guangzhou, China
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Demeng Chen
- Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Cheng Wang
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yatsen University, Guangzhou, China
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Cheng Wang,
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26
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Yang R, Zhan Y, Li Y, Dai SY, He SW, Ye CJ, Meng LD, Chen DQ, Dong CB, Chen L, Chen G, Dong KR, Li K, Zheng S, Li J, Yao W, Dong R. The Cellular and Molecular Landscape of Synchronous Pediatric Sialoblastoma and Hepatoblastoma. Front Oncol 2022; 12:893206. [PMID: 35860547 PMCID: PMC9289541 DOI: 10.3389/fonc.2022.893206] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 05/31/2022] [Indexed: 01/05/2023] Open
Abstract
Sialoblastoma (SBL) is an infrequent embryonal malignant tumor originating from the salivary gland, resembling primitive salivary gland anlage, whereas hepatoblastoma (HB) is the most common pediatric liver malignancy. The simultaneous occurrence of both tumors is extremely rare. Here we reported a case of a 6-month-old infant diagnosed with synchronous SBL and HB. The patient received neoadjuvant chemotherapy followed by surgical resection. Fresh tissues of both tumors were collected before and after chemotherapy, which were further profiled by whole exome sequencing (WES) and single-cell RNA sequencing (scRNA-seq). WES analysis revealed potential somatic driver mutation PIK3CA p.Glu454Lys for SBL and canonical mutation CTNNB1 p.Ser45Pro for HB. No shared somatic variants or common copy number alterations were found between SBL and HB primary tumor samples. Though scRNA-seq, single-cell atlases were constructed for both tumors. SBL may recapitulate a pre-acinar stage in the development of salivary gland, including basaloid, duct-like, myoepithelial-like, and cycling phenotypes. In the meantime, HB was composed of tumor cells resembling different stages of the liver, including hepatocyte-like, hepatic progenitor-like, and hepatoblast-like cells. After chemotherapy, both tumors were induced into a more mature phenotype. In terms of transcriptional signatures, SBL and HB showed enhanced expression of epithelial markers KRT8, KRT18, and essential embryo development genes SDC1, MDK, indicating the disruption of normal embryo epithelium development. Finally, heterozygous deleterious germline mutation BLM and FANCI were identified which could predispose the patient to higher cancer risk. It partially explained the reason for the co-occurrence of SBL and HB. Taken together, we provided valuable resources for deciphering cellular heterogeneity and adaptive change of tumor cells after chemotherapy for synchronous SBL and HB, providing insights into the mechanisms leading to synchronous pediatric tumors.
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Affiliation(s)
- Ran Yang
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
| | - Yong Zhan
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
| | - Yi Li
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
| | - Shu-Yang Dai
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
| | - Shi-Wei He
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
| | - Chun-Jing Ye
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
| | - Ling-Du Meng
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
| | - De-Qian Chen
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
| | - Chen-Bin Dong
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
| | - Lian Chen
- Department of Pathology, Children’s Hospital of Fudan University, Shanghai, China
| | - Gong Chen
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
| | - Kui-Ran Dong
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
| | - Kai Li
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
| | - Shan Zheng
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
| | - Jun Li
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
- *Correspondence: Rui Dong, ; Wei Yao, ; Jun Li,
| | - Wei Yao
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
- *Correspondence: Rui Dong, ; Wei Yao, ; Jun Li,
| | - Rui Dong
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
- *Correspondence: Rui Dong, ; Wei Yao, ; Jun Li,
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Hamidi AA, Taghehchian N, Basirat Z, Zangouei AS, Moghbeli M. MicroRNAs as the critical regulators of cell migration and invasion in thyroid cancer. Biomark Res 2022; 10:40. [PMID: 35659780 PMCID: PMC9167543 DOI: 10.1186/s40364-022-00382-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 05/07/2022] [Indexed: 12/14/2022] Open
Abstract
Thyroid cancer (TC) is one of the most frequent endocrine malignancies that is more common among females. Tumor recurrence is one of the most important clinical manifestations in differentiated TC which is associated with different factors including age, tumor size, and histological features. Various molecular processes such as genetic or epigenetic modifications and non-coding RNAs are also involved in TC progression and metastasis. The epithelial-to-mesenchymal transition (EMT) is an important biological process during tumor invasion and migration that affects the initiation and transformation of early-stage tumors into invasive malignancies. A combination of transcription factors, growth factors, signaling pathways, and epigenetic regulations affect the thyroid cell migration and EMT process. MicroRNAs (miRNAs) are important molecular factors involved in tumor metastasis by regulation of EMT-activating signaling pathways. Various miRNAs are involved in the signaling pathways associated with TC metastasis which can be used as diagnostic and therapeutic biomarkers. Since, the miRNAs are sensitive, specific, and non-invasive, they can be suggested as efficient and optimal biomarkers of tumor invasion and metastasis. In the present review, we have summarized all of the miRNAs which have been significantly involved in thyroid tumor cells migration and invasion. We also categorized all of the reported miRNAs based on their cellular processes to clarify the molecular role of miRNAs during thyroid tumor cell migration and invasion. This review paves the way of introducing a non-invasive diagnostic and prognostic panel of miRNAs in aggressive and metastatic TC patients.
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Affiliation(s)
- Amir Abbas Hamidi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Negin Taghehchian
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra Basirat
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Sadra Zangouei
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Huldani H, Jasim SA, Sergeenva KN, Bokov DO, Abdelbasset WK, Turakulov R, Al-Gazally ME, Ahmadzadeh B, Jawhar ZH, Siahmansouri H. Mechanisms of cancer stem cells drug resistance and the pivotal role of HMGA2. Pathol Res Pract 2022; 234:153906. [PMID: 35468338 DOI: 10.1016/j.prp.2022.153906] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 04/02/2022] [Accepted: 04/15/2022] [Indexed: 11/24/2022]
Abstract
Nowadays, the focus of researchers is on perceiving the heterogeneity observed in a tumor. The researchers studied the role of a specific subset of cancer cells with high resistance to traditional treatments, recurrence, and unregulated metastasis. This small population of tumor cells that have stem-cell-like specifications was named Cancer Stem Cells (CSCs). The unique features that distinguish this type of cancer cell are self-renewing, generating clones of the tumor, plasticity, recurrence, and resistance to therapies. There are various mechanisms that contribute to the drug resistance of CSCs, such as CSCs markers, Epithelial mesenchymal transition, hypoxia, other cells, inflammation, and signaling pathways. Recent investigations have revealed the primary role of HMGA2 in the development and invasion of cancer cells. Importantly, HMGA2 also plays a key role in resistance to treatment through their function in the drug resistance mechanisms of CSCs and challenge it. Therefore, a deep understanding of this issue can provide a clearer perspective for researchers in the face of this problem.
