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Cáceres A, Pérez-Jurado LA, Alegret-García A, Dwaraka VB, Smith R, González JR. Defective X-chromosome inactivation and cancer risk in women. Commun Biol 2025; 8:289. [PMID: 39987288 PMCID: PMC11846847 DOI: 10.1038/s42003-025-07691-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 02/06/2025] [Indexed: 02/24/2025] Open
Abstract
X-chromosome inactivation (XCI) is a fundamental mechanism in placental mammals that compensates for gene dosage differences between sexes. Using methylation levels of genes under XCI, we establish defective levels of XCI as a new source of interindividual variation among cancer types in females, characterized by a significant and consistent lowering of XIST expression and enrichment of differentially expressed genes under XCI. We show that defective XCI is an additive factor to the cancer risk of XCI escape deregulation in women. Defective XCI of more than 10% has an attributable risk of 40% among 12 different cancers from The Cancer Genome Atlas. Validations between independent studies of breast cancer samples show that defective XCI increases triple-negative subtype frequency, decreases survival rates, and is reduced by chemotherapy treatment. Mechanistically, it is associated with somatic mutations at TP53 and top MYC gains. In independent studies, defective XCI is detectable in blood and increases with aging, menopause, and cancer diagnosis.
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Affiliation(s)
- Alejandro Cáceres
- Instituto de Salud Global de Barcelona (ISGlobal), Barcelona, Spain.
- Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.
| | - Luis A Pérez-Jurado
- Genetics Unit, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
- Genetics Service, Hospital del Mar and Institut Hospital del Mar d'Investigacions Mediques (IMIM), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
| | - Albert Alegret-García
- Instituto de Salud Global de Barcelona (ISGlobal), Barcelona, Spain
- Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
| | | | | | - Juan R González
- Instituto de Salud Global de Barcelona (ISGlobal), Barcelona, Spain
- Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
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2
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Lee S, Ricci B, Tran J, Eul E, Ye J, Ren Q, Clever D, Wang J, Wong P, Haas MS, Stewart SA, Ma CX, Fehniger TA, Faccio R. Stroma-derived Dickkopf-1 contributes to the suppression of NK cell cytotoxicity in breast cancer. Nat Commun 2025; 16:1183. [PMID: 39885132 PMCID: PMC11782527 DOI: 10.1038/s41467-025-56420-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 01/14/2025] [Indexed: 02/01/2025] Open
Abstract
Mechanisms related to tumor evasion from NK cell-mediated immune surveillance remain enigmatic. Dickkopf-1 (DKK1) is a Wnt/β-catenin inhibitor, whose levels correlate with breast cancer progression. We find DKK1 to be expressed by tumor cells and cancer-associated fibroblasts (CAFs) in patient samples and orthotopic breast tumors, and in bone. By using genetic approaches, we find that bone-derived DKK1 contributes to the systemic DKK1 elevation in tumor-bearing female mice, while CAFs contribute to DKK1 at primary tumor site. Systemic and bone-specific DKK1 targeting reduce tumor growth. Intriguingly, deletion of CAF-derived DKK1 also limits breast cancer progression, without affecting its levels in circulation, and regardless of DKK1 expression in the tumor cells. While not directly supporting tumor proliferation, stromal-DKK1 suppresses NK cell activation and cytotoxicity by downregulating AKT/ERK/S6 phosphorylation. Importantly, increased DKK1 levels and reduced cytotoxic NK cells are detected in women with progressive breast cancer. Our findings indicate that DKK1 represents a barrier to anti-tumor immunity through suppression of NK cells.
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Affiliation(s)
- Seunghyun Lee
- Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Biancamaria Ricci
- Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Jennifer Tran
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Emily Eul
- Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Jiayu Ye
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA
| | - Qihao Ren
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA
| | - David Clever
- Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Julia Wang
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
- McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, USA
| | - Pamela Wong
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | | | - Sheila A Stewart
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA
- Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Cynthia X Ma
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Todd A Fehniger
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Roberta Faccio
- Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA.
- Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
- Shriners Hospitals for Children St Louis, St Louis, MO, USA.
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Sikder S, Bhattacharya A, Agrawal A, Sethi G, Kundu TK. Micro-RNAs in breast cancer progression and metastasis: A chromatin and metabolic perspective. Heliyon 2024; 10:e38193. [PMID: 39386816 PMCID: PMC11462366 DOI: 10.1016/j.heliyon.2024.e38193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 09/06/2024] [Accepted: 09/19/2024] [Indexed: 10/12/2024] Open
Abstract
Breast cancer is a highly complex disease with multiple subtypes. While many of the breast cancer cases are sporadic some can be familial or hereditary. Genomic integrity is closely monitored by several mechanisms, such as DNA damage machinery and mitotic checkpoints. Any defect in the key genes involved in the regulation of these mechanisms often results in genomic instability, predisposing the cells to malignancy. This results in altered expression of many coding and noncoding genes. The noncoding RNAs especially the long noncoding RNA (lncRNAs) and microRNA (miRNAs) act as key regulators of cancer gene networks. Some miRNAs repress the expression of the heterochromatin-associated proteins, inducing the formation of open chromatin, and promoting the expression of genes required for oncogenesis. Additionally, specific miRNAs may also favour cancer progression and metastasis by regulating the expression of genes that support the metabolic microenvironment essential for cancer cell growth and proliferation. Understanding how these noncoding RNAs contribute to breast cancer development opens potential avenues for therapeutic intervention, targeting their dysregulated activity.
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Affiliation(s)
- Sweta Sikder
- Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, 560064, India
| | - Aditya Bhattacharya
- Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, 560064, India
| | - Aayushi Agrawal
- Division of Cancer Biology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, UP, India
- Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, 117600, Singapore
| | - Tapas K. Kundu
- Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, 560064, India
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Zhang W, Xiao Y, Zhu X, Zhang Y, Xiang Q, Wu S, Song X, Zhao J, Yuan R, Li Q, Xiao B, Li L. Integrative Pan-Cancer Analysis Reveals the Oncogenic Role of MND1 and Validation of MND1's Role in Breast Cancer. J Inflamm Res 2024; 17:4721-4746. [PMID: 39051055 PMCID: PMC11268618 DOI: 10.2147/jir.s458832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 06/25/2024] [Indexed: 07/27/2024] Open
Abstract
Purpose Meiotic nuclear division 1 (MND1) is a meiosis-specific protein that promotes lung adenocarcinoma progression. However, its expression and biological function across cancers remain largely unexplored. Patients and Methods The expression, prognostic significance, mutation status, and methylation profile of MND1 in various cancers were comprehensively analyzed using the TIMER, GTEX, Kaplan-Meier plotter, cBioPortal, and GSCA databases. Additionally, we constructed a PPI network, enrichment analysis and single-cell transcriptomic sequencing to elucidate the underlying mechanism of MND1. Furthermore, we investigated the association between MND1 expression and drug sensitivity using CellMiner. Moreover, we also explored the correlation between MND1 expression and immune infiltration. Finally, we validated the functional role of MND1 in breast cancer through IHC staining, CCK8, EdU, colony formation, and flow cytometry assays. Results MND1 has been reported to be highly expressed in Pan-cancer, High MND1 expression was significantly associated with poor prognosis in cancers. Additionally, MND1 mutation frequency is high in most cancers, and its expression correlates with methylation. Furthermore, MND1 expression significantly correlates with immune checkpoint blockade (ICB) markers, including PD-L1, PD-1, and CTLA-4. The PPI network reveals interactions between MND1 and PSMC3IP, BRCA1, and BRCA2. Enrichment analysis and single-cell sequencing indicate that MND1 positively correlates with cell cycle. ROC curve reveals favorable diagnostic efficacy of MND1 in breast cancer. In vitro, MND1 overexpression promotes breast cancer cell proliferation and increases the expression of key cell cycle regulators (CDK4, CDK6, and cyclin D3), accelerating the G1/S phase transition and leading to abnormal breast cancer cell proliferation. The immunohistochemical analysis revealed a robust expression of MND1 in breast cancer tissues, exhibiting a significant positive correlation with PD-L1 and FOXP3. Conclusion MND1 is an oncogene and may serve as a biomarker for cancer prognosis and immunotherapy. Targeting MND1 may be a potential tumor treatment strategy.
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Affiliation(s)
- Wenwu Zhang
- Department of Laboratory Medicine, The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan, Guangdong, 511518, People’s Republic of China
- Department of Laboratory Medicine, Suzhou Municipal Hospital, Affiliated to Nanjing Medical University, Suzhou, 21500, People’s Republic of China
| | - Yuhan Xiao
- School of Public Health, Dali University, Dali, 671000, People’s Republic of China
| | - Xin Zhu
- Department of Laboratory Medicine, The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan, Guangdong, 511518, People’s Republic of China
| | - Yanxia Zhang
- Department of Laboratory Medicine, The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan, Guangdong, 511518, People’s Republic of China
| | - Qin Xiang
- Department of Laboratory Medicine, The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan, Guangdong, 511518, People’s Republic of China
| | - Shunhong Wu
- Department of Laboratory Medicine, The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan, Guangdong, 511518, People’s Republic of China
| | - Xiaoyu Song
- Department of Laboratory Medicine, The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan, Guangdong, 511518, People’s Republic of China
| | - Junxiu Zhao
- School of Public Health, Dali University, Dali, 671000, People’s Republic of China
| | - Ruanfei Yuan
- Department of Laboratory Medicine, The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan, Guangdong, 511518, People’s Republic of China
| | - Qiguang Li
- Department of Laboratory Medicine, The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan, Guangdong, 511518, People’s Republic of China
| | - Bin Xiao
- Department of Laboratory Medicine, The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan, Guangdong, 511518, People’s Republic of China
| | - Linhai Li
- Department of Laboratory Medicine, The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan, Guangdong, 511518, People’s Republic of China
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Carey-Smith SL, Kotecha RS, Cheung LC, Malinge S. Insights into the Clinical, Biological and Therapeutic Impact of Copy Number Alteration in Cancer. Int J Mol Sci 2024; 25:6815. [PMID: 38999925 PMCID: PMC11241182 DOI: 10.3390/ijms25136815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 06/15/2024] [Accepted: 06/17/2024] [Indexed: 07/14/2024] Open
Abstract
Copy number alterations (CNAs), resulting from the gain or loss of genetic material from as little as 50 base pairs or as big as entire chromosome(s), have been associated with many congenital diseases, de novo syndromes and cancer. It is established that CNAs disturb the dosage of genomic regions including enhancers/promoters, long non-coding RNA and gene(s) among others, ultimately leading to an altered balance of key cellular functions. In cancer, CNAs have been associated with almost all steps of the disease: predisposition, initiation, development, maintenance, response to treatment, resistance, and relapse. Therefore, understanding how specific CNAs contribute to tumourigenesis may provide prognostic insight and ultimately lead to the development of new therapeutic approaches to improve patient outcomes. In this review, we provide a snapshot of what is currently known about CNAs and cancer, incorporating topics regarding their detection, clinical impact, origin, and nature, and discuss the integration of innovative genetic engineering strategies, to highlight the potential for targeting CNAs using novel, dosage-sensitive and less toxic therapies for CNA-driven cancer.
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Affiliation(s)
- Shannon L. Carey-Smith
- Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia; (S.L.C.-S.); (R.S.K.); (L.C.C.)
- Curtin Medical School, Curtin University, Perth, WA 6102, Australia
| | - Rishi S. Kotecha
- Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia; (S.L.C.-S.); (R.S.K.); (L.C.C.)
- Curtin Medical School, Curtin University, Perth, WA 6102, Australia
- Department of Clinical Haematology, Oncology, Blood and Marrow Transplantation, Perth Children’s Hospital, Perth, WA 6009, Australia
- UWA Medical School, University of Western Australia, Perth, WA 6009, Australia
| | - Laurence C. Cheung
- Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia; (S.L.C.-S.); (R.S.K.); (L.C.C.)
- Curtin Medical School, Curtin University, Perth, WA 6102, Australia
- Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia
| | - Sébastien Malinge
- Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia; (S.L.C.-S.); (R.S.K.); (L.C.C.)
- Curtin Medical School, Curtin University, Perth, WA 6102, Australia
- UWA Medical School, University of Western Australia, Perth, WA 6009, Australia
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Parimita S, Das A, Samanta S. VGLL1 stabilization of cytoplasmic TAZ promotes EGFR expression and maintains tumor initiating cells in breast cancer independent of TEAD. Cell Signal 2024; 118:111120. [PMID: 38417636 DOI: 10.1016/j.cellsig.2024.111120] [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: 10/17/2023] [Revised: 02/22/2024] [Accepted: 02/25/2024] [Indexed: 03/01/2024]
Abstract
Vestigial-like family member 1 (VGLL1) is one of the X-linked genes whose expression is elevated in basal-like breast cancer (BLBC) because of X-chromosome isodisomy. As an approach towards understanding its function, we performed correlation study using transcript data of breast cancer patients from cBioPortal for Cancer Genomics. Our analysis identified EGFR as the most correlated transcript with VGLL1. We demonstrate that VGLL1 promotes EGFR expression and increases the frequency of breast tumor initiating cells (CD44high/+CD24low/-). These findings are crucial because an elevated EGFR expression and high frequency of CD44high/+CD24low/- cells are defining features of BLBC, and we provide a new mechanistic insight into how their expressions are controlled. Importantly, VGLL1 regulation of EGFR and CD44high/+CD24low/- population is mediated by the hippo-transducer TAZ which exerts its oncogenic roles by binding and activating TEAD transcription factors. A crucial finding is that TEAD-binding domain of TAZ is dispensable for its regulation of EGFR and CD44high/+CD24low/- cells. Instead, VGLL1 stabilization of cytoplasmic TAZ is essential for these functions. Also, we show that VGLL1/TAZ restricts the surface expression of CD24 which contributes to the increased number of CD44high/+CD24low/- cells. In addition, we observed that VGLL1 represses AXL expression and suppresses claudin-low phenotype, and that is caused by the VGLL1 mediated nuclear expulsion of TAZ. Therefore, EGFR and AXL seem to represent two different breast tumor subtypes, and their differential expressions is controlled by VGLL1.
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Affiliation(s)
- Shubhashree Parimita
- Department of Applied Biology, Council of Scientific & Industrial Research-Indian Institute of Chemical Technology (CSIR-IICT), Uppal Road, Tarnaka, Hyderabad, TS 500007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Amitava Das
- Department of Applied Biology, Council of Scientific & Industrial Research-Indian Institute of Chemical Technology (CSIR-IICT), Uppal Road, Tarnaka, Hyderabad, TS 500007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Sanjoy Samanta
- Department of Applied Biology, Council of Scientific & Industrial Research-Indian Institute of Chemical Technology (CSIR-IICT), Uppal Road, Tarnaka, Hyderabad, TS 500007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Dakal TC, Dhabhai B, Pant A, Moar K, Chaudhary K, Yadav V, Ranga V, Sharma NK, Kumar A, Maurya PK, Maciaczyk J, Schmidt‐Wolf IGH, Sharma A. Oncogenes and tumor suppressor genes: functions and roles in cancers. MedComm (Beijing) 2024; 5:e582. [PMID: 38827026 PMCID: PMC11141506 DOI: 10.1002/mco2.582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 04/21/2024] [Accepted: 04/26/2024] [Indexed: 06/04/2024] Open
Abstract
Cancer, being the most formidable ailment, has had a profound impact on the human health. The disease is primarily associated with genetic mutations that impact oncogenes and tumor suppressor genes (TSGs). Recently, growing evidence have shown that X-linked TSGs have specific role in cancer progression and metastasis as well. Interestingly, our genome harbors around substantial portion of genes that function as tumor suppressors, and the X chromosome alone harbors a considerable number of TSGs. The scenario becomes even more compelling as X-linked TSGs are adaptive to key epigenetic processes such as X chromosome inactivation. Therefore, delineating the new paradigm related to X-linked TSGs, for instance, their crosstalk with autosome and involvement in cancer initiation, progression, and metastasis becomes utmost importance. Considering this, herein, we present a comprehensive discussion of X-linked TSG dysregulation in various cancers as a consequence of genetic variations and epigenetic alterations. In addition, the dynamic role of X-linked TSGs in sex chromosome-autosome crosstalk in cancer genome remodeling is being explored thoroughly. Besides, the functional roles of ncRNAs, role of X-linked TSG in immunomodulation and in gender-based cancer disparities has also been highlighted. Overall, the focal idea of the present article is to recapitulate the findings on X-linked TSG regulation in the cancer landscape and to redefine their role toward improving cancer treatment strategies.
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Affiliation(s)
- Tikam Chand Dakal
- Department of BiotechnologyGenome and Computational Biology LabMohanlal Sukhadia UniversityUdaipurRajasthanIndia
| | - Bhanupriya Dhabhai
- Department of BiotechnologyGenome and Computational Biology LabMohanlal Sukhadia UniversityUdaipurRajasthanIndia
| | - Anuja Pant
- Department of BiochemistryCentral University of HaryanaMahendergarhHaryanaIndia
| | - Kareena Moar
- Department of BiochemistryCentral University of HaryanaMahendergarhHaryanaIndia
| | - Kanika Chaudhary
- School of Life Sciences. Jawaharlal Nehru UniversityNew DelhiIndia
| | - Vikas Yadav
- School of Life Sciences. Jawaharlal Nehru UniversityNew DelhiIndia
| | - Vipin Ranga
- Dearptment of Agricultural BiotechnologyDBT‐NECAB, Assam Agricultural UniversityJorhatAssamIndia
| | | | - Abhishek Kumar
- Manipal Academy of Higher EducationManipalKarnatakaIndia
- Institute of Bioinformatics, International Technology ParkBangaloreIndia
| | - Pawan Kumar Maurya
- Department of BiochemistryCentral University of HaryanaMahendergarhHaryanaIndia
| | - Jarek Maciaczyk
- Department of Stereotactic and Functional NeurosurgeryUniversity Hospital of BonnBonnGermany
| | - Ingo G. H. Schmidt‐Wolf
- Department of Integrated OncologyCenter for Integrated Oncology (CIO)University Hospital BonnBonnGermany
| | - Amit Sharma
- Department of Stereotactic and Functional NeurosurgeryUniversity Hospital of BonnBonnGermany
- Department of Integrated OncologyCenter for Integrated Oncology (CIO)University Hospital BonnBonnGermany
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Chen Q, Zhou Q. Identification of exosome-related gene signature as a promising diagnostic and therapeutic tool for breast cancer. Heliyon 2024; 10:e29551. [PMID: 38665551 PMCID: PMC11043961 DOI: 10.1016/j.heliyon.2024.e29551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 04/08/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
Background Exosomes are promising tools for the development of new diagnostic and therapeutic approaches. Exosomes possess the ability to activate signaling pathways that contribute to the remodeling of the tumor microenvironment, angiogenesis, and the regulation of immune responses. We aimed to develop a prognostic score based on exosomes derived from breast cancer. Materials and methods Training was conducted on the TCGA-BRCA dataset, while validation was conducted on GSE20685, GSE5764, GSE7904, and GSE29431. A total of 121 genes related to exosomes were retrieved from the ExoBCD database. The Cox proportional hazards model is used to develop risk score model. The GSVA package was utilized to analyze single-sample gene sets and identify exosome signatures, while the WGCNA package was utilized to identify gene modules associated with clinical outcomes. The clusterProfiler and GSVA R packages facilitated gene set enrichment and variation analyses. Furthermore, CIBERSORT quantified immune infiltration, and a correlation between gene expression and drug sensitivity was assessed using the TIDE algorithm. Results An exosome-related prognostic score was established using the following selected genes: ABCC9, PIGR, CXCL13, DOK7, CD24, and IVL. Various immune cells that promote cancer immune evasion were associated with a high-risk prognostic score, which was an independent predictor of outcome. High-risk and low-risk groups exhibited significantly different infiltration abundances (p < 0.05). By conducting a sensitivity comparison, we found that patients with high-risk scores exhibited more favorable responses to immunotherapy than those with low-risk scores. Conclusion The exosome-related gene signature exhibits outstanding performance in predicting the prognosis and cancer status of patients with breast cancer and guiding immunotherapy.
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Affiliation(s)
- Qitong Chen
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Clinical Research Center for Breast Disease in Hunan Province, Changsha, Hunan, China
| | - Qin Zhou
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Clinical Research Center for Breast Disease in Hunan Province, Changsha, Hunan, China
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9
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Tan Z, Boyapati K, Tressler CM, Jenkinson NM, Glunde K. Glutamine transporter SLC38A3 promotes breast cancer metastasis via Gsk3β/β-catenin/EMT pathway. Cancer Lett 2024; 586:216653. [PMID: 38309615 DOI: 10.1016/j.canlet.2024.216653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 12/06/2023] [Accepted: 01/15/2024] [Indexed: 02/05/2024]
Abstract
Breast cancer is the leading cancer-related cause of death in women. Here we show that solute carrier family 38-member 3 (SLC38A3) is overexpressed in breast cancer, particularly in triple-negative breast cancer (TNBC) cells and tissues. Our study reveals that SLC38A3 regulates cellular glutamine, glutamate, asparagine, aspartate, alanine, and glutathione (GSH) levels in breast cancer cells. Our data demonstrate that SLC38A3 enhances cell viability, cell migration and invasion in vitro, and promotes tumor growth and metastasis in vivo, while reducing apoptosis and oxidative stress. Mechanistically, we show that SLC38A3 suppresses the activity of glycogen synthase kinase 3-β (Gsk3β), a negative regulator of β-catenin, and increases protein levels of β-catenin, leading to the upregulation of epithelial-to-mesenchymal-transition (EMT)-inducing transcription factors and EMT markers in breast cancer. In summary, we show that SLC38A3 is overexpressed in breast cancer and promotes breast cancer metastasis via the GSK3β/β-catenin/EMT pathway, presenting a novel therapeutic target to explore for breast cancer.
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Affiliation(s)
- Zheqiong Tan
- Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Keerti Boyapati
- Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Caitlin M Tressler
- Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Nicole M Jenkinson
- Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kristine Glunde
- Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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10
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Deb R, Sengar GS, Sonowal J, Pegu SR, Das PJ, Singh I, Chakravarti S, Selvaradjou A, Attupurum N, Rajkhowa S, Gupta VK. Transcriptome signatures of host tissue infected with African swine fever virus reveal differential expression of associated oncogenes. Arch Virol 2024; 169:54. [PMID: 38381218 DOI: 10.1007/s00705-023-05959-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 11/27/2023] [Indexed: 02/22/2024]
Abstract
African swine fever (ASF) has emerged as a threat to swine production worldwide. Evasion of host immunity by ASF virus (ASFV) is well understood. However, the role of ASFV in triggering oncogenesis is still unclear. In the present study, ASFV-infected kidney tissue samples were subjected to Illumina-based transcriptome analysis. A total of 2463 upregulated and 825 downregulated genes were differentially expressed (p < 0.05). A literature review revealed that the majority of the differentially expressed host genes were key molecules in signaling pathways involved in oncogenesis. Bioinformatic analysis indicated the activation of certain oncogenic KEGG pathways, including basal cell carcinoma, breast cancer, transcriptional deregulation in cancer, and hepatocellular carcinoma. Analysis of host-virus interactions revealed that the upregulated oncogenic RELA (p65 transcription factor) protein of Sus scrofa can interact with the A238L (hypothetical protein of unknown function) of ASFV. Differential expression of oncogenes was confirmed by qRT-PCR, using the H3 histone family 3A gene (H3F3A) as an internal control to confirm the RNA-Seq data. The levels of gene expression indicated by qRT-PCR matched closely to those determined through RNA-Seq. These findings open up new possibilities for investigation of the mechanisms underlying ASFV infection and offer insights into the dynamic interaction between viral infection and oncogenic processes. However, as these investigations were conducted on pigs that died from natural ASFV infection, the role of ASFV in oncogenesis still needs to be investigated in controlled experimental studies.
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Affiliation(s)
- Rajib Deb
- ICAR-National Research Centre on Pig, Rani, Guwahati, Assam, 781131, India.
| | | | - Joyshikh Sonowal
- ICAR-National Research Centre on Pig, Rani, Guwahati, Assam, 781131, India
- Multidisciplinary Research Unit, Jorhat Medical College and Hospital, Jorhat, Assam, 785001, India
| | - Seema Rani Pegu
- ICAR-National Research Centre on Pig, Rani, Guwahati, Assam, 781131, India
| | - Pranab Jyoti Das
- ICAR-National Research Centre on Pig, Rani, Guwahati, Assam, 781131, India.
| | | | - Soumendu Chakravarti
- ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, UP, 243122, India
- Pirbright Institute, Ash Road, Pirbright, Surrey, United Kingdom
| | | | - Nitin Attupurum
- ICAR-National Research Centre on Pig, Rani, Guwahati, Assam, 781131, India
| | - Swaraj Rajkhowa
- ICAR-National Research Centre on Pig, Rani, Guwahati, Assam, 781131, India
| | - Vivek Kumar Gupta
- ICAR-National Research Centre on Pig, Rani, Guwahati, Assam, 781131, India.
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11
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Sheng G, Li F, Jin W, Wang K. Pan-caner analysis identifies PSMA7 as a targets for amplification at 20q13.33 in tumorigenesis. Sci Rep 2024; 14:3034. [PMID: 38321088 PMCID: PMC10847487 DOI: 10.1038/s41598-024-53585-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 02/02/2024] [Indexed: 02/08/2024] Open
Abstract
The chromosome 20 long arm (20q) is one of the genomic hotspots where copy number alterations frequently occur in multiple types of tumors. However, it remains elusive which genes are implicated in 20q-related tumorigenesis. Here, by querying TCGA and GEO databases, we observed frequent copy number amplification at 20q and the chromosome subband 20q13.33 was amplificated in multiple cancers. Among those genes at 20q13.33, PSMA7 was found with the strongest correlation with cancers. Further analysis revealed that PSMA7 amplification was the most frequent genetic alteration event conferring adverse prognosis in various cancers. Consistent with the strong positive correlation between PSMA7 amplification and gene expression, elevated PSMA7 expression was observed in 20 of 33 types of cancers with a close link to adverse outcomes in certain tumors. In addition, PSMA7 was essential for the growth of almost 1095 cancer lines. Mechanistically, aberrant PSMA7 most probably influenced the proteasome and protease-related pathways to promote tumorigenesis and might be antagonized by several compounds, e.g., Docetaxel in relevant cancers. The current in-depth pan-cancer analysis refines our understanding of the crucial oncogenic role of copy number amplifications at PSMA7 loci at the novel chromosome amplicon 20q13.33 across different tumors.