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Affiliation(s)
- Huldani Huldani
- Department of Physiology, Lambung Mangkurat University, Banjarmasin, South Borneo, Indonesia
| | - Saade Abdalkareem Jasim
- Medical Laboratory Techniques Department, Al-Maarif University College, Al-Anbar-Ramadi, Iraq
| | - Klunko Nataliya Sergeenva
- Department of post-graduate and doctoral programs, Russian New University, Building 5, Radio Street, Moscow City, Russian Federation
| | - Dmitry Olegovich Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, 8 Trubetskaya St., Bldg. 2, Moscow 119991, Russian Federation
| | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia; Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | - Rustam Turakulov
- Department of Internal diseases, Tashkent Medical Academy, Tashkent, Uzbekistan
| | | | - Behnam Ahmadzadeh
- Doctoral School of the University of Szczecin, Institute of Biology, University of Szczecin, 71-412 Szczecin, Poland
| | - Zanko Hassan Jawhar
- Department of Medical Laboratory Science, College of Health Science, Lebanese French University, Kurdistan Region, Iraq
| | - Homayoon Siahmansouri
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Cui J, Dean D, Hornicek FJ, Yi G, Duan Z. Expression and Clinical Significance of High-Mobility Group AT-hook 2 (HMGA2) in Osteosarcoma. Orthop Surg 2022; 14:955-966. [PMID: 35388973 PMCID: PMC9087380 DOI: 10.1111/os.13167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 09/27/2021] [Accepted: 10/09/2021] [Indexed: 11/29/2022] Open
Abstract
Objective Although high‐mobility group AT‐hook 2 (HMGA2) has been shown to have crucial roles in the pathogenesis and metastasis of various malignancies, its expression and significance in osteosarcoma remain unknown. Here we evaluate the expression, clinical prognostic value, and overall function of HMGA2 in osteosarcoma. Methods Sixty‐nine osteosarcoma patient specimens within a tissue microarray (TMA) were analyzed by immunohistochemistry for HMGA2 expression. Demographics and clinicopathological information including age, gender, tumor location, metastasis, recurrence, chemotherapy response, follow‐up time, and disease status were also collected. After validation of expression, we determined whether there was a correlation between HMGA2 expression and patient clinicopathology. HMGA2 expression was also evaluated in osteosarcoma cell lines and patient tissues by Western blot, we analyzed the expression of HMGA2 in the human osteosarcoma cell lines MG63, 143B, U2OS, Saos‐2, MNNG/HOS, and KHOS. HMGA2‐specific siRNA and clonogenic assays were then used to determine the effect of HMGA2 inhibition on osteosarcoma cell proliferation, growth, and chemosensitivity. Results HMGA2 expression was elevated in the osteosarcoma patient specimens and human osteosarcoma cell lines. HMGA2 was differentially expressed in human osteosarcoma cell lines. Specifically, a relatively high expression of HMGA2 was present in KHOS, MNNG/HOS, 143B and a relatively low expression was in MG63, U2OS as well as Saos‐2. HMGA2 expression is correlated with metastasis and shorter overall survival. High HMGA2 expression is an independent predictor of poor osteosarcoma prognosis. There was no significant correlation between HMGA2 expression and the age, gender, or tumor site of the patient. HMGA2 expression is predominantly within the nucleus. The expression of HMGA2 also directly correlated to neoadjuvant chemoresistance. There was a significant reduction of HMGA2 expression in the siRNA transfection group. After the use of siRNA, the proliferation of osteosarcoma cells is decreased and the chemosensitivity of osteosarcoma cells is significantly increased. Conclusion Our study supports HMGA2 as a potential prognostic biomarker and therapeutic target in osteosarcoma.
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Affiliation(s)
- Juncheng Cui
- Department of Orthopedic Surgery, The First Affiliated Hospital of University of South China, Hengyang, China.,Department of Orthopedic Surgery, Sarcoma Biology Laboratory, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Dylan Dean
- Department of Orthopedic Surgery, Sarcoma Biology Laboratory, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Francis J Hornicek
- Department of Orthopedic Surgery, Sarcoma Biology Laboratory, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Guoliang Yi
- Department of Orthopedic Surgery, The First Affiliated Hospital of University of South China, Hengyang, China
| | - Zhenfeng Duan
- Department of Orthopedic Surgery, Sarcoma Biology Laboratory, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
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Ohmori K, Kamei A, Watanabe Y, Abe K. Gene Expression over Time during Cell Transformation Due to Non-Genotoxic Carcinogen Treatment of Bhas 42 Cells. Int J Mol Sci 2022; 23:ijms23063216. [PMID: 35328637 PMCID: PMC8954493 DOI: 10.3390/ijms23063216] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 03/11/2022] [Accepted: 03/11/2022] [Indexed: 02/05/2023] Open
Abstract
The Bhas 42 cell transformation assay (Bhas 42 CTA) is the first Organization for Economic Cooperation and Development (OECD)-certificated method used as a specific tool for the detection of the cell-transformation potential of tumor-promoting compounds, including non-genotoxic carcinogens (NGTxCs), as separate from genotoxic carcinogens. This assay offers the great advantage of enabling the phenotypic detection of oncotransformation. A key benefit of using the Bhas 42 CTA in the study of the cell-transformation mechanisms of tumor-promoting compounds, including non-genotoxic carcinogens, is that the cell-transformation potential of the chemical can be detected directly without treatment with a tumor-initiating compound since Bhas 42 cell line was established by transfecting the v-Ha-ras gene into a mouse fibroblast cloned cell line. Here, we analyzed the gene expression over time, using DNA microarrays, in Bhas 42 cells treated with the tumor-promoting compound 12-O-tetradecanoylphorbol-13-acetate (TPA), and NGTxC, with a total of three repeat experiments. This is the first paper to report on gene expression over time during the process of cell transformation with only a tumor-promoting compound. Pathways that were activated or inactivated during the process of cell transformation in the Bhas 42 cells treated with TPA were related not only directly to RAS but also to various pathways in the hallmarks of cancer.
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Affiliation(s)
- Kiyomi Ohmori
- Chemical Division, Kanagawa Prefectural Institute of Public Health, Chigasaki 2530087, Japan
- Research Initiatives and Promotion Organization, Yokohama National University, Yokohama 2408501, Japan
- Correspondence: or ; Tel./Fax: +81-046-783-4400 or +81-045-339-4448
| | - Asuka Kamei
- Group for Food Functionality Assessment, Kanagawa Institute of Industrial Science and Technology, Kawasaki 2100821, Japan; (A.K.); (K.A.)
| | - Yuki Watanabe
- Health and Anti-Aging Project, Kanagawa Academy of Science and Technology, Kawasaki 2130012, Japan;
| | - Keiko Abe
- Group for Food Functionality Assessment, Kanagawa Institute of Industrial Science and Technology, Kawasaki 2100821, Japan; (A.K.); (K.A.)
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 1138657, Japan
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31
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Windels SFL, Malod-Dognin N, Pržulj N. Graphlet eigencentralities capture novel central roles of genes in pathways. PLoS One 2022; 17:e0261676. [PMID: 35077468 PMCID: PMC8789115 DOI: 10.1371/journal.pone.0261676] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 12/07/2021] [Indexed: 01/16/2023] Open
Abstract
MOTIVATION Graphlet adjacency extends regular node adjacency in a network by considering a pair of nodes being adjacent if they participate in a given graphlet (small, connected, induced subgraph). Graphlet adjacencies captured by different graphlets were shown to contain complementary biological functions and cancer mechanisms. To further investigate the relationships between the topological features of genes participating in molecular networks, as captured by graphlet adjacencies, and their biological functions, we build more descriptive pathway-based approaches. CONTRIBUTION We introduce a new graphlet-based definition of eigencentrality of genes in a pathway, graphlet eigencentrality, to identify pathways and cancer mechanisms described by a given graphlet adjacency. We compute the centrality of genes in a pathway either from the local perspective of the pathway or from the global perspective of the entire network. RESULTS We show that in molecular networks of human and yeast, different local graphlet adjacencies describe different pathways (i.e., all the genes that are functionally important in a pathway are also considered topologically important by their local graphlet eigencentrality). Pathways described by the same graphlet adjacency are functionally similar, suggesting that each graphlet adjacency captures different pathway topology and function relationships. Additionally, we show that different graphlet eigencentralities describe different cancer driver genes that play central roles in pathways, or in the crosstalk between them (i.e. we can predict cancer driver genes participating in a pathway by their local or global graphlet eigencentrality). This result suggests that by considering different graphlet eigencentralities, we can capture different functional roles of genes in and between pathways.
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Affiliation(s)
- Sam F. L. Windels
- Department of Computer Science, University College London, London, United Kingdom
- Barcelona Supercomputing Center (BSC), Barcelona, Spain
| | - Noël Malod-Dognin
- Department of Computer Science, University College London, London, United Kingdom
- Barcelona Supercomputing Center (BSC), Barcelona, Spain
| | - Nataša Pržulj
- Department of Computer Science, University College London, London, United Kingdom
- Barcelona Supercomputing Center (BSC), Barcelona, Spain
- ICREA, Barcelona, Spain
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Garabedian A, Jeanne Dit Fouque K, Chapagain PP, Leng F, Fernandez-Lima F. OUP accepted manuscript. Nucleic Acids Res 2022; 50:2431-2439. [PMID: 35212375 PMCID: PMC8934665 DOI: 10.1093/nar/gkac115] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 12/30/2021] [Accepted: 02/08/2022] [Indexed: 11/25/2022] Open
Abstract
The mammalian high mobility group protein AT-hook 2 (HMGA2) houses three motifs that preferentially bind short stretches of AT-rich DNA regions. These DNA binding motifs, known as ‘AT-hooks’, are traditionally characterized as being unstructured. Upon binding to AT-rich DNA, they form ordered assemblies. It is this disordered-to-ordered transition that has implicated HMGA2 as a protein actively involved in many biological processes, with abnormal HMGA expression linked to a variety of health problems including diabetes, obesity, and oncogenesis. In the current work, the solution binding dynamics of the three ‘AT-hook’ peptides (ATHPs) with AT-rich DNA hairpin substrates were studied using DNA UV melting studies, fluorescence spectroscopy, native ion mobility spectrometry-mass spectrometry (IMS-MS), solution isothermal titration calorimetry (ITC) and molecular modeling. Results showed that the ATHPs bind to the DNA to form a single, 1:1 and 2:1, ‘key-locked’ conformational ensemble. The molecular models showed that 1:1 and 2:1 complex formation is driven by the capacity of the ATHPs to bind to the minor and major grooves of the AT-rich DNA oligomers. Complementary solution ITC results confirmed that the 2:1 stoichiometry of ATHP: DNA is originated under native conditions in solution.
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Affiliation(s)
- Alyssa Garabedian
- Department of Chemistry and Biochemistry, Florida International University, Miami, 33199, USA
| | - Kevin Jeanne Dit Fouque
- Department of Chemistry and Biochemistry, Florida International University, Miami, 33199, USA
- Biomolecular Sciences Institute, Florida International University, Miami, 33199, USA
| | - Prem P Chapagain
- Department of Physics, Florida International University, Miami, 33199, USA
- Biomolecular Sciences Institute, Florida International University, Miami, 33199, USA
| | - Fenfei Leng
- Department of Chemistry and Biochemistry, Florida International University, Miami, 33199, USA
- Biomolecular Sciences Institute, Florida International University, Miami, 33199, USA
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OUP accepted manuscript. Carcinogenesis 2022; 43:671-681. [DOI: 10.1093/carcin/bgac030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 03/15/2022] [Accepted: 03/28/2022] [Indexed: 11/14/2022] Open
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Zhao T, Chiang ZD, Morriss JW, LaFave LM, Murray EM, Del Priore I, Meli K, Lareau CA, Nadaf NM, Li J, Earl AS, Macosko EZ, Jacks T, Buenrostro JD, Chen F. Spatial genomics enables multi-modal study of clonal heterogeneity in tissues. Nature 2022; 601:85-91. [PMID: 34912115 PMCID: PMC9301586 DOI: 10.1038/s41586-021-04217-4] [Citation(s) in RCA: 154] [Impact Index Per Article: 51.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 11/08/2021] [Indexed: 12/29/2022]
Abstract
The state and behaviour of a cell can be influenced by both genetic and environmental factors. In particular, tumour progression is determined by underlying genetic aberrations1-4 as well as the makeup of the tumour microenvironment5,6. Quantifying the contributions of these factors requires new technologies that can accurately measure the spatial location of genomic sequence together with phenotypic readouts. Here we developed slide-DNA-seq, a method for capturing spatially resolved DNA sequences from intact tissue sections. We demonstrate that this method accurately preserves local tumour architecture and enables the de novo discovery of distinct tumour clones and their copy number alterations. We then apply slide-DNA-seq to a mouse model of metastasis and a primary human cancer, revealing that clonal populations are confined to distinct spatial regions. Moreover, through integration with spatial transcriptomics, we uncover distinct sets of genes that are associated with clone-specific genetic aberrations, the local tumour microenvironment, or both. Together, this multi-modal spatial genomics approach provides a versatile platform for quantifying how cell-intrinsic and cell-extrinsic factors contribute to gene expression, protein abundance and other cellular phenotypes.