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Affiliation(s)
- Guangying Sheng
- State Key Laboratory of Medical Genomics, Ruijin Hospital Shanghai Institute of Hematology, National Research Center for Translational Medicine at Shanghai, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Rd, Shanghai, 200025, China
- Ruijin Hospital, Sino-French Research Center for Life Sciences and Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fuyu Li
- State Key Laboratory of Medical Genomics, Ruijin Hospital Shanghai Institute of Hematology, National Research Center for Translational Medicine at Shanghai, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Rd, Shanghai, 200025, China
- Ruijin Hospital, Sino-French Research Center for Life Sciences and Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Wen Jin
- State Key Laboratory of Medical Genomics, Ruijin Hospital Shanghai Institute of Hematology, National Research Center for Translational Medicine at Shanghai, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Rd, Shanghai, 200025, China
| | - Kankan Wang
- State Key Laboratory of Medical Genomics, Ruijin Hospital Shanghai Institute of Hematology, National Research Center for Translational Medicine at Shanghai, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Rd, Shanghai, 200025, China.
- Ruijin Hospital, Sino-French Research Center for Life Sciences and Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
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12
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Islam SS, Al-Tweigeri T, Al-Harbi L, Ujjahan S, Al-Mozaini M, Tulbah A, Aboussekhra A. Long noncoding RNA DLEU2 and ROR1 pathway induces epithelial-to-mesenchymal transition and cancer stem cells in breast cancer. Cell Death Discov 2024; 10:61. [PMID: 38296962 PMCID: PMC10830457 DOI: 10.1038/s41420-024-01829-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 01/15/2024] [Accepted: 01/19/2024] [Indexed: 02/02/2024] Open
Abstract
Breast cancer (BC) patient who receives chemotherapy for an extended length of time may experience profound repercussions in terms of metastases and clinical outcomes due to the involvement of the epithelial-to-mesenchymal transition (EMT) mechanism and enriched cancer stem cells (CSCs). BC cells that express high levels of lncRNA deleted in lymphocytic leukemia-2 (lncRNA DLEU2) and type I tyrosine kinase-like orphan receptor ROR1 (ROR1) may play roles in the enhanced ability of the activation EMT and CSC induction. Here we find that lncRNA DLEU2 and ROR1 are specifically upregulated in tumor tissues compared to their normal counterparts in TCGA, PubMed GEO datasets, and samples from archived breast cancer tumor tissues. Following chemotherapy, lncRNA DLEU2 and ROR1 were enhanced in BC tumor cells, coupled with the expression of CSCs, EMT-related genes, and BMI1. Mechanistically, ROR1 and lncRNA DLEU2 overexpression led to enhanced tumor cell proliferation, inhibition of apoptosis, cell-cycle dysregulation, chemoresistance, as well as BC cell's abilities to invade, migrate, develop spheroids. These findings imply that the role of lncRNA DLEU2 and ROR1 in BC therapeutic failure is largely attributed to EMT, which is intricately linked to enriched CSCs. In conclusion, our findings indicate that a lncRNA DLEU2 and ROR1-based regulatory loop governs EMT and CSC self-renewal, implying that targeting this regulatory pathway may improve patients' responses to chemotherapy and survival.
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Affiliation(s)
- Syed S Islam
- Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
- School of Medicine, Al-Faisal University, Riyadh, Saudi Arabia.
| | - Taher Al-Tweigeri
- Breast Cancer Unit, Oncology Centre, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Layla Al-Harbi
- Department of Infection and Immunity, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Shafat Ujjahan
- Department of Medical Oncology and Radiotherapy, Park View Hospital, Chattagram, Bangladesh
| | - Maha Al-Mozaini
- Department of Infection and Immunity, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Asma Tulbah
- Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Abdelilah Aboussekhra
- Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
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Mu S, Tian Q, Shen L. NOP16 promotes hepatocellular carcinoma progression and triggers EMT through the Keap1-Nrf2 signaling pathway. Technol Health Care 2024; 32:2463-2483. [PMID: 38251077 PMCID: PMC11322705 DOI: 10.3233/thc-231256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Accepted: 11/29/2023] [Indexed: 01/23/2024]
Abstract
BACKGROUND Nucleolar protein 16 (NOP16) is present in the protein complex of the nucleolus. The NOP16 promoter contains a c-Myc binding site, and the transcriptional regulation by c-Myc directly regulates NOP16 expression levels. OBJECTIVE Dysregulation of NOP 16 is currently reported in only a small number of cancers. In this study, the expression profile of NOP 16 in hepatocellular carcinoma (LIHC) and its clinical significance were analyzed. METHODS NOP16 expression in hepatocellular carcinoma (LIHC) and its relationship with the clinical characters of LIHC were examined using the Cancer Genome Atlas (TCGA), the Gene Expression comprehensive database (GEO), Kaplan-Meier survival analysis, univariate Cox analysis, multivariate Cox analysis, ROC curve analysis of KEGG enrichment, GSEA enrichment, in vitro experiments (e.g., siRNA interference of NOP16 expression in hepatoma cells, Keap1-Nrf2 pathway, cell cycle, cell apoptosis and Transwell assays), and LIHC single-cell sequencing (scRNA). RESULTS Pan-cancer analysis revealed that NOP16 was highly expressed in 20 cancer types, including LIHC, and high NOP16 expression was an independent adverse prognostic factor in LIHC patients. The expression levels of NOP16 mRNA and protein were significantly increased in tumour tissues of LIHC patients compared to normal tissues. The functions of co-expressed genes were primarily enriched in the cell cycle and reactive oxygen species metabolism. The experimental results showed that knockdown of NOP16 activated the Keap/Nrf2 signalling pathway and inhibited the invasion, migration, and EMT progression of LIHC cells. LIHC scRNA-seq data showed that NOP16 was primarily expressed in T lymphocytes. CONCLUSIONS NOP16 promoted cancer development in LIHC and caused an imbalance in Keap/Nrf2 signalling, which subsequently caused the aberrant expression of genes typical for EMT, cell cycle progression and apoptosis. NOP16 is a potential prognostic marker and therapeutic target for hepatocellular carcinoma progression.
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Affiliation(s)
- Shangdong Mu
- Department of Oncology, Health Science Center, 3201 Hospital of Xi’an Jiaotong University, Hanzhong, Shaanxi, China
| | - Qiusi Tian
- Department of Neurosurgery, Health Science Center, 3201 Hospital of Xi’an Jiaotong University, Hanzhong, Shaanxi, China
| | - Liangyu Shen
- Department of Anesthesia, Operation Center, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
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14
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Williams NO, Quiroga D, Johnson C, Brufsky A, Chambers M, Bhattacharya S, Patterson M, Sardesai SD, Stover D, Lustberg M, Noonan AM, Cherian M, Bystry DM, Hill KL, Chen M, Phelps MA, Grever M, Stephens JA, Ramaswamy B, Carson WE, Wesolowski R. Phase Ib study of HSP90 inhibitor, onalespib (AT13387), in combination with paclitaxel in patients with advanced triple-negative breast cancer. Ther Adv Med Oncol 2023; 15:17588359231217976. [PMID: 38152697 PMCID: PMC10752118 DOI: 10.1177/17588359231217976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 11/15/2023] [Indexed: 12/29/2023] Open
Abstract
Background Heat shock protein 90 (HSP90) is a molecular chaperone required for stabilization of client proteins over-activated in triple-negative breast cancer (TNBC). Over-expression of HSP90 client proteins has been implicated in paclitaxel resistance. Onalespib (AT13387) is a potent inhibitor of HSP90 that could improve paclitaxel efficacy when administered in combination. Design This phase Ib trial administered onalespib with paclitaxel in patients with advanced TNBC to assess safety and establish a recommended phase II dose (RP2D). Objectives The primary objectives were determining the dose-limiting toxicities and maximum tolerated dose of combination therapy. Secondary objectives included pharmacokinetic (PK) analysis and determination of overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Methods Patients with advanced TNBC were treated with standard dose intravenous paclitaxel in combination with intravenous onalespib at doses ranging from 120 to 260 mg/m2 administered on days 1, 8, and 15 of a 28-day cycle using a standard 3 + 3 design. A total of 15 patients were enrolled to dose expansion cohort at RP2D to confirm safety profile. Results Thirty-one patients were enrolled in the study, of which over 90% had received prior taxane therapy. Paclitaxel was given for metastatic disease in 23% of patients. Adverse events (AEs) included anemia (grade 3: 20%), lymphopenia (grade 3: 17%), and neutropenia (grade 3: 33%, grade 4: 4%). The most frequent grade ⩾3 non-hematologic AE was diarrhea (7%). The established RP2D was 260 mg/m2 onalespib when given with paclitaxel at 80 mg/m2. PK analysis revealed a modest drug interaction profile for onalespib in the combination regimen. ORR was 20%. Three patients achieved complete responses, all of whom had received prior taxane therapy. Median DOR was 5.6 months; median PFS was 2.9 months. Conclusion Combination treatment with onalespib and paclitaxel had an acceptable toxicity profile and RP2D was determined to be 260 mg/m2 of onalespib. Combination therapy showed antitumor activity in patients with advanced TNBC. Trial registration Onalespib and paclitaxel in treating patients with advanced TNBC https://clinicaltrials.gov/ct2/show/NCT02474173.
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Affiliation(s)
- Nicole O. Williams
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Dionisia Quiroga
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Courtney Johnson
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Adam Brufsky
- University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA
| | - Mara Chambers
- University of Kentucky Markey Cancer Center, Lexington, KY, USA
| | | | - Maria Patterson
- Stefanie Spielman Comprehensive Breast Center, The Ohio State University, Columbus, OH, USA
| | - Sagar D. Sardesai
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Daniel Stover
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Maryam Lustberg
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Anne M. Noonan
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Mathew Cherian
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Darlene M. Bystry
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Kasey L. Hill
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Min Chen
- The Ohio State University College of Pharmacy, Columbus, OH, USA
| | - Mitch A. Phelps
- The Ohio State University – Arthur G. James Comprehensive Cancer Center, Columbus, OH, USA
- The Ohio State University College of Pharmacy, Columbus, OH, USA
| | - Michael Grever
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Julie A. Stephens
- Center for Biostatistics, Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, USA
| | | | - William E. Carson
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Robert Wesolowski
- The Ohio State University Comprehensive Cancer Center, 1800 Cannon Drive, 1310D Lincoln Tower, Columbus, OH 43210, USA
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15
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Berkel C, Cacan E. The expression of O-linked glycosyltransferase GALNT7 in breast cancer is dependent on estrogen-, progesterone-, and HER2-receptor status, with prognostic implications. Glycoconj J 2023; 40:631-644. [PMID: 37947928 DOI: 10.1007/s10719-023-10137-4] [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: 04/04/2023] [Revised: 10/22/2023] [Accepted: 10/23/2023] [Indexed: 11/12/2023]
Abstract
GALNT7 is a glycosyltransferase enzyme transferring N-acetylgalactosamine to initiate O-linked glycosylation in the Golgi apparatus. Breast cancer is the most common cancer in women globally. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2; ERBB2) are important biomarkers in the prognosis and molecular subtyping of breast cancer. Here, we showed that ER-positive, PR-positive or HER2-positive breast tumors have higher expression of GALNT7 compared to ER-negative, PR-negative or HER2-negative breast tumors, respectively. We found that CpG-aggregated methylation of GALNT7 gene is decreased, and in parallel, its transcript levels are increased in breast cancer compared to healthy breast tissue. We observed that the difference in the expression of GALNT7 between negative and positive status of the receptors is the highest for HER2, followed by ER and PR, pointing that HER2 might be relatively more influential than ER and PR on the expression of GALNT7 in breast cancer. We reported that basal-like breast tumors have decreased expression of GALNT7 compared to non-basal-like tumors, and that high GALNT7 expression is associated with favorable relapse-free and distant metastasis-free survival in HER2 status-dependent manner in breast cancer patients. Moreover, we showed that GALNT7 expression in breast cancer is cell type- (epithelial vs stromal cells), tumor grade- and ethnicity-dependent. Combined, we propose that GALNT7 might contribute to different clinical outcomes depending on the receptor status in breast cancer, and that a better understanding of GALNT7 and its function in the context of breast cancer is needed.
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Affiliation(s)
- Caglar Berkel
- Department of Molecular Biology and Genetics, Tokat Gaziosmanpasa University, Tokat, Turkey.
| | - Ercan Cacan
- Department of Molecular Biology and Genetics, Tokat Gaziosmanpasa University, Tokat, Turkey
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16
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Weston WA, Barr AR. A cell cycle centric view of tumour dormancy. Br J Cancer 2023; 129:1535-1545. [PMID: 37608096 PMCID: PMC10645753 DOI: 10.1038/s41416-023-02401-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 07/31/2023] [Accepted: 08/10/2023] [Indexed: 08/24/2023] Open
Abstract
Tumour dormancy and recurrent metastatic cancer remain the greatest clinical challenge for cancer patients. Dormant tumour cells can evade treatment and detection, while retaining proliferative potential, often for years, before relapsing to tumour outgrowth. Cellular quiescence is one mechanism that promotes and maintains tumour dormancy due to its central role in reducing proliferation, elevating cyto-protective mechanisms, and retaining proliferative potential. Quiescence/proliferation decisions are dictated by intrinsic and extrinsic signals, which regulate the activity of cyclin-dependent kinases (CDKs) to modulate cell cycle gene expression. By clarifying the pathways regulating CDK activity and the signals which activate them, we can better understand how cancer cells enter, maintain, and escape from quiescence throughout the progression of dormancy and metastatic disease. Here we review how CDK activity is regulated to modulate cellular quiescence in the context of tumour dormancy and highlight the therapeutic challenges and opportunities it presents.
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Affiliation(s)
- William A Weston
- MRC London Institute of Medical Sciences, Du Cane Road, London, W12 0NN, UK
| | - Alexis R Barr
- MRC London Institute of Medical Sciences, Du Cane Road, London, W12 0NN, UK.
- Institute of Clinical Sciences, Imperial College London, Du Cane Rd, London, W12 0NN, UK.
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17
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Petrović N, Essack M, Šami A, Perry G, Gojobori T, Isenović ER, Bajić VP. MicroRNA networks linked with BRCA1/2, PTEN, and common genes for Alzheimer's disease and breast cancer share highly enriched pathways that may unravel targets for the AD/BC comorbidity treatment. Comput Biol Chem 2023; 106:107925. [PMID: 37487248 DOI: 10.1016/j.compbiolchem.2023.107925] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 06/29/2023] [Accepted: 07/13/2023] [Indexed: 07/26/2023]
Abstract
MicroRNAs (miRNAs) are involved in the regulation of various cellular processes including pathological conditions. MiRNA networks have been extensively researched in age-related degenerative diseases, such as cancer, Alzheimer's disease (AD), and heart failure. Thus, miRNA has been studied from different approaches, in vivo, in vitro, and in silico including miRNA networks. Networks linking diverse biomedical entities unveil information not readily observable by other means. This work focuses on biological networks related to Breast cancer susceptibility 1 (BRCA1) in AD and breast cancer (BC). Using various bioinformatics approaches, we identified subnetworks common to AD and BC that suggest they are linked. According to our results, miR-107 was identified as a potentially good candidate for both AD and BC treatment (targeting BRCA1/2 and PTEN in both diseases), accompanied by miR-146a and miR-17. The analysis also confirmed the involvement of the miR-17-92 cluster, and miR-124-3p, and highlighted the importance of poorly researched miRNAs such as mir-6785 mir-6127, mir-6870, or miR-8485. After filtering the in silico analysis results, we found 49 miRNA molecules that modulate the expression of at least five genes common to both BC and AD. Those 49 miRNAs regulate the expression of 122 genes in AD and 93 genes in BC, from which 26 genes are common genes for AD and BC involved in neuron differentiation and genesis, cell differentiation and migration, regulation of cell cycle, and cancer development. Additionally, the highly enriched pathway was associated with diabetic complications, pointing out possible interplay among molecules underlying BC, AD, and diabetes pathology.
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Affiliation(s)
- Nina Petrović
- Laboratory for Radiobiology and Molecular Genetics, Department of Health and Environment, "VINČA "Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, Mike Petrovića Alasa 12-14, 11001 Belgrade, Serbia; Department for Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia
| | - Magbubah Essack
- Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), Computational Bioscience Research Center, Computer (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Kingdom of Saudi Arabia
| | - Ahmad Šami
- Cellular and Molecular Radiation Oncology Laboratory, Department of Radiation Oncology, Universitatsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - George Perry
- Department of Biology, The University of Texas at San Antonio, San Antonio, TX, USA
| | - Takashi Gojobori
- Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), Computational Bioscience Research Center, Computer (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Kingdom of Saudi Arabia
| | - Esma R Isenović
- Laboratory for Radiobiology and Molecular Genetics, Department of Health and Environment, "VINČA "Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, Mike Petrovića Alasa 12-14, 11001 Belgrade, Serbia
| | - Vladan P Bajić
- Laboratory for Radiobiology and Molecular Genetics, Department of Health and Environment, "VINČA "Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, Mike Petrovića Alasa 12-14, 11001 Belgrade, Serbia.
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18
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Caramia F, Speed TP, Shen H, Haupt Y, Haupt S. Establishing the Link between X-Chromosome Aberrations and TP53 Status, with Breast Cancer Patient Outcomes. Cells 2023; 12:2245. [PMID: 37759468 PMCID: PMC10526523 DOI: 10.3390/cells12182245] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 09/04/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Ubiquitous to normal female human somatic cells, X-chromosome inactivation (XCI) tightly regulates the transcriptional silencing of a single X chromosome from each pair. Some genes escape XCI, including crucial tumour suppressors. Cancer susceptibility can be influenced by the variability in the genes that escape XCI. The mechanisms of XCI dysregulation remain poorly understood in complex diseases, including cancer. Using publicly available breast cancer next-generation sequencing data, we show that the status of the major tumour suppressor TP53 from Chromosome 17 is highly associated with the genomic integrity of the inactive X (Xi) and the active X (Xa) chromosomes. Our quantification of XCI and XCI escape demonstrates that aberrant XCI is linked to poor survival. We derived prognostic gene expression signatures associated with either large deletions of Xi; large amplifications of Xa; or abnormal X-methylation. Our findings expose a novel insight into female cancer risks, beyond those associated with the standard molecular subtypes.
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Affiliation(s)
- Franco Caramia
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; (F.C.); (Y.H.)
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Terence P. Speed
- Walter and Eliza Hall Institute for Medical Research, Parkville, VIC 3052, Australia;
| | - Hui Shen
- Van Andel Institute, Grand Rapids, MI 49503, USA;
| | - Ygal Haupt
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; (F.C.); (Y.H.)
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Sue Haupt
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; (F.C.); (Y.H.)
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia
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19
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Chu HM, Kong XZ, Liu JX, Zheng CH, Zhang H. A New Binary Biclustering Algorithm Based on Weight Adjacency Difference Matrix for Analyzing Gene Expression Data. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2023; 20:2802-2809. [PMID: 37285246 DOI: 10.1109/tcbb.2023.3283801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Biclustering algorithms are essential for processing gene expression data. However, to process the dataset, most biclustering algorithms require preprocessing the data matrix into a binary matrix. Regrettably, this type of preprocessing may introduce noise or cause information loss in the binary matrix, which would reduce the biclustering algorithm's ability to effectively obtain the optimal biclusters. In this paper, we propose a new preprocessing method named Mean-Standard Deviation (MSD) to resolve the problem. Additionally, we introduce a new biclustering algorithm called Weight Adjacency Difference Matrix Binary Biclustering (W-AMBB) to effectively process datasets containing overlapping biclusters. The basic idea is to create a weighted adjacency difference matrix by applying weights to a binary matrix that is derived from the data matrix. This allows us to identify genes with significant associations in sample data by efficiently identifying similar genes that respond to specific conditions. Furthermore, the performance of the W-AMBB algorithm was tested on both synthetic and real datasets and compared with other classical biclustering methods. The experiment results demonstrate that the W-AMBB algorithm is significantly more robust than the compared biclustering methods on the synthetic dataset. Additionally, the results of the GO enrichment analysis show that the W-AMBB method possesses biological significance on real datasets.
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Zhang J, Wei Z, Qi X, Jiang Y, Liu D, Liu K. Kinesin family member 11 promotes progression of hepatocellular carcinoma via the OCT4 pathway. Funct Integr Genomics 2023; 23:284. [PMID: 37648881 DOI: 10.1007/s10142-023-01209-7] [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: 05/21/2023] [Revised: 08/04/2023] [Accepted: 08/11/2023] [Indexed: 09/01/2023]
Abstract
Hepatocellular carcinoma (HCC) is the tumor with the second highest mortality rate worldwide. Recent research data show that KIF11, a member of the kinesin family (KIF), plays an important role in the progression of various tumors. However, its expression and molecular mechanism in HCC remain elusive. Here, we evaluated the potential role of KIF11 in HCC. The effect of KIF11 was evaluated using the hepatocellular carcinoma cell lines, LM3 and Huh7, after genetic or pharmacological treatment. Evaluating the role of KIF11 in the xenograft animal models using its specific inhibitor. The role of KIF11 was systematically evaluated using specimens obtained from the aforementioned animal and cell models after various in vivo and in vitro experiments. The clinicopathological analysis showed that KIF11 was expressed at high levels in patients with hepatocellular carcinoma. Cell experiments in vitro showed that KIF11 deficiency significantly slowed the proliferation of liver tumor cells. And in the experiment using liver cancer cells overexpressing OCT4, overexpression of OCT4 substantially increased the proliferation of tumor cells compared with tumor cells with KIF11 knockdown alone. Both in vitro cell experiment and in vivo xenotransplantation tumor experiment showed that monastrol, an inhibitor of KIF11, could effectively delay the proliferation and migration of tumor cells. Based on these results, KIF11 is expressed at high levels in hepatocellular carcinoma and promotes tumor proliferation in an OCT4-dependent manner. KIF11 may become a therapeutic target for hepatocellular carcinoma, and its inhibitor monastrol may become a clinical antitumor drug.
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Affiliation(s)
- Ju Zhang
- Department of General Surgery, The Second Xiangya Hospital of Central South University, No. 139 Renminzhong Road, Changsha, 410012, China
| | - Zuxing Wei
- Department of General Surgery, The Second Xiangya Hospital of Central South University, No. 139 Renminzhong Road, Changsha, 410012, China
| | - Xiaoyan Qi
- Department of General Surgery, The Second Xiangya Hospital of Central South University, No. 139 Renminzhong Road, Changsha, 410012, China
| | - Yuhong Jiang
- Department of General Surgery, The Second Xiangya Hospital of Central South University, No. 139 Renminzhong Road, Changsha, 410012, China
| | - Dekun Liu
- Department of General Surgery, The Second Xiangya Hospital of Central South University, No. 139 Renminzhong Road, Changsha, 410012, China
| | - Kuijie Liu
- Department of General Surgery, The Second Xiangya Hospital of Central South University, No. 139 Renminzhong Road, Changsha, 410012, China.
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21
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Cacioppo R, Akman HB, Tuncer T, Erson-Bensan AE, Lindon C. Differential translation of mRNA isoforms underlies oncogenic activation of cell cycle kinase Aurora A. eLife 2023; 12:RP87253. [PMID: 37384380 DOI: 10.7554/elife.87253] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/01/2023] Open
Abstract
Aurora Kinase A (AURKA) is an oncogenic kinase with major roles in mitosis, but also exerts cell cycle- and kinase-independent functions linked to cancer. Therefore, control of its expression, as well as its activity, is crucial. A short and a long 3'UTR isoform exist for AURKA mRNA, resulting from alternative polyadenylation (APA). We initially observed that in triple-negative breast cancer, where AURKA is typically overexpressed, the short isoform is predominant and this correlates with faster relapse times of patients. The short isoform is characterized by higher translational efficiency since translation and decay rate of the long isoform are targeted by hsa-let-7a tumor-suppressor miRNA. Additionally, hsa-let-7a regulates the cell cycle periodicity of translation of the long isoform, whereas the short isoform is translated highly and constantly throughout interphase. Finally, disrupted production of the long isoform led to an increase in proliferation and migration rates of cells. In summary, we uncovered a new mechanism dependent on the cooperation between APA and miRNA targeting likely to be a route of oncogenic activation of human AURKA.
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Affiliation(s)
- Roberta Cacioppo
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
| | - Hesna Begum Akman
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
- Department of Biological Sciences, Orta Dogu Teknik Universitesi, Ankara, Turkey
| | - Taner Tuncer
- Department of Biology, Ondokuz Mayis Universitesi, Samsun, Turkey
| | | | - Catherine Lindon
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
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22
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Dahlgren M, Lettiero B, Dalal H, Mårtensson K, Gaber A, Nodin B, Gruvberger-Saal SK, Saal LH, Howlin J. CITED1 as a marker of favourable outcome in anti-endocrine treated, estrogen-receptor positive, lymph-node negative breast cancer. BMC Res Notes 2023; 16:105. [PMID: 37322548 PMCID: PMC10268435 DOI: 10.1186/s13104-023-06376-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 06/02/2023] [Indexed: 06/17/2023] Open
Abstract
OBJECTIVE To investigate CITED1 as a potential biomarker of anti-endocrine response and breast cancer recurrence, given its previously determined role in mediating estrogen-dependant transcription. The study is a continuation of earlier work establishing the role of CITED1 in mammary gland development. RESULTS CITED1 mRNA is associated with estrogen-receptor positivity and selectively expressed in the GOBO dataset of cell lines and tumours representing the luminal-molecular subtype. In patients treated with tamoxifen, higher CITED1 correlated with better outcome, suggesting a role in anti-estrogen response. The effect was particularly evident in the subset of estrogen-receptor positive, lymph-node negative (ER+/LN-) patients although noticeable divergence of the groups was apparent only after five years. Tissue microarray (TMA) analysis further validated the association of CITED1 protein, by immunohistochemistry, with favourable outcome in ER+, tamoxifen-treated patients. Although we also found a favourable response to anti-endocrine treatment in a larger TCGA dataset, the tamoxifen-specific effect was not replicated. Finally, MCF7 cells overexpressing CITED1 showed selective amplification of AREG but not TGFα suggesting that maintenance of specific ERα-CITED1 mediated transcription is important for the long-term response to anti-endocrine therapy. These findings together confirm the proposed mechanism of action of CITED1 and support its potential use as a prognostic biomarker.