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Affiliation(s)
- Tongtong Zhao
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA,Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Zachary D. Chiang
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA,Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA,Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Julia W. Morriss
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA,Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Lindsay M. LaFave
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA,Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA,David H. Koch Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Evan M. Murray
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA,Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Isabella Del Priore
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA,David H. Koch Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Kevin Meli
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA,David H. Koch Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Caleb A. Lareau
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA,Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Naeem M. Nadaf
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Jilong Li
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Andrew S. Earl
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA,Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA,Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Evan Z. Macosko
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA,Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Tyler Jacks
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA,Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA,David H. Koch Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Jason D. Buenrostro
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA,Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA,Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA,Correspondence and requests for materials should be addressed to or
| | - Fei Chen
- Broad Institute of MIT and Harvard, Cambridge, MA, USA. .,Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. .,Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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Lawal B, Kuo YC, Tang SL, Liu FC, Wu ATH, Lin HY, Huang HS. Transcriptomic-Based Identification of the Immuno-Oncogenic Signature of Cholangiocarcinoma for HLC-018 Multi-Target Therapy Exploration. Cells 2021; 10:2873. [PMID: 34831096 PMCID: PMC8616156 DOI: 10.3390/cells10112873] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/22/2021] [Accepted: 10/22/2021] [Indexed: 12/14/2022] Open
Abstract
Cholangiocarcinomas (CHOLs), hepatobiliary malignancies, are characterized by high genetic heterogeneity, a rich tumor microenvironment, therapeutic resistance, difficulty diagnosing, and poor prognoses. Current knowledge of genetic alterations and known molecular markers for CHOL is insufficient, necessitating the need for further evaluation of the genome and RNA expression data in order to identify potential therapeutic targets, clarify the roles of these targets in the tumor microenvironment, and explore novel therapeutic drugs against the identified targets. Consequently, in our attempt to explore novel genetic markers associated with the carcinogenesis of CHOL, five genes (SNX15, ATP2A1, PDCD10, BET1, and HMGA2), collectively termed CHOL-hub genes, were identified via integration of differentially expressed genes (DEGs) from relatively large numbers of samples from CHOL GEO datasets. We further explored the biological functions of the CHOL-hub genes and found significant enrichment in several biological process and pathways associated with stem cell angiogenesis, cell proliferation, and cancer development, while the interaction network revealed high genetic interactions with a number of onco-functional genes. In addition, we established associations between the CHOL-hub genes and tumor progression, metastasis, tumor immune and immunosuppressive cell infiltration, dysfunctional T-cell phenotypes, poor prognoses, and therapeutic resistance in CHOL. Thus, we proposed that targeting CHOL-hub genes could be an ideal therapeutic approach for treating CHOLs, and we explored the potential of HLC-018, a novel benzamide-linked small molecule, using molecular docking of ligand-receptor interactions. To our delight, HLC-018 was well accommodated with high binding affinities to binding pockets of CHOL-hub genes; more importantly, we found specific interactions of HLC-018 with the conserved sequence of the AT-hook DNA-binding motif of HMGA2. Altogether, our study provides insights into the immune-oncogenic phenotypes of CHOL and provides valuable information for our ongoing experimental validation.
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Affiliation(s)
- Bashir Lawal
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan;
- Graduate Institute of Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Yu-Cheng Kuo
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- School of Post-baccalaureate Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan
| | - Sung-Ling Tang
- Department of Pharmacy Practice, Tri-Service General Hospital, School of Pharmacy, National Defense Medical Center, Taipei 11490, Taiwan;
| | - Feng-Cheng Liu
- Department of Rheumatology/Immunology and Allergy, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan;
| | - Alexander T. H. Wu
- The PhD Program of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
| | - Hung-Yun Lin
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan;
- Graduate Institute of Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
| | - Hsu-Shan Huang
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan;
- Graduate Institute of Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan
- PhD Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan
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Gundlach JP, Hauser C, Schlegel FM, Willms A, Halske C, Röder C, Krüger S, Röcken C, Becker T, Kalthoff H, Trauzold A. Prognostic significance of high mobility group A2 (HMGA2) in pancreatic ductal adenocarcinoma: malignant functions of cytoplasmic HMGA2 expression. J Cancer Res Clin Oncol 2021; 147:3313-3324. [PMID: 34302528 PMCID: PMC8484217 DOI: 10.1007/s00432-021-03745-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 07/16/2021] [Indexed: 01/26/2023]
Abstract
PURPOSE HMGA2 has frequently been found in benign as well as malignant tumors and a significant association between HMGA2 overexpression and poor survival in different malignancies was described. In pancreatic ductal adenocarcinoma (PDAC), nuclear HMGA2 expression is associated with tumor dedifferentiation and presence of lymph node metastasis. Nevertheless, the impact of HMGA2 occurrence in other cell compartments is unknown. METHODS Intracellular distribution of HMGA2 was analyzed in PDAC (n = 106) and peritumoral, non-malignant ducts (n = 28) by immunohistochemistry. Findings were correlated with clinico-pathological data. Additionally, intracellular HMGA2 presence was studied by Western blotting of cytoplasmic and nuclear fractions of cultured cells. RESULTS HMGA2 was found in the cytoplasm and in the nucleus of cultured cells. In human tumor tissue, HMGA2 was also frequently found in the cytoplasm and the nucleus of tumor cells, however, nuclear staining was generally stronger. Direct comparison from tumor tissue with corresponding non-neoplastic peritumoral tissue revealed significantly stronger expression in tumors (p = 0.003). Of note, the nuclear staining was significantly stronger in lymph node metastatic cell nuclei compared to primary tumor cell nuclei (p = 0.049). Interestingly, cytoplasmic staining positively correlated with lymph vessel (p = 0.004) and venous invasion (p = 0.046). CONCLUSION HMGA2 is a prognostic marker in PDAC. Firstly, we found a positive correlation for cytoplasmic HMGA2 expression with lympho-vascular invasion and, secondly, we found a significantly stronger nuclear expression of HMGA2 in cancer-positive lymph node nuclei compared to primary tumor cell nuclei. So far, the role of cytoplasmic HMGA2 is nearly unknown, however, our data lend support to the hypothesis that cytoplasmic HMGA2 expression is involved in nodal spread.
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Affiliation(s)
- Jan-Paul Gundlach
- Department of General Surgery, Visceral-, Thoracic-, Transplantation- and Pediatric-Surgery, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Str. 3, Building C, 24105, Kiel, Germany.,Institute for Experimental Cancer Research, University of Kiel, Arnold-Heller-Str. 3, Building U30, 24105, Kiel, Germany
| | - Charlotte Hauser
- Department of General Surgery, Visceral-, Thoracic-, Transplantation- and Pediatric-Surgery, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Str. 3, Building C, 24105, Kiel, Germany.,Institute for Experimental Cancer Research, University of Kiel, Arnold-Heller-Str. 3, Building U30, 24105, Kiel, Germany
| | - Franka Maria Schlegel
- Institute for Experimental Cancer Research, University of Kiel, Arnold-Heller-Str. 3, Building U30, 24105, Kiel, Germany
| | - Anna Willms
- Institute for Experimental Cancer Research, University of Kiel, Arnold-Heller-Str. 3, Building U30, 24105, Kiel, Germany
| | - Christine Halske
- Department of Pathology, UKSH, Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105, Kiel, Germany
| | - Christian Röder
- Institute for Experimental Cancer Research, University of Kiel, Arnold-Heller-Str. 3, Building U30, 24105, Kiel, Germany
| | - Sandra Krüger
- Department of Pathology, UKSH, Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105, Kiel, Germany
| | - Christoph Röcken
- Department of Pathology, UKSH, Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105, Kiel, Germany
| | - Thomas Becker
- Department of General Surgery, Visceral-, Thoracic-, Transplantation- and Pediatric-Surgery, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Str. 3, Building C, 24105, Kiel, Germany
| | - Holger Kalthoff
- Institute for Experimental Cancer Research, University of Kiel, Arnold-Heller-Str. 3, Building U30, 24105, Kiel, Germany
| | - Anna Trauzold
- Department of General Surgery, Visceral-, Thoracic-, Transplantation- and Pediatric-Surgery, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Str. 3, Building C, 24105, Kiel, Germany. .,Institute for Experimental Cancer Research, University of Kiel, Arnold-Heller-Str. 3, Building U30, 24105, Kiel, Germany.