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Affiliation(s)
- Malin Dahlgren
- Translational Oncogenomics, Faculty of Medicine, Department of Clinical Sciences Lund and Lund University Cancer Center, Lund University, Lund, Sweden
| | - Barbara Lettiero
- Translational Oncogenomics, Faculty of Medicine, Department of Clinical Sciences Lund and Lund University Cancer Center, Lund University, Lund, Sweden
| | - Hina Dalal
- Translational Oncogenomics, Faculty of Medicine, Department of Clinical Sciences Lund and Lund University Cancer Center, Lund University, Lund, Sweden
| | - Kira Mårtensson
- Translational Oncogenomics, Faculty of Medicine, Department of Clinical Sciences Lund and Lund University Cancer Center, Lund University, Lund, Sweden
| | - Alexander Gaber
- Therapeutic Pathology, Faculty of Medicine, Department of Clinical Sciences Lund and Lund University Cancer Center, Lund University, Lund, Sweden
| | - Björn Nodin
- Therapeutic Pathology, Faculty of Medicine, Department of Clinical Sciences Lund and Lund University Cancer Center, Lund University, Lund, Sweden
| | - Sofia K Gruvberger-Saal
- Translational Oncogenomics, Faculty of Medicine, Department of Clinical Sciences Lund and Lund University Cancer Center, Lund University, Lund, Sweden
| | - Lao H Saal
- Translational Oncogenomics, Faculty of Medicine, Department of Clinical Sciences Lund and Lund University Cancer Center, Lund University, Lund, Sweden
| | - Jillian Howlin
- Translational Oncogenomics, Faculty of Medicine, Department of Clinical Sciences Lund and Lund University Cancer Center, Lund University, Lund, Sweden.
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23
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Wu Q, Tian P, He D, Jia Z, He Y, Luo W, Lv X, Wang Y, Zhang P, Liang Y, Zhao W, Qin J, Su P, Jiang YZ, Shao ZM, Yang Q, Hu G. SCUBE2 mediates bone metastasis of luminal breast cancer by modulating immune-suppressive osteoblastic niches. Cell Res 2023; 33:464-478. [PMID: 37142671 PMCID: PMC10235122 DOI: 10.1038/s41422-023-00810-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 04/02/2023] [Indexed: 05/06/2023] Open
Abstract
Estrogen receptor (ER)-positive luminal breast cancer is a subtype with generally lower risk of metastasis to most distant organs. However, bone recurrence occurs preferentially in luminal breast cancer. The mechanisms of this subtype-specific organotropism remain elusive. Here we show that an ER-regulated secretory protein SCUBE2 contributes to bone tropism of luminal breast cancer. Single-cell RNA sequencing analysis reveals osteoblastic enrichment by SCUBE2 in early bone-metastatic niches. SCUBE2 facilitates release of tumor membrane-anchored SHH to activate Hedgehog signaling in mesenchymal stem cells, thus promoting osteoblast differentiation. Osteoblasts deposit collagens to suppress NK cells via the inhibitory LAIR1 signaling and promote tumor colonization. SCUBE2 expression and secretion are associated with osteoblast differentiation and bone metastasis in human tumors. Targeting Hedgehog signaling with Sonidegib and targeting SCUBE2 with a neutralizing antibody both effectively suppress bone metastasis in multiple metastasis models. Overall, our findings provide a mechanistic explanation for bone preference in luminal breast cancer metastasis and new approaches for metastasis treatment.
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Affiliation(s)
- Qiuyao Wu
- Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Pu Tian
- Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Dasa He
- Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Zhenchang Jia
- Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yunfei He
- Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Wenqian Luo
- Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Xianzhe Lv
- Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yuan Wang
- Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Peiyuan Zhang
- Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yajun Liang
- Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Wenjin Zhao
- Pathology Tissue Bank, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Jun Qin
- Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Peng Su
- Department of Pathology, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Yi-Zhou Jiang
- Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Zhi-Ming Shao
- Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Qifeng Yang
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China.
| | - Guohong Hu
- Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
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Pei CZ, Choi BC, Park JH, Park HY, Paek J, Lee KJ, Yun BS, Kim YJ, Baek KH. Cellular Functions of High-Temperature Requirement Factor A4 in Placenta. Cells 2023; 12:1459. [PMID: 37296580 PMCID: PMC10252923 DOI: 10.3390/cells12111459] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/21/2023] [Accepted: 05/23/2023] [Indexed: 06/12/2023] Open
Abstract
The expression of High-temperature requirement factor A4 (HtrA4) mRNA is significantly lower in the chorionic villi of patients with recurrent pregnancy loss (RPL) than in the control group. We conducted an investigation into the cellular functions of HtrA4 using the CRISPR/Cas9 system and shRNA-HtrA4 to create knockout BeWo cells and HtrA4 knockdown JEG3 cells. Our results indicated that the knockout BeWo cells exhibited reduced capacity for invasion and fusion, but increased levels of proliferation and migration, with a significantly shortened cell cycle compared to wild-type cells. Wild-type BeWo cells highly expressed cell invasion- and fusion-related factors, while knockout BeWo cells highly expressed migration-, proliferation-, and cell cycle-related factors. The shRNA-HtrA4 JEG3 cells showed a decreased capacity for invasion, but an increased capacity for migration, accompanied by a decrease in the expression of cell invasion-related factors and an increase in migration-related factors. Moreover, our ELISA results revealed that the serum HtrA4 level was lower in patients with RPL than in the controls. These findings suggest that HtrA4 depletion may be associated with placental dysfunction.
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Affiliation(s)
- Chang-Zhu Pei
- Department of Biomedical Science, Cell and Gene Therapy Research Institute, CHA University, Seongnam 13488, Republic of Korea; (C.-Z.P.); (J.-H.P.)
| | - Bum-Chae Choi
- Department of Obstetrics and Gynecology, CL Women’s Hospital, Gwangju 61917, Republic of Korea; (B.-C.C.); (H.Y.P.)
| | - Jun-Hyeok Park
- Department of Biomedical Science, Cell and Gene Therapy Research Institute, CHA University, Seongnam 13488, Republic of Korea; (C.-Z.P.); (J.-H.P.)
| | - Hyo Young Park
- Department of Obstetrics and Gynecology, CL Women’s Hospital, Gwangju 61917, Republic of Korea; (B.-C.C.); (H.Y.P.)
| | - Jinyoung Paek
- Department of Laboratory Medicine, Gangnam CHA Hospital, College of Medicine, Seoul 06135, Republic of Korea;
| | - Kyung-Ju Lee
- Department of Obstetrics and Gynecology, Korea University Anam Hospital, Korea University College of Medicine, Seoul 02841, Republic of Korea;
| | - Bo-Seong Yun
- Department of Obstetrics and Gynecology, Ilsan CHA Hospital, College of Medicine, Seoul 06135, Republic of Korea;
| | - Young Ju Kim
- Department of Obstetrics and Gynecology, Ewha Woman’s University College of Medicine, Seoul 07985, Republic of Korea;
| | - Kwang-Hyun Baek
- Department of Biomedical Science, Cell and Gene Therapy Research Institute, CHA University, Seongnam 13488, Republic of Korea; (C.-Z.P.); (J.-H.P.)
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Baraibar I, Ros J, Saoudi N, Salvà F, García A, Castells M, Tabernero J, Élez E. Sex and gender perspectives in colorectal cancer. ESMO Open 2023; 8:101204. [PMID: 37018873 PMCID: PMC10163160 DOI: 10.1016/j.esmoop.2023.101204] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 02/26/2023] [Accepted: 02/28/2023] [Indexed: 04/05/2023] Open
Abstract
Historically women were frequently excluded from clinical trials and drug usage to protect unborn babies from potential harm. As a consequence, the impact of sex and gender on both tumour biology and clinical outcomes has been largely underestimated. Although interrelated and often used interchangeably, sex and gender are not equivalent concepts. Sex is a biological attribute that defines species according to their chromosomal makeup and reproductive organ, while gender refers to a chosen sexual identity. Sex dimorphisms are rarely taken into account, in either preclinical or clinical research, with inadequate analysis of differences in outcomes according to sex or gender still widespread, reflecting a gap in our knowledge for a large proportion of the target population. Underestimation of sex-based differences in study design and analyses has invariably led to 'one-drug' treatment regimens for both males and females. For patients with colorectal cancer (CRC), sex also has an impact on the disease incidence, clinicopathological features, therapeutic outcomes, and tolerability to anticancer treatments. Although the global incidence of CRC is higher in male subjects, the proportion of patients presenting right-sided tumours and BRAF mutations is higher among females. Concerning sex-related differences in treatment efficacy and toxicity, drug dosage does not take into account sex-specific differences in pharmacokinetics. Toxicity associated with fluoropyrimidines, targeted therapies, and immunotherapies has been reported to be more extensive for females with CRC than for males, although evidence about differences in efficacy is more controversial. This article aims to provide an overview of the research achieved so far into sex and gender differences in cancer and summarize the growing body of literature illustrating the sex and gender perspective in CRC and their impact in relation to tumour biology and treatment efficacy and toxicity. We propose endorsing research on how biological sex and gender influence CRC as an added value for precision oncology.
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LRRC superfamily expression in stromal cells predicts the clinical prognosis and platinum resistance of ovarian cancer. BMC Med Genomics 2023; 16:10. [PMID: 36653841 PMCID: PMC9850808 DOI: 10.1186/s12920-023-01435-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Accepted: 01/09/2023] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Leucine-rich repeat sequence domains are known to mediate protein‒protein interactions. Recently, some studies showed that members of the leucine rich repeat containing (LRRC) protein superfamily may become new targets for the diagnosis and treatment of tumours. However, it is not known whether any of the LRRC superfamily genes is expressed in the stroma of ovarian cancer (OC) and is associated with prognosis. METHODS The clinical data and transcriptional profiles of OC patients from the public databases TCGA (n = 427), GTEx (n = 88) and GEO (GSE40266 and GSE40595) were analysed by R software. A nomogram model was also generated through R. An online public database was used for auxiliary analysis of prognosis, immune infiltration and protein‒protein interaction (PPI) networks. Immunohistochemistry and qPCR were performed to determine the protein and mRNA levels of genes in high-grade serous ovarian cancer (HGSC) tissues of participants and the MRC-5 cell line induced by TGF-β. RESULTS LRRC15 and LRRC32 were identified as differentially expressed genes from the LRRC superfamily by GEO transcriptome analysis. PPI network analysis suggested that they were most enriched in TGF-β signalling. The TCGA-GTEx analysis results showed that only LRRC15 was highly expressed in both cancer-associated fibroblasts (CAFs) and the tumour stroma of OC and was related to clinical prognosis. Based on this, we developed a nomogram model to predict the incidence of adverse outcomes in OC. Moreover, LRRC15 was positively correlated with CAF infiltration and negatively correlated with CD8 + T-cell infiltration. As a single indicator, LRRC15 had the highest accuracy (AUC = 0.920) in predicting the outcome of primary platinum resistance. CONCLUSIONS The LRRC superfamily is related to the TGF-β pathway in the microenvironment of OC. LRRC15, as a stromal biomarker, can predict the clinical prognosis of HGSC and promote the immunosuppressive microenvironment. LRRC15 may be a potential therapeutic target for reversing primary resistance in OC.