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Papantonis A. HMGs as rheostats of chromosomal structure and cell proliferation. Trends Genet 2021; 37:986-994. [PMID: 34311989 DOI: 10.1016/j.tig.2021.07.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/30/2021] [Accepted: 07/03/2021] [Indexed: 11/18/2022]
Abstract
High mobility group proteins (HMGs) are the most abundant nuclear proteins next to histones and are robustly expressed across tissues and organs. HMGs can uniquely bend or bind distorted DNA, and are central to such processes as transcription, recombination, and DNA repair. However, their dynamic association with chromatin renders capturing HMGs on chromosomes challenging. Recent work has changed this and now implicates these factors in spatial genome organization. Here, I revisit older and review recent literature to describe how HMGs rewire spatial chromatin interactions to sustain homeostasis or promote cellular aging. I propose a 'rheostat' model to explain how HMG-box proteins (HMGBs), and to some extent HMG A proteins (HMGAs), may control cellular aging and, likely, cancer progression.
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Affiliation(s)
- Argyris Papantonis
- Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany.
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38
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Pandey R, Zhou M, Chen Y, Darmoul D, Kisiel CC, Nfonsam VN, Ignatenko NA. Molecular Pathways Associated with Kallikrein 6 Overexpression in Colorectal Cancer. Genes (Basel) 2021; 12:749. [PMID: 34065672 PMCID: PMC8157155 DOI: 10.3390/genes12050749] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/01/2021] [Accepted: 05/14/2021] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide. The high mortality of CRC is related to its ability to metastasize to distant organs. The kallikrein-related peptidase Kallikrein 6 (KLK6) is overexpressed in CRC and contributes to cancer cell invasion and metastasis. The goal of this study was to identify KLK6-associated markers for the CRC prognosis and treatment. Tumor Samples from the CRC patients with significantly elevated KLK6 transcript levels were identified in the RNA-Seq data from Cancer Genome Atlas (TCGA) and their expression profiles were evaluated using Gene Ontology (GO), Phenotype and Reactome enrichment, and protein interaction methods. KLK6-high cases had a distinct spectrum of mutations in titin (TTN), APC, K-RAS, and MUC16 genes. Differentially expressed genes (DEGs) found in the KLK6-overexpressing CRCs were associated with cell signaling, extracellular matrix organization, and cell communication regulatory pathways. The top KLK6-interaction partners were found to be the members of kallikrein family (KLK7, KLK8, KLK10), extracellular matrix associated proteins (keratins, integrins, small proline rich repeat, S100A families) and TGF-β, FOS, and Ser/Thr protein kinase signaling pathways. Expression of selected KLK6-associated genes was validated in a subset of paired normal and tumor CRC patient-derived organoid cultures. The performed analyses identified KLK6 itself and a set of genes, which are co-expressed with KLK6, as potential clinical biomarkers for the management of the CRC disease.
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Affiliation(s)
- Ritu Pandey
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, USA;
- University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA;
| | - Muhan Zhou
- Bioinformatics Shared Resource, University of Arizona Cancer Center, Tucson, AZ 85724, USA; (M.Z.); (Y.C.)
| | - Yuliang Chen
- Bioinformatics Shared Resource, University of Arizona Cancer Center, Tucson, AZ 85724, USA; (M.Z.); (Y.C.)
| | - Dalila Darmoul
- Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Lariboisière Hospital, 75010 Paris, France;
| | - Conner C. Kisiel
- University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA;
| | - Valentine N. Nfonsam
- Department of Surgery, Section of Surgical Oncology, University of Arizona, Tucson, AZ 85724, USA;
| | - Natalia A. Ignatenko
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, USA;
- University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA;
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Shirai K, Nagae G, Seki M, Kudo Y, Kamio A, Hayashi A, Okabe A, Ota S, Tsutsumi S, Fujita T, Yamamoto S, Nakaki R, Kanki Y, Osawa T, Midorikawa Y, Tateishi K, Ichinose M, Aburatani H. TET1 upregulation drives cancer cell growth through aberrant enhancer hydroxymethylation of HMGA2 in hepatocellular carcinoma. Cancer Sci 2021; 112:2855-2869. [PMID: 33970549 PMCID: PMC8253281 DOI: 10.1111/cas.14897] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 03/17/2021] [Accepted: 03/18/2021] [Indexed: 12/12/2022] Open
Abstract
Ten‐eleven translocation 1 (TET1) is an essential methylcytosine dioxygenase of the DNA demethylation pathway. Despite its dysregulation being known to occur in human cancer, the role of TET1 remains poorly understood. In this study, we report that TET1 promotes cell growth in human liver cancer. The transcriptome analysis of 68 clinical liver samples revealed a subgroup of TET1‐upregulated hepatocellular carcinoma (HCC), demonstrating hepatoblast‐like gene expression signatures. We performed comprehensive cytosine methylation and hydroxymethylation (5‐hmC) profiling and found that 5‐hmC was aberrantly deposited preferentially in active enhancers. TET1 knockdown in hepatoma cell lines decreased hmC deposition with cell growth suppression. HMGA2 was highly expressed in a TET1high subgroup of HCC, associated with the hyperhydroxymethylation of its intronic region, marked as histone H3K4–monomethylated, where the H3K27‐acetylated active enhancer chromatin state induced interactions with its promoter. Collectively, our findings point to a novel type of epigenetic dysregulation, methylcytosine dioxygenase TET1, which promotes cell proliferation via the ectopic enhancer of its oncogenic targets, HMGA2, in hepatoblast‐like HCC.
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Affiliation(s)
- Kiyokazu Shirai
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.,Department of Gastroenterology, Wakayama Medical University, Wakayama, Japan
| | - Genta Nagae
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Motoaki Seki
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.,Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yotaro Kudo
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Asuka Kamio
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.,Laboratory of Genetics, Department of Biological Sciences, The University of Tokyo, Tokyo, Japan
| | - Akimasa Hayashi
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.,Department of Pathology, Kyorin University Faculty of Medicine, Mitaka, Japan
| | - Atsushi Okabe
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.,Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Satoshi Ota
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Shuichi Tsutsumi
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Takanori Fujita
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Shogo Yamamoto
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Ryo Nakaki
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Yasuharu Kanki
- Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Tsuyoshi Osawa
- Division of Integrative Nutriomics and Oncology, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Yutaka Midorikawa
- Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Keisuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masao Ichinose
- Department of Gastroenterology, Wakayama Medical University, Wakayama, Japan.,Faculty of Medicine, Teikyo University, Tokyo, Japan
| | - Hiroyuki Aburatani
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
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40
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Lan YL, Zhang J. Modulation of untranslated region alternative polyadenylation in glioma tumorigenesis. Biomed Pharmacother 2021; 137:111416. [DOI: 10.1016/j.biopha.2021.111416] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/12/2021] [Accepted: 02/16/2021] [Indexed: 01/10/2023] Open
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Barca I, Mignogna C, Donato G, Cristofaro MG. Expression of PLAG1, HMGA1 and HMGA2 in minor salivary glands tumours. Gland Surg 2021; 10:1609-1617. [PMID: 34164305 DOI: 10.21037/gs-20-667] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Background Diagnosis of minor salivary gland (MSG) tumours is often difficult, due to the scarce tissue obtained from bioptic excision and complex histopathological differential diagnosis. In our study we performed an immunohistochemical analysis of PLAG1, HMGA1 and HMGA2 on a series of MSG tumours, in order to develop a new helpful diagnostic panel. Methods A retrospective series of 17 surgical specimens of MSG tumours were analysed for the expression of PLAG1, HMGA1 and HMGA2. Three control cases were enrolled and analysed. An intensity and percentage-based approach was performed, creating a combined score panel. Results PLAG1 facilitate the diagnosis of benign tumours, discriminating it from malignant histotypes, with a defined cut-off value. Similarly, HMGA1 is significantly higher in benign histotypes than in malignant ones. HMGA2 in our series, did not reveal any association in identifying benign from malignant histotypes. Conclusions In this study we assessed the diagnostic role of PLAG1, HMGA1 and HMGA2 immunohistochemical analysis. The score panel facilitate histopathological diagnosis of these rare tumours, helping to distinguish benign tumours from malignant ones and ameliorating the differential diagnosis of specific histotypes.
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Affiliation(s)
- Ida Barca
- Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy
| | - Chiara Mignogna
- Department of Health Science, Magna Græcia University, Catanzaro, Italy
| | - Giuseppe Donato
- Department of Health Science, Magna Græcia University, Catanzaro, Italy
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Ma J, Kong FF, Yang D, Yang H, Wang C, Cong R, Ma XX. lncRNA MIR210HG promotes the progression of endometrial cancer by sponging miR-337-3p/137 via the HMGA2-TGF-β/Wnt pathway. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 24:905-922. [PMID: 34094710 PMCID: PMC8141672 DOI: 10.1016/j.omtn.2021.04.011] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Accepted: 04/09/2021] [Indexed: 02/07/2023]
Abstract
Epithelial-mesenchymal transition (EMT) promotes tumorigenesis and metastasis and increases tumor tolerance to treatment intervention. Abnormal activation of transforming growth factor β (TGF-β) and Wnt pathway induces EMT. Long non-coding RNAs (lncRNAs) significantly influence EMT regulation. Herein, we show that MIR210HG is overexpressed in endometrial cancer tissues, which is associated with poor prognosis. MIR210HG silencing significantly inhibited proliferation, migration, invasion, and EMT phenotype formation in vitro as well as tumorigenesis in vivo. Mechanistically, bioinformatics analyses, RNA binding protein immunoprecipitation (RIP) assays, and luciferase assays showed that MIR210HG acts as a molecular sponge of miR-337-3p and miR-137 to regulate the expression of HMGA2. Additionally, MIR210HG overexpression significantly enriched the Wnt/β-catenin and TGF-β/Smad3 signaling pathway genes, while MIR210HG or HMGA2 knockdown suppressed the Wnt/β-catenin and TGF-β/Smad3 signaling pathway. Our findings on the MIR210HG-miR-337-3p/137-HMGA2 axis illustrate its potential as a target for endometrial cancer therapeutic development.
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Affiliation(s)
- Jian Ma
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Fan-Fei Kong
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Di Yang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Hui Yang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Cuicui Wang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Rong Cong
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Xiao-Xin Ma
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China
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HMGA2 as a Critical Regulator in Cancer Development. Genes (Basel) 2021; 12:genes12020269. [PMID: 33668453 PMCID: PMC7917704 DOI: 10.3390/genes12020269] [Citation(s) in RCA: 117] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 02/01/2021] [Accepted: 02/08/2021] [Indexed: 02/07/2023] Open
Abstract
The high mobility group protein 2 (HMGA2) regulates gene expression by binding to AT-rich regions of DNA. Akin to other DNA architectural proteins, HMGA2 is highly expressed in embryonic stem cells during embryogenesis, while its expression is more limited at later stages of development and in adulthood. Importantly, HMGA2 is re-expressed in nearly all human malignancies, where it promotes tumorigenesis by multiple mechanisms. HMGA2 increases cancer cell proliferation by promoting cell cycle entry and inhibition of apoptosis. In addition, HMGA2 influences different DNA repair mechanisms and promotes epithelial-to-mesenchymal transition by activating signaling via the MAPK/ERK, TGFβ/Smad, PI3K/AKT/mTOR, NFkB, and STAT3 pathways. Moreover, HMGA2 supports a cancer stem cell phenotype and renders cancer cells resistant to chemotherapeutic agents. In this review, we discuss these oncogenic roles of HMGA2 in different types of cancers and propose that HMGA2 may be used for cancer diagnostic, prognostic, and therapeutic purposes.
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Mahmood N, Mushtaq S, Jamal Q, Hanif M, Akhlaq H, Rehman DES, Awan R. Potential Utility of Cell Free High Mobility Group AT-hook 2 (HMGA2) as a Prognostic Biomarker in Liquid Biopsies of Oral Squamous Cell Carcinoma. Asian Pac J Cancer Prev 2021; 22:407-412. [PMID: 33639654 PMCID: PMC8190352 DOI: 10.31557/apjcp.2021.22.2.407] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Indexed: 12/24/2022] Open
Abstract
Background: Locoregional spread is a frequent finding in oral cancer which dictates poor prognosis. HMGA2 expression has been linked to malignant traits of oral cancer in tissue biopsies however, data on HMGA2 expression in liquid biopsies in oral cancer is sparse. Purpose of this study was to explore prognostic relevance of HMGA2 in liquid biopsies of oral cancer patients. Patients and Methods: After obtaining approval from Institutional Review Board of Ziauddin University and informed written consent from study subjects, expression of circulating HMGA2 was evaluated in 96 OSCC cases and 100 age and sex matched controls via real time PCR using specific set of primers. We further analyzed relationship of various sociodemographic and clinicopathological variables with HMGA2expression and explored its prognostic potential. Results: Expression was seen in 22 (23%) cases. A higher expression was observed among subjects with local invasion (52.6% vs 47.4 %), distant metastasis (71.4% vs 28.6%) and tumor recurrence (57.1% vs 42.9%) p <0.05. Subjects having HMGA2 expression had a poor survival compared to HMGA2 negative (13.6% vs 35.4%), p <0.05. Conclusion: Circulating HMGA2 reflects presence of local invasion and distant metastasis and dictates poor prognosis in OSCC. It may contribute in categorizing high risk patients using a minimally invasive technique who are likely to benefit from targeted therapy.