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LINC02381 suppresses cell proliferation and promotes apoptosis via attenuating IGF1R/PI3K/AKT signaling pathway in breast cancer. Funct Integr Genomics 2023; 23:40. [PMID: 36648607 DOI: 10.1007/s10142-023-00965-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 01/01/2023] [Accepted: 01/03/2023] [Indexed: 01/18/2023]
Abstract
Identification of the genes and genetic networks involved in breast cancer development is a major need for prevention and therapy. LINC02381 (lncRNA) has already been introduced as a tumor suppressor in colorectal and gastric cancers. Here, we intended to investigate its potential functional effects on breast cancer. In the analysis performed on RNA-Seq and microarray data, the LINC02381 lncRNA was found to be significantly downregulated in the breast tumors and associated with poor survival of the patients. Then, the differential expression of LINC02381 was confirmed in breast tumor tissues and cancer cell lines using RT-qPCR. Overexpression of LINC02381 resulted in reduced IGF1R and p-AKT expression levels which indicates decreased PI3K pathway activity, detected by RT-qPCR and western blotting. At the cellular level, LINC02381 overexpression was followed by a decreased proliferation rate of transfected breast cell lines, detected by PI flow cytometry, RT-qPCR, colony formation, and MTT assays. Consistently, the results of Annexin-V/PI flow cytometry, RT-qPCR, caspase3/7 activity, and AO/EB-H33342/PI dual staining revealed that LINC02381 overexpression induced apoptosis and cell death. The reduced migration rate of these cells was also verified through wound healing assay and RT-qPCR against the EMT-involved genes. Our data show that LINC02381 exerts its tumor suppressor effect at least partly through attenuation of the IGF1R/PI3K/AKT signaling pathway, which originated from IGF1R downregulation.
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RBCK1 regulates the progression of ER-positive breast cancer through the HIF1α signaling. Cell Death Dis 2022; 13:1023. [PMID: 36473847 PMCID: PMC9726878 DOI: 10.1038/s41419-022-05473-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 11/24/2022] [Accepted: 11/25/2022] [Indexed: 12/12/2022]
Abstract
Breast cancer is the most common malignancy in women on a global scale. It can generally be divided into four main categories, of which estrogen receptor ER-positive breast cancer accounts for most breast cancer cases. RBCK1 protein is an E3 ubiquitin ligase containing the UBL, NZF, and RBR domains. It is well known to exhibit abnormal expression in breast tumors, making it a valuable diagnostic marker and drug target. Additionally, studies have confirmed that in breast cancer, about 25 to 40% of tumors appear as visible hypoxic regions, while in hypoxia, tumor cells can activate the hypoxia-inducing factor HIF1 pathway and widely activate the expression of downstream genes. Previous studies have confirmed that in the hypoxic environment of tumors, HIF1α promotes the remodeling of extracellular matrix, induces the recruitment of tumor-associated macrophages (TAM) and immunosuppression of allogeneic tumors, thereby influencing tumor recurrence and metastasis. This research aims to identify RBCK1 as an important regulator of HIF1α signaling pathway. Targeted therapy with RBCK1 could be a promising treatment strategy for ER-positive breast cancer.
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Hirota A, Clément JE, Tanikawa S, Nonoyama T, Komatsuzaki T, Gong JP, Tanaka S, Imajo M. ERK MAP Kinase Signaling Regulates RAR Signaling to Confer Retinoid Resistance on Breast Cancer Cells. Cancers (Basel) 2022; 14:cancers14235890. [PMID: 36497371 PMCID: PMC9739577 DOI: 10.3390/cancers14235890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 11/18/2022] [Accepted: 11/24/2022] [Indexed: 12/05/2022] Open
Abstract
Retinoic acid (RA) and its synthetic derivatives, retinoids, have been established as promising anticancer agents based on their ability to regulate cell proliferation and survival. Clinical trials, however, have revealed that cancer cells often acquire resistance to retinoid therapy. Therefore, elucidation of underlying mechanisms of retinoid resistance has been considered key to developing more effective use of retinoids in cancer treatment. In this study, we show that constitutive activation of ERK MAP kinase signaling, which is often caused by oncogenic mutations in RAS or RAF genes, suppresses RA receptor (RAR) signaling in breast cancer cells. We show that activation of the ERK pathway suppresses, whereas its inhibition promotes, RA-induced transcriptional activation of RAR and the resultant upregulation of RAR-target genes in breast cancer cells. Importantly, ERK inhibition potentiates the tumor-suppressive activity of RA in breast cancer cells. Moreover, we also reveal that suppression of RAR signaling and activation of ERK signaling are associated with poor prognoses in breast cancer patients and represent hallmarks of specific subtypes of breast cancers, such as basal-like, HER2-enriched and luminal B. These results indicate that ERK-dependent suppression of RAR activity underlies retinoid resistance and is associated with cancer subtypes and patient prognosis in breast cancers.
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Affiliation(s)
- Akira Hirota
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
| | - Jean-Emmanuel Clément
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
- Research Center of Mathematics for Social Creativity, Research Institute for Electronic Science, Hokkaido University, Sapporo 001-0020, Japan
| | - Satoshi Tanikawa
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
| | - Takayuki Nonoyama
- Faculty of Advanced Life Science, Hokkaido University, Sapporo 001-0021, Japan
| | - Tamiki Komatsuzaki
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
- Research Center of Mathematics for Social Creativity, Research Institute for Electronic Science, Hokkaido University, Sapporo 001-0020, Japan
| | - Jian Ping Gong
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
- Faculty of Advanced Life Science, Hokkaido University, Sapporo 001-0021, Japan
| | - Shinya Tanaka
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
- Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Masamichi Imajo
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
- Correspondence: ; Tel.: +81-11-706-9683
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Wang S, Li H, Liu J, Zhang Q, Xu W, Xiang J, Fang L, Xu P, Li Z. Integrative analysis of m3C associated genes reveals METTL2A as a potential oncogene in breast Cancer. J Transl Med 2022; 20:476. [PMID: 36266694 PMCID: PMC9583565 DOI: 10.1186/s12967-022-03683-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 10/03/2022] [Indexed: 12/02/2022] Open
Abstract
RNA methylation modifications, especially m6A mRNA modification, are known to be extensively involved in tumor development. However, the relationship between N3-methylcytidine (m3C) related genes and tumorigenesis has rarely been studied. In this research, we found that m3C-related genes were expressed at different levels and affected patients’ prognosis across multiple cancer types from The Cancer Genome Atlas and multi-omics levels. Importantly, methyltransferase-like proteins 2A (METTL2A) had a high amplification frequency (~ 7%) in patients with breast invasive carcinoma (BRCA), and its overexpression was an independent predictor of poor overall survival. Enrichment analysis of associated genes revealed that METTL2A may activate DNA synthesis and cell proliferation pathways in BRCA cells. Through drug sensitivity analysis, Trifluridine, PD407824, and Taselisib were shown to be effective drugs for METTL2A-positive BRCA patients. Overall, our research conducts a holistic view of the expression level and prognostic signature of m3C-related genes with multiple malignancies. Importantly, METTL2A has been intensely explored as a potential oncogene in BRCA, to aid the development of potential drug agents for precision therapy in breast cancer patients.
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Affiliation(s)
- Shuai Wang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Huiting Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Jiheng Liu
- Department of Hematology and Oncology, First Hospital of Changsha, Changsha, Hunan, China
| | - Qianqian Zhang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Wei Xu
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Juanjuan Xiang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Li Fang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Ping Xu
- Departments of Respiratory and Critical Care Medicine, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Zheng Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
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31
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Chu HM, Liu JX, Zhang K, Zheng CH, Wang J, Kong XZ. A binary biclustering algorithm based on the adjacency difference matrix for gene expression data analysis. BMC Bioinformatics 2022; 23:381. [PMID: 36123637 PMCID: PMC9484244 DOI: 10.1186/s12859-022-04842-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 07/14/2022] [Indexed: 11/20/2022] Open
Abstract
Biclustering algorithm is an effective tool for processing gene expression datasets. There are two kinds of data matrices, binary data and non-binary data, which are processed by biclustering method. A binary matrix is usually converted from pre-processed gene expression data, which can effectively reduce the interference from noise and abnormal data, and is then processed using a biclustering algorithm. However, biclustering algorithms of dealing with binary data have a poor balance between running time and performance. In this paper, we propose a new biclustering algorithm called the Adjacency Difference Matrix Binary Biclustering algorithm (AMBB) for dealing with binary data to address the drawback. The AMBB algorithm constructs the adjacency matrix based on the adjacency difference values, and the submatrix obtained by continuously updating the adjacency difference matrix is called a bicluster. The adjacency matrix allows for clustering of gene that undergo similar reactions under different conditions into clusters, which is important for subsequent genes analysis. Meanwhile, experiments on synthetic and real datasets visually demonstrate that the AMBB algorithm has high practicability.
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Affiliation(s)
- He-Ming Chu
- School of Computer Science, Qufu Normal University, Rizhao, 276826, China
| | - Jin-Xing Liu
- School of Computer Science, Qufu Normal University, Rizhao, 276826, China
| | - Ke Zhang
- Department of Oncology, Rizhao People's Hospital, Rizhao, 276826, China.
| | - Chun-Hou Zheng
- School of Computer Science, Qufu Normal University, Rizhao, 276826, China
| | - Juan Wang
- School of Computer Science, Qufu Normal University, Rizhao, 276826, China
| | - Xiang-Zhen Kong
- School of Computer Science, Qufu Normal University, Rizhao, 276826, China.
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32
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Liu BW, Wang XY, Cao JL, Chen LL, Wang YL, Zhao BQ, Zhou J, Shen ZF. TDP-43 upregulates lipid metabolism modulator ABHD2 to suppress apoptosis in hepatocellular carcinoma. Commun Biol 2022; 5:816. [PMID: 35963893 PMCID: PMC9376094 DOI: 10.1038/s42003-022-03788-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 08/02/2022] [Indexed: 11/11/2022] Open
Abstract
TAR DNA-Binding Protein 43 (TDP-43) has been well studied in neurodegenerative diseases, but its potential role in malignance is still unclear. Here, we demonstrate that TDP-43 contributes to the suppression of apoptosis by facilitating lipid metabolism in hepatocellular carcinoma (HCC). In HCC cells, TDP-43 is able to suppress apoptosis while deletion of it markedly induces apoptosis. RNA-sequencing identifies the lipid metabolism gene abhydrolase domain containing 2 (ABHD2) as the target gene of TDP-43. Tissue microarray analysis shows the positive correlation of TDP-43 and ABHD2 in HCC. Mechanistically, TDP-43 binds with the UG-rich sequence1 of ABHD2 3’UTR to enhance the mRNA stability of ABHD2, thereby upregulating ABHD2. Afterwards, TDP-43 promotes the production of free fatty acid and fatty acid oxidation-originated reactive oxygen species (ROS) in an ABHD2-dependent manner, so as to suppress apoptosis of HCC. Our findings provide insights into the mechanism of HCC progression and reveal TDP-43/ABHD2 as potential targets for the precise treatment of HCC. TDP-43 acts as an RNA-binding protein that regulates the RNA stability of ABHD2 and affects the release of fatty acids and ROS, which in turn regulates apoptosis and affects the growth of liver tumors.
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Affiliation(s)
- Bo-Wen Liu
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, PR China.
| | - Xiang-Yun Wang
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, PR China
| | - Jin-Ling Cao
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, PR China
| | - Lu-Lu Chen
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, PR China
| | - Yi-Lei Wang
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, PR China
| | - Bing-Qian Zhao
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, PR China
| | - Jia Zhou
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, PR China
| | - Zhi-Fa Shen
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, PR China.
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33
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Alnoumas L, van den Driest L, Apczynski Z, Lannigan A, Johnson CH, Rattray NJW, Rattray Z. Evaluation of the role of KPNA2 mutations in breast cancer prognosis using bioinformatics datasets. BMC Cancer 2022; 22:874. [PMID: 35948941 PMCID: PMC9364282 DOI: 10.1186/s12885-022-09969-4] [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: 01/18/2022] [Accepted: 08/04/2022] [Indexed: 11/10/2022] Open
Abstract
Breast cancer, comprising of several sub-phenotypes, is a leading cause of female cancer-related mortality in the UK and accounts for 15% of all cancer cases. Chemoresistant sub phenotypes of breast cancer remain a particular challenge. However, the rapidly-growing availability of clinical datasets, presents the scope to underpin a data-driven precision medicine-based approach exploring new targets for diagnostic and therapeutic interventions.We report the application of a bioinformatics-based approach probing the expression and prognostic role of Karyopherin-2 alpha (KPNA2) in breast cancer prognosis. Aberrant KPNA2 overexpression is directly correlated with aggressive tumour phenotypes and poor patient survival outcomes. We examined the existing clinical data available on a range of commonly occurring mutations of KPNA2 and their correlation with patient survival.Our analysis of clinical gene expression datasets show that KPNA2 is frequently amplified in breast cancer, with differences in expression levels observed as a function of patient age and clinicopathologic parameters. We also found that aberrant KPNA2 overexpression is directly correlated with poor patient prognosis, warranting further investigation of KPNA2 as an actionable target for patient stratification or the design of novel chemotherapy agents.In the era of big data, the wealth of datasets available in the public domain can be used to underpin proof of concept studies evaluating the biomolecular pathways implicated in chemotherapy resistance in breast cancer.
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Affiliation(s)
- Layla Alnoumas
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | - Lisa van den Driest
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | - Zoe Apczynski
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | | | | | - Nicholas J W Rattray
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
| | - Zahra Rattray
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
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Identifying General Tumor and Specific Lung Cancer Biomarkers by Transcriptomic Analysis. BIOLOGY 2022; 11:biology11071082. [PMID: 36101460 PMCID: PMC9313083 DOI: 10.3390/biology11071082] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/25/2022] [Accepted: 07/03/2022] [Indexed: 11/17/2022]
Abstract
The bioinformatic pipeline previously developed in our research laboratory is used to identify potential general and specific deregulated tumor genes and transcription factors related to the establishment and progression of tumoral diseases, now comparing lung cancer with other two types of cancer. Twenty microarray datasets were selected and analyzed separately to identify hub differentiated expressed genes and compared to identify all the deregulated genes and transcription factors in common between the three types of cancer and those unique to lung cancer. The winning DEGs analysis allowed to identify an important number of TFs deregulated in the majority of microarray datasets, which can become key biomarkers of general tumors and specific to lung cancer. A coexpression network was constructed for every dataset with all deregulated genes associated with lung cancer, according to DAVID’s tool enrichment analysis, and transcription factors capable of regulating them, according to oPOSSUM´s tool. Several genes and transcription factors are coexpressed in the networks, suggesting that they could be related to the establishment or progression of the tumoral pathology in any tissue and specifically in the lung. The comparison of the coexpression networks of lung cancer and other types of cancer allowed the identification of common connectivity patterns with deregulated genes and transcription factors correlated to important tumoral processes and signaling pathways that have not been studied yet to experimentally validate their role in lung cancer. The Kaplan–Meier estimator determined the association of thirteen deregulated top winning transcription factors with the survival of lung cancer patients. The coregulatory analysis identified two top winning transcription factors networks related to the regulatory control of gene expression in lung and breast cancer. Our transcriptomic analysis suggests that cancer has an important coregulatory network of transcription factors related to the acquisition of the hallmarks of cancer. Moreover, lung cancer has a group of genes and transcription factors unique to pulmonary tissue that are coexpressed during tumorigenesis and must be studied experimentally to fully understand their role in the pathogenesis within its very complex transcriptomic scenario. Therefore, the downstream bioinformatic analysis developed was able to identify a coregulatory metafirm of cancer in general and specific to lung cancer taking into account the great heterogeneity of the tumoral process at cellular and population levels.
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35
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Seo B, Coates D, Lewis J, Seymour G, Rich A. Unfolded protein response is involved in the metabolic and apoptotic regulation of oral squamous cell carcinoma. Pathology 2022; 54:874-881. [DOI: 10.1016/j.pathol.2022.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 03/21/2022] [Accepted: 04/07/2022] [Indexed: 11/17/2022]
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Wang L, Wang H, Yang C, Wu Y, Lei G, Yu Y, Gao Y, Du J, Tong X, Zhou F, Li Y, Wang Y. Investigating CENPW as a Novel Biomarker Correlated With the Development and Poor Prognosis of Breast Carcinoma. Front Genet 2022; 13:900111. [PMID: 35783290 PMCID: PMC9247308 DOI: 10.3389/fgene.2022.900111] [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: 05/24/2022] [Indexed: 11/22/2022] Open
Abstract
Breast invasive carcinoma (BRCA) is a carcinoma with a fairly high incidence, and the therapeutic schedules are generally surgery and chemotherapy. However, chemotherapeutic drugs tend to produce serious toxic side effects, which lead to the cessation of treatment. Therefore, it is imperative to develop treatment strategies that are more effective and have fewer side effects at the genetic level. Centromeric protein W (CENPW) is an oncogene that plays an important part in nucleosome assembly. To date, no studies have reported the prognostic significance of CENPW in breast carcinoma. In this study, we verified that CENPW expression is up-regulated in breast carcinoma and positively associated with the level of immune cell infiltration. The clinicopathological characteristics further suggest that CENPW expression is correlated with a worse prognosis of breast carcinoma. Interestingly, the CENPW mutation contributes to the poor prognosis. Next, we discovered that the genes interacting with CENPW are mainly concentrated in the cell cycle pathway, and CENPW is co-expressed with CDCA7, which is also highly expressed in breast carcinoma and leads to a worse prognosis. Our subsequent studies verified that knockdown of CENPW significantly inhibits the proliferation and migration of breast carcinoma cells and promotes their apoptosis rate. Notably, inhibition of CEMPW sensitizes breast cancer cells to chemotherapeutic drugs that have been found to induce cell cycle arrest. In summary, these results provide extensive data and experimental evidence that CENPW can serve as a novel predictor of breast cancer and may act as a prospective therapeutic target.
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Affiliation(s)
- Luyang Wang
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
- Department of Central Laboratory, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- School of Pharmacy, Hangzhou Medical College, Hangzhou, China
| | - Hairui Wang
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China
| | - Chen Yang
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Yunyi Wu
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Guojie Lei
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Yanhua Yu
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Yan Gao
- School of Pharmacy, Hangzhou Medical College, Hangzhou, China
| | - Jing Du
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Xiangmin Tong
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
- School of Pharmacy, Hangzhou Medical College, Hangzhou, China
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China
| | - Feifei Zhou
- Traditional Chinese Medicine Department, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
- *Correspondence: Feifei Zhou, ; Yanchun Li, ; Ying Wang,
| | - Yanchun Li
- Department of Central Laboratory, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- *Correspondence: Feifei Zhou, ; Yanchun Li, ; Ying Wang,
| | - Ying Wang
- Department of Central Laboratory, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- School of Pharmacy, Hangzhou Medical College, Hangzhou, China
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China
- *Correspondence: Feifei Zhou, ; Yanchun Li, ; Ying Wang,
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XIST loss impairs mammary stem cell differentiation and increases tumorigenicity through Mediator hyperactivation. Cell 2022; 185:2164-2183.e25. [PMID: 35597241 DOI: 10.1016/j.cell.2022.04.034] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 01/10/2022] [Accepted: 04/27/2022] [Indexed: 12/27/2022]
Abstract
X inactivation (XCI) is triggered by upregulation of XIST, which coats the chromosome in cis, promoting formation of a heterochromatic domain (Xi). XIST role beyond initiation of XCI is only beginning to be elucidated. Here, we demonstrate that XIST loss impairs differentiation of human mammary stem cells (MaSCs) and promotes emergence of highly tumorigenic and metastatic carcinomas. On the Xi, XIST deficiency triggers epigenetic changes and reactivation of genes overlapping Polycomb domains, including Mediator subunit MED14. MED14 overdosage results in increased Mediator levels and hyperactivation of the MaSC enhancer landscape and transcriptional program, making differentiation less favorable. We further demonstrate that loss of XIST and Xi transcriptional instability is common among human breast tumors of poor prognosis. We conclude that XIST is a gatekeeper of human mammary epithelium homeostasis, thus unveiling a paradigm in the control of somatic cell identity with potential consequences for our understanding of gender-specific malignancies.
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38
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Liu FR, Jiang MJ, Mei Z, Lin CJ, Tian L. cGAS-STING signalings potentiate tumor progression via sustaining cancer stemness. Transl Oncol 2022; 20:101404. [PMID: 35364558 PMCID: PMC8968062 DOI: 10.1016/j.tranon.2022.101404] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 03/07/2022] [Accepted: 03/20/2022] [Indexed: 12/19/2022] Open
Abstract
Intrinsic activation of cGAS-STING signalings potentiate tumorigenesis. cGAS-STING signalings promote tumor progression by sustaining cancer stemness. STAT3 may act as a downstream effector of cGAS-STING signalings to stimulate cancer stemness. The cytosolic DNA-sensing cGAS-STING pathway has been proved to be involved in tumor progression and influence the effect of cancer immunotherapy. However, little attentions have been paid to the role of cGAS-STING pathway on cancer stemness. Herein, we found that the cGAS-STING pathway was activated in different tumor cells. cGAS- or STING-knockout impaired the capability of tumor formation in vivo and tumorsphere formation in vitro. In addition, loss of cGAS-STING cascade promoted tumor apoptosis, but inhibited tumor growth and metastasis. We further demonstrated that cGAS-STING pathway potentiated tumor formation by sustaining cancer stemness. Moreover, analysis of RNA-seq showed that cGAS-STING pathway maintained cancer stemness probably by activating STAT3. Our findings highlight the role of intrinsic activation of cGAS-STING pathway in tumorigenesis, and reveal a new mechanism of its regulation of tumor progression via sustaining cancer stemness through STAT3 activation.
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39
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Jiang YH, Long J, Zhao ZB, Li L, Lian ZX, Liang Z, Wu JR. Gene co-expression network based on part mutual information for gene-to-gene relationship and gene-cancer correlation analysis. BMC Bioinformatics 2022; 23:194. [PMID: 35610556 PMCID: PMC9128248 DOI: 10.1186/s12859-022-04732-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 05/09/2022] [Indexed: 11/10/2022] Open
Abstract
Background Finding correlation patterns is an important goal of analyzing biological data. Currently available methods for correlation analysis mainly use non-direct associations, such as the Pearson correlation coefficient, and focus on the interpretation of networks at the level of modules. For biological objects such as genes, their collective function depends on pairwise gene-to-gene interactions. However, a large amount of redundant results from module level methods often necessitate further detailed analysis of gene interactions. New approaches of measuring direct associations among variables, such as the part mutual information (PMI), may help us better interpret the correlation pattern of biological data at the level of variable pairs. Results We use PMI to calculate gene co-expression networks of cancer mRNA transcriptome data. Our results show that the PMI-based networks with fewer edges could represent the correlation pattern and are robust across biological conditions. The PMI-based networks recall significantly more important parts of omics defined gene-pair relationships than the Pearson Correlation Coefficient (PCC)-based networks. Based on the scores derived from PMI-recalled copy number variation or DNA methylation gene-pairs, the patients with cancer can be divided into groups with significant differences on disease specific survival. Conclusions PMI, measuring direct associations between variables, extracts more important biological relationships at the level of gene pairs than conventional indirect association measures do. It can be used to refine module level results from other correlation methods. Particularly, PMI is beneficial to analysis of biological data of the complicated systems, for example, cancer transcriptome data. Supplementary Information The online version contains supplementary material available at 10.1186/s12859-022-04732-9.
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Affiliation(s)
- Yi-Hua Jiang
- Hefei National Laboratory for Physical Sciences at Microscale and School of Life Science, University of Science and Technology of China, Hefei, China
| | - Jie Long
- Chronic Disease Laboratory, School of Medicine, South China University of Technology, Guangzhou, China
| | - Zhi-Bin Zhao
- Chronic Disease Laboratory, School of Medicine, South China University of Technology, Guangzhou, China
| | - Liang Li
- Chronic Disease Laboratory, School of Medicine, South China University of Technology, Guangzhou, China
| | - Zhe-Xiong Lian
- Chronic Disease Laboratory, School of Medicine, South China University of Technology, Guangzhou, China
| | - Zhi Liang
- Hefei National Laboratory for Physical Sciences at Microscale and School of Life Science, University of Science and Technology of China, Hefei, China.
| | - Jia-Rui Wu
- Hefei National Laboratory for Physical Sciences at Microscale and School of Life Science, University of Science and Technology of China, Hefei, China. .,Key Laboratory of Systems Health Science of Zhejiang Province, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, 310024, China.
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40
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Comprehensive Landscape of STEAP Family Members Expression in Human Cancers: Unraveling the Potential Usefulness in Clinical Practice Using Integrated Bioinformatics Analysis. DATA 2022. [DOI: 10.3390/data7050064] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
The human Six-Transmembrane Epithelial Antigen of the Prostate (STEAP) family comprises STEAP1-4. Several studies have pointed out STEAP proteins as putative biomarkers, as well as therapeutic targets in several types of human cancers, particularly in prostate cancer. However, the relationships and significance of the expression pattern of STEAP1-4 in cancer cases are barely known. Herein, the Oncomine database and cBioPortal platform were selected to predict the differential expression levels of STEAP members and clinical prognosis. The most common expression pattern observed was the combination of the over- and underexpression of distinct STEAP genes, but cervical and gastric cancer and lymphoma showed overexpression of all STEAP genes. It was also found that STEAP genes’ expression levels were already deregulated in benign lesions. Regarding the prognostic value, it was found that STEAP1 (prostate), STEAP2 (brain and central nervous system), STEAP3 (kidney, leukemia and testicular) and STEAP4 (bladder, cervical, gastric) overexpression correlate with lower patient survival rate. However, in prostate cancer, overexpression of the STEAP4 gene was correlated with a higher survival rate. Overall, this study first showed that the expression levels of STEAP genes are highly variable in human cancers, which may be related to different patients’ outcomes.