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Affiliation(s)
| | - Shamim Mushtaq
- Biochemsitry, Director Postgraduate Ziauddin University, Pakistan
| | | | - Muhammad Hanif
- Karachi Institute of Radiotherapy and Nuclear Medicine, Pakistan
| | | | | | - Rashid Awan
- Internal, Medicine, Chinniot General Hospital, Pakistan
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45
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Wang YD, Mao JD, Wang JF, Xu MQ. MiR-590 Suppresses Proliferation and Induces Apoptosis in Pancreatic Cancer by Targeting High Mobility Group A2. Technol Cancer Res Treat 2021; 19:1533033820928143. [PMID: 32588766 PMCID: PMC7325540 DOI: 10.1177/1533033820928143] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma is a common malignancy with high morbidity. MicroRNAs have been demonstrated to be critical posttranscriptional regulators in tumorigenesis. This study aimed to investigate the effect of microRNA-590 on the proliferation and apoptosis of pancreatic ductal adenocarcinoma. MATERIAL AND METHODS The expression of microRNA-590 and high mobility group AT-hook 2 were examined in clinical pancreatic ductal adenocarcinoma tissues. Pancreatic ductal adenocarcinoma cell line Capan-2 was employed and transfected with microRNA-590 mimics or inhibitor. The correlation between microRNA-590 and high mobility group AT-hook 2 was verified by luciferase reporter assay. Cell viability and apoptosis were detected by MTT and flow cytometry assay. The protein level of high mobility group AT-hook 2, AKT, p-AKT, mTOR, and phosphorylated mTOR were analyzed by Western blotting. RESULTS MicroRNA-590 was found to be negatively correlated with the expression of high mobility group AT-hook 2 in pancreatic ductal adenocarcinoma tissues. Further studies identified high mobility group AT-hook 2 as a direct target of microRNA-590. Moreover, overexpression of microRNA-590 downregulated expression of high mobility group AT-hook 2, reduced cell viability, and promoted cell apoptosis, while knockdown of miR-590 led to an inverse result. MicroRNA-590 also suppressed the phosphorylation of AKT and mTOR without altering total AKT and mTOR levels. CONCLUSION Our study indicated that microRNA-590 negatively regulates the expression of high mobility group AT-hook 2 in clinical specimens and in vitro. MicroRNA-590 can inhibit cell proliferation and induce cell apoptosis in pancreatic ductal adenocarcinoma cells. This regulatory effect of microRNA-590 may be associated with AKT signaling pathway. Therefore, microRNA-590 has the potential to be used as a biomarker for predicting the progression of pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Ya-Dong Wang
- Department of general surgery, Wuhu Hospital of Traditional Chinese Medicine, Wuhu, Anhui, People’s Republic of China
| | - Jia-Ding Mao
- Department of General Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, People’s Republic of China
- Jia-Ding Mao, Department of General Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui 241000, People’s Republic of China.
| | - Jun-Feng Wang
- Department of General Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, People’s Republic of China
| | - Mao-Qi Xu
- Department of general surgery, Wuhu Hospital of Traditional Chinese Medicine, Wuhu, Anhui, People’s Republic of China
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Li C, Li Y, Lu Y, Niu Z, Zhao H, Peng Y, Li M. miR-26 family and its target genes in tumorigenesis and development. Crit Rev Oncol Hematol 2021; 157:103124. [PMID: 33254041 DOI: 10.1016/j.critrevonc.2020.103124] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 08/27/2020] [Accepted: 10/02/2020] [Indexed: 12/12/2022] Open
Abstract
The microRNA-26 family, including miR-26a, miR-26b, miR-1297 and miR-4465, is a group of broadly conserved small RNAs with identical sequences at the seed region. The expression of miR-26 could be induced by hypoxia via a HIF-dependent mechanism, and up-regulated during multiple cell differentiation. Accumulating studies have demonstrated that miR-26 family members could be detected in many different kinds of tumors, and their validated target genes are involved in cell metabolism, proliferation, differentiation, apoptosis, invasion and metastasis. The expression of miR-26 might be a potentially valuable biomarker and a new target for cancer therapy. In this review, miR-26 family and its target genes in tumorigenesis and development will be summarized as follows.
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Affiliation(s)
- Chuangang Li
- The Second Affiliated Hospital of Dalian Medical University, Dalian 116027, China.
| | - Yongyi Li
- University of Virginia, Charlottesville, VA 22903, USA
| | - Yufeng Lu
- Dalian Medical University, Dalian 116044, China
| | - Zhaorui Niu
- Dalian Medical University, Dalian 116044, China
| | - Henan Zhao
- College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Yan Peng
- College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Molin Li
- College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
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Xu J, Fang X, Long L, Wang S, Qian S, Lyu J. HMGA2 promotes breast cancer metastasis by modulating Hippo-YAP signaling pathway. Cancer Biol Ther 2020; 22:5-11. [PMID: 33307962 DOI: 10.1080/15384047.2020.1832429] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Breast cancer is the most common cancer in women, and triple-negative breast cancer (TNBC) accounts for about 15-20% of all breast cancer. High mobility group AT-hook 2 (HMGA2) is overexpressed in some tumors and closely associated with patients' prognosis. However, the mechanisms involved in the regulation of HMGA2 in TNBC still remain unclear. METHODS In this study, HMGA2 level in TNBC cell lines was analyzed by western blot. After knockdown of HMGA2 expression by RNA interference in TNBC cell lines MDA-MB-231 and SUM149, wound healing and transwell assays were conducted to examine the effects of HMGA2 on migration and invasion. Tumor metastasis was assessed in amouse xenograft model invivo. Furthermore, expression levels of epithelial-mesenchymal transition (EMT) biomarkers and involvement of the Hippo-YAP pathway were detected by western blot. RESULTS Compared to normal breast epithelial cells, the expression levels of HMGA2 were significantly increased in TNBC cell lines (all P< .05). Downregulation of HMGA2 dramatically inhibited the migration and invasion of MDA-MB-231 and SUM149 cells (all P< .01) invitro, and suppressed the tumor metastasis of nude mice xenograft model invivo. Western blot analysis revealed alterations in EMT biomarkers: the expression of mesenchymal markers N-cadherin, Vimentin and Snail were decreased, while the expression of epithelial marker E-cadherin was increased. Downregulated expression of HMGA2 attenuated Hippo-YAP related protein expression and the stability of YAP. CONCLUSIONS HMGA2 is highly expressed in TNBC cells. Downregulation of HMGA2 inhibits the migration and invasion of TNBC and invivo tumor metastasis mediated through inhibition of EMT and Hippo-YAP pathway.
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Affiliation(s)
- Jianxin Xu
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University , Wenzhou, Zhejiang, China
| | - Xuejiao Fang
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University , Wenzhou, Zhejiang, China
| | - Luye Long
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University , Wenzhou, Zhejiang, China
| | - Sixuan Wang
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University , Wenzhou, Zhejiang, China
| | - Shihan Qian
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University , Wenzhou, Zhejiang, China
| | - Jianxin Lyu
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University , Wenzhou, Zhejiang, China
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Zhang L, Xie H, Li S. LncRNA LOXL1-AS1 controls osteogenic and adipocytic differentiation of bone marrow mesenchymal stem cells in postmenopausal osteoporosis through regulating the miR-196a-5p/Hmga2 axis. J Bone Miner Metab 2020; 38:794-805. [PMID: 32651705 DOI: 10.1007/s00774-020-01123-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 06/26/2020] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Exploring molecular mechanisms of human bone marrow mesenchymal stem cells (hBMMSCs) differentiation, a crucial step for bone formation, is a new direction for treating postmenopausal osteoporosis. LncRNAs are involved in lots of biological processes including hBMMSCs differentiation. The present study aimed to explore the effect of LOXL1-AS1 on hBMMSCs differentiation. MATERIALS AND METHODS We examined the expression levels of LOXL1-AS1, miR-196a-5p and Hmga2 in peripheral blood from postmenopausal osteoporosis patients by RT-qPCR, and detected their changes during the osteogenic differentiation of hBMMSCs by RT-qPCR. RT-qPCR and western blot measured the level of biomarkers of bone formation and osteogenic differentiation (osteopontin, OPN; Alkaline phosphatase, ALP; Runt-related transcription factor-2, Runx-2). The effects of LOXL1-AS1 on the osteogenic and adipocytic differentiation of hBMMSCs were, respectively, determined by ALP, ARS staining assays and oil red O staining assay. RESULTS The abnormal high expression of LOXL1-AS1 was found in patients. LOXL1-AS1 expression showed a gradual decrease during the osteogenic differentiation of hBMMSCs. However, LOXL1-AS1 overexpression inhibited the hBMMSCs osteogenic differentiation but promoted adipocytic differentiation. Furthermore, LOXL1-AS1 was identified to be a sponge of miR-196a-5p and Hmga2 as a target gene of miR-196a-5p. Besides, LOXL1-AS1 sponged miR-196a-5p to mediate Hmga2 expression, which played contrary effects on regulating osteogenic and adipocytic differentiation of hBMMSCs. Moreover, LOXL1-AS1/miR-196a-5p/Hmga2 axis regulated hBMMSCs differentiation through controlling C/EBPβ-mediated PPARγ expression. CONCLUSION These findings facilitate understanding the molecular mechanism of hBMMSCs differentiation and bring up a novel sight for postmenopausal osteoporosis therapy.
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Affiliation(s)
- Ling Zhang
- Department of Geriatrics, the First Affiliated Hospital, Sun Yat-Sen University, No. 58 Zhongshan 2nd Road, Guangzhou City, 510080, Guangdong Province, China.
| | - Haiqin Xie
- Department of Ultrasound, Peking University Shenzhen Hospital, Shenzhen City, 518036, Guangdong Province, China
| | - Shiliang Li
- Healthcare Office, the First Affiliated Hospital, Sun Yat-Sen University, No. 58 Zhongshan 2nd Road, Guangzhou City, 510080, Guangdong Province, China
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Pegoraro S, Ros G, Sgubin M, Petrosino S, Zambelli A, Sgarra R, Manfioletti G. Targeting the intrinsically disordered architectural High Mobility Group A (HMGA) oncoproteins in breast cancer: learning from the past to design future strategies. Expert Opin Ther Targets 2020; 24:953-969. [PMID: 32970506 DOI: 10.1080/14728222.2020.1814738] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Triple-negative breast cancer (TNBC) is the most difficult breast cancer subtype to treat because of its heterogeneity and lack of specific therapeutic targets. High Mobility Group A (HMGA) proteins are chromatin architectural factors that have multiple oncogenic functions in breast cancer, and they represent promising molecular therapeutic targets for this disease. AREAS COVERED We offer an overview of the strategies that have been exploited to counteract HMGA oncoprotein activities at the transcriptional and post-transcriptional levels. We also present the possibility of targeting cancer-associated factors that lie downstream of HMGA proteins and discuss the contribution of HMGA proteins to chemoresistance. EXPERT OPINION Different strategies have been exploited to counteract HMGA protein activities; these involve interfering with their nucleic acid binding properties and the blocking of HMGA expression. Some approaches have provided promising results. However, some unique characteristics of the HMGA proteins have not been exploited; these include their extensive protein-protein interaction network and their intrinsically disordered status that present the possibility that HMGA proteins could be involved in the formation of proteinaceous membrane-less organelles (PMLO) by liquid-liquid phase separation. These unexplored characteristics could open new pharmacological avenues to counteract the oncogenic contributions of HMGA proteins.
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Affiliation(s)
- Silvia Pegoraro
- Department of Life Sciences, University of Trieste , Trieste, Italy
| | - Gloria Ros
- Department of Life Sciences, University of Trieste , Trieste, Italy
| | - Michela Sgubin
- Department of Life Sciences, University of Trieste , Trieste, Italy
| | - Sara Petrosino
- Department of Life Sciences, University of Trieste , Trieste, Italy
| | | | - Riccardo Sgarra
- Department of Life Sciences, University of Trieste , Trieste, Italy
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Takahashi T, Kawaji H, Murakawa Y, Hayashizaki Y, Murakami T, Yabushita Y, Homma Y, Kumamoto T, Matsuyama R, Endo I. Significance of HMGA2 expression as independent poor prognostic marker in perihilar and distal cholangiocarcinoma resected with curative intent. Eur J Surg Oncol 2020; 47:394-400. [PMID: 32878723 DOI: 10.1016/j.ejso.2020.08.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 06/13/2020] [Accepted: 08/05/2020] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Extrahepatic cholangiocarcinoma requires invasive surgery and is associated with poor prognosis; thus, a prognostic biomarker is highly needed. Extrahepatic cholangiocarcinoma is sub-classified into two types based on their location, namely perihilar and distal. Perihilar cholangiocarcinoma requires lobectomy as curative surgical resection, whereas the distal requires pancreatoduodenectomy. HMGA2 overexpression is reported to correlate with progression, aggressiveness, dissemination and poor prognosis in several types of cancers. Although its association with extrahepatic cholangiocarcinoma has been reported, none of the previous studies assessed its significance in each subtype. METHODS We assessed the expression of HMGA2 protein in surgical specimens after curative intent surgery in 80 patients including 41 with perihilar cholangiocarcinoma and 39 with distal cholangiocarcinoma by immunohistochemistry. We then examined its association with clinicopathological findings and patient survival outcomes. RESULTS We found that HMGA2 was expressed in 51% (21 of 41) of perihilar cholangiocarcinoma and 41% (16 of 39) of distal cholangiocarcinoma samples. In perihilar cholangiocarcinoma, we found significant correlations between expression and vascular invasion and perineural invasion. In distal cholangiocarcinoma, we found that protein levels correlated with tumor grade. Univariate and multivariate analyses demonstrated that HMGA2 expression was an independent poor prognostic factor for patients with both subtypes of disease. CONCLUSIONS Our results revealed that HMGA2 expression as an independent prognostic marker for both perihilar and distal cholangiocarcinoma that were resected with curative intent.
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Affiliation(s)
- Tomoaki Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Hideya Kawaji
- Preventive Medicine and Applied Genomics Unit, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Tokyo Metropolitan Institute of Medical Sciences, Tokyo, Japan; RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Japan
| | - Yasuhiro Murakawa
- RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Japan; RIKEN-IFOM Joint Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; RIKEN-HMC Clinical Omics Unit, RIKEN Baton Zone Program, Yokohama, Japan
| | | | - Takashi Murakami
- Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Yasuhiro Yabushita
- Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Yuki Homma
- Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Takafumi Kumamoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
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