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41
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Wang Z, Li S, Xu F, Fu J, Sun J, Gan X, Yang C, Mao Z. ncRNAs-mediated high expression of TIMM8A correlates with poor prognosis and act as an oncogene in breast cancer. Cancer Cell Int 2022; 22:177. [PMID: 35501914 PMCID: PMC9063222 DOI: 10.1186/s12935-022-02595-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 04/18/2022] [Indexed: 11/17/2022] Open
Abstract
Background Breast cancer is notorious for its increasing incidence for decades. Ascending evidence has demonstrated that translocase of inner mitochondrial membrane (TIMM) proteins play vital roles in progression of several types of human cancer. However, the biological behaviors and molecular mechanisms of TIMM8A in breast cancer remain not fully illustrated. Methods Pan-cancer analysis was firstly performed for TIMM8A’s expression and prognosis by Oncomine database. Subsequently, TIMM8A-related noncoding RNAs (ncRNAs) were identified by a series of bioinformatics analyses and dual-luciferase reporter assay, including expression analysis, correlation analysis, and survival analysis. Moreover, the effect of TIMM8A on breast cancer proliferation and apoptosis was evaluated in vitro by CCK-8 assays, EdU cell proliferation assays, JC-1 mitochondrial membrane potential detection assays and Western blot assays and the in vivo effect was revealed through a patient-derived xenograft mouse model. Results We found that TIMM8A showed higher expression level in breast cancer and the higher TIMM8A mRNA expression group had a poorer prognosis than the lower TIMM8A group. hsa-circ-0107314/hsa-circ-0021867/hsa-circ-0122013 might be the three most potential upstream circRNAs of hsa-miR-34c-5p/hsa-miR-449a-TIMM8A axis in breast cancer. TIMM8A promotes proliferation of breast cancer cells in vitro and tumor growth in vivo. Conclusion Our results confirmed that ncRNAs-mediated upregulation of TIMM8A correlated with poor prognosis and act as an oncogene in breast cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-022-02595-x.
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Affiliation(s)
- Zhonglin Wang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Soochow, 215006, China.,Department of Breast Surgery, The Second People's Hospital of Lianyungang, Lianyungang, 222006, China
| | - Shuqin Li
- Department of Breast Surgery, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, 222006, China
| | - Feng Xu
- Jiangsu Breast Disease Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, 210029, China
| | - Jingyue Fu
- Jiangsu Breast Disease Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, 210029, China
| | - Jie Sun
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Soochow, 215006, China
| | - XinLi Gan
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Soochow, 215006, China
| | - Chuang Yang
- Jiangsu Breast Disease Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, 210029, China.
| | - Zhongqi Mao
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Soochow, 215006, China.
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Gurova K. Can aggressive cancers be identified by the "aggressiveness" of their chromatin? Bioessays 2022; 44:e2100212. [PMID: 35452144 DOI: 10.1002/bies.202100212] [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] [Received: 09/07/2021] [Revised: 04/08/2022] [Accepted: 04/12/2022] [Indexed: 12/15/2022]
Abstract
Phenotypic plasticity is a crucial feature of aggressive cancer, providing the means for cancer progression. Stochastic changes in tumor cell transcriptional programs increase the chances of survival under any condition. I hypothesize that unstable chromatin permits stochastic transitions between transcriptional programs in aggressive cancers and supports non-genetic heterogeneity of tumor cells as a basis for their adaptability. I present a mechanistic model for unstable chromatin which includes destabilized nucleosomes, mobile chromatin fibers and random enhancer-promoter contacts, resulting in stochastic transcription. I suggest potential markers for "unsettled" chromatin in tumors associated with poor prognosis. Although many of the characteristics of unstable chromatin have been described, they were mostly used to explain changes in the transcription of individual genes. I discuss approaches to evaluate the role of unstable chromatin in non-genetic tumor cell heterogeneity and suggest using the degree of chromatin instability and transcriptional noise in tumor cells to predict cancer aggressiveness.
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Affiliation(s)
- Katerina Gurova
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
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43
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Montero JC, Calvo-Jiménez E, Del Carmen S, Abad M, Ocaña A, Pandiella A. Surfaceome analyses uncover CD98hc as an antibody drug-conjugate target in triple negative breast cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:106. [PMID: 35317825 PMCID: PMC8941813 DOI: 10.1186/s13046-022-02330-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 03/12/2022] [Indexed: 11/10/2022]
Abstract
Background Despite the incorporation of novel therapeutics, advanced triple negative breast cancer (TNBC) still represents a relevant clinical problem. Considering this, as well as the clinical efficacy of antibody-drug conjugates (ADCs), we aimed at identifying novel ADC targets that could be used to treat TNBC. Methods Transcriptomic analyses were performed on TNBC and normal samples from three different studies. Plasma membrane proteins of three cell lines representative of the TNBC subtype were identified by cell surface biotinylation or plasma membrane isolation, followed by analyses of cell surface proteins using the Surfaceome online tool. Immunofluorescence and western studies were used to characterize the action of a CD98hc-directed ADC, which was prepared by in house coupling of emtansine to an antibody that recognized the ectodomain of CD98hc. Xenografted TNBC cells were used to analyze the antitumoral properties of the anti-CD98hc ADC. Results Comparative genomic studies between normal breast and TNBC tissues, together with proteomic and bioinformatic analyses resulted in the elaboration of a catalog of potential ADC targets. One of them, the CD98hc transmembrane protein, was validated as an ADC target. An antibody recognizing the ectodomain of CD98hc efficiently internalized and reached the lysosomal compartment. An emtansine-based ADC derived from such antibody was prepared and showed antitumoral properties in TNBC in vitro and in vivo models. Mechanistically, the anti-CD98hc ADC blocked cell cycle progression, that was followed by cell death caused by mitotic catastrophe. Conclusions This work describes a list of potential ADC targets in TNBC and validates one of them, the transmembrane protein CD98hc. The studies presented here also demonstrate the robustness of the multiomic approach herewith described to identify novel potential ADC targets. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02330-4.
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Affiliation(s)
- Juan Carlos Montero
- Institute of Biomedical Research of Salamanca (IBSAL), Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca) and CIBERONC, Salamanca, Spain. .,Department of Pathology and IBSAL, University Hospital of Salamanca, University of Salamanca, 37007, Salamanca, Spain.
| | - Elisa Calvo-Jiménez
- Institute of Biomedical Research of Salamanca (IBSAL), Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca) and CIBERONC, Salamanca, Spain
| | - Sofía Del Carmen
- Department of Pathology and IBSAL, University Hospital of Salamanca, University of Salamanca, 37007, Salamanca, Spain
| | - Mar Abad
- Department of Pathology and IBSAL, University Hospital of Salamanca, University of Salamanca, 37007, Salamanca, Spain
| | | | - Atanasio Pandiella
- Institute of Biomedical Research of Salamanca (IBSAL), Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca) and CIBERONC, Salamanca, Spain
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Abdollahzadeh R, Azarnezhad A, Paknahad S, Mansoori Y, Pirhoushiaran M, Kanaani K, Bafandeh N, Jafari D, Tavakkoly-Bazzaz J. A Proposed TUSC7/miR-211/Nurr1 ceRNET Might Potentially be Disturbed by a cer-SNP rs2615499 in Breast Cancer. Biochem Genet 2022; 60:2200-2225. [PMID: 35296964 DOI: 10.1007/s10528-022-10216-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 02/24/2022] [Indexed: 12/09/2022]
Abstract
Evidence and in silico analyses showed that TUSC7, miR-211, and Nurr1 may be involved in BC pathogenesis by ceRNET signaling axis. This study aimed to investigate the potential role of TUSC7/miR-211/Nurr1 ceRNET and rs2615499 variant as a novel cer-SNP in BC subjects. The expression assays were conducted by qPCR on tumor tissues (n = 50), tumor-adjacent normal tissues (TANTs) (n = 50), and clinically healthy control tissues (n = 50). The expression of TUSC7 and Nurr1 significantly decreased, but the level of miR-211 significantly increased in tumor tissues compared to TANTs and healthy normal tissues. Altered expression of TUSC7 and miR-211 was associated with poor prognosis of patients. The Nurr1 exhibited a double-edged sword-like activity in BC. In addition, TUSC7, Nurr1, and miR-211 expressions were significantly related to a novel BC-associated rs2615499 (A > C) located in the miR-211 binding site on Nurr1 3'-UTR. In the second part of the study, a case-control study was performed on BC patients (n = 100) and matched healthy controls (n = 100). The genomic DNA was isolated and genotyping was performed using Tetra-Primer ARMS PCR. The CC and AC genotypes were associated with higher expression levels of Nurr1 and worse outcomes of the disease. Our findings revealed that TUSC7 functions as a tumor suppressor in BC potentially via miR-211/Nurr1, which might be disturbed by the cer-SNP rs2615499. However, functional studies are needed to validate these results.
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Affiliation(s)
- Rasoul Abdollahzadeh
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Asaad Azarnezhad
- Liver and Digestive Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran.,Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Sahereh Paknahad
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Yaser Mansoori
- Department of Medical Genetics, Fasa University of Medical Sciences, Fasa, Iran
| | - Maryam Pirhoushiaran
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Khaled Kanaani
- Faculty of Nursing and Midwifery, Kowsar Hospital, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Neda Bafandeh
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Davood Jafari
- Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Tehran, Iran
| | - Javad Tavakkoly-Bazzaz
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Yan L, He J, Liao X, Liang T, Zhu J, Wei W, He Y, Zhou X, Peng T. A comprehensive analysis of the diagnostic and prognostic value associated with the SLC7A family members in breast cancer. Gland Surg 2022; 11:389-411. [PMID: 35284318 PMCID: PMC8899434 DOI: 10.21037/gs-21-909] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 01/30/2022] [Indexed: 07/21/2023]
Abstract
BACKGROUND The solute carrier (SLC) 7 family genes play central roles in cancer cell metabolism as glucose and glutamate transporters. However, their expression and prognostic value in breast cancer (BC) remains to be elucidated. METHODS Clinical data from BC patients were downloaded from The Cancer Genome Atlas (TCGA) and the Kaplan-Meier (KM) plotter database. The mechanisms underlying the association between SLC7A expression and overall survival (OS) were explored using Cox regression and log-rank tests. ESTIMATE gives a measure of the immune-cell infiltrates. Single-sample (ss) Gene Set Enrichment Analysis (GSEA) was conducted to quantify immune cell infiltration. RESULTS High SLC7A5 expression was associated with a poorer survival time in BC patients according to the TCGA and KM plotter data. SLC7A4 was associated with good progression-free interval (PFI) and disease-specific survival (DSS) according to the TCGA data. Furthermore, SLC7A4 was correlated with good prognosis of OS, distant metastasis-free survival (DMFS), relapse-free survival (RFS), and post-progression survival (PPS) according to the KM plotter data. SLC7A3 expression was positively associated with OS, but was not strongly associated with PFI nor DSS in the TCGA data. However, SLC7A3 was positively correlated with DMFS and RFS in the KM database analysis. SLC7A had excellent diagnostic value in BC patients and was strongly correlated with tumor infiltration. T helper 2 (Th2) cells, CD56 bright natural killer (NK) cells, and NK cells were the most strongly correlated with the SLC7A family genes, suggesting that these genes play a crucial role in BC partly by modulating immune infiltration. CONCLUSIONS SLC7A4 and SLC7A5 expression levels may be sensitive biomarkers for predicting BC outcomes. SLC7A3 may be a potential diagnostic and prognostic biomarker in BC, but further studies are warranted to verify these results.
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Affiliation(s)
- Liping Yan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Key Laboratory of High-Incidence-Tumor Prevention and Treatment Guangxi Medical University, Nanning, China
| | - Jianxin He
- Department of Ultrasound Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiwen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Tianyi Liang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jia Zhu
- Department of Breast Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Wensong Wei
- Department of Breast Surgery, The Third Hospital of Nanchang, Nanchang, China
| | - Yongfei He
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xin Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Key Laboratory of High-Incidence-Tumor Prevention and Treatment Guangxi Medical University, Nanning, China
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Song S, Liu J, Zhang M, Gao X, Sun W, Liu P, Wang Y, Li J. Eukaryotic translation initiation factor 3 subunit B could serve as a potential prognostic predictor for breast cancer. Bioengineered 2022; 13:2762-2776. [PMID: 35040374 PMCID: PMC8974155 DOI: 10.1080/21655979.2021.2017567] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The EIF3 gene family is essential in controlling translation initiation during the cell cycle. The significance of the EIF3 subunits as prognostic markers and therapeutic targets in breast cancer is not yet clear. We analyzed the expression of EIF3 subunits in breast cancer on the GEPIA and Oncomine databases and compared their expression in breast cancer and normal tissues using BRCA data downloaded from TCGA. Then we performed clinical survival analysis on the Kaplan–Meier Plotter database and clinicopathologic analysis on the bc-genexMiner v4.1 database. And EIF3B was chosen for mutation analysis via the Cancer SEA online tool. Meanwhile, we performed the immunohistochemical assay, real-time RT-PCR, and Western blotting to analyze EIF3B expression levels in breast cancer. An EIF3B knockdown and a negative control cell line were conducted for MTT assay and cell cycle analysis to assess cell growth. Specifically, the results of TCGA and online databases demonstrated that upregulated EIF3B was associated with poorer overall and advanced tumor progression. We also confirmed that EIF3B was more highly expressed in breast cancer cells and tissues than normal and correlated with a worse outcome. And knockdown of EIF3B expression inhibited the cell cycle and proliferation. Furthermore, EIF3B was highly mutated in breast cancer. Collectively, our results suggested EIF3B as a potential prognostic marker and therapeutic target for breast cancer.
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Affiliation(s)
- Shaoran Song
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,The Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi China
| | - Jie Liu
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,The Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi China
| | - Miao Zhang
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,The Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi China
| | - Xiaoqian Gao
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,The Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi China
| | - Wei Sun
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,The Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi China
| | - Peijun Liu
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,The Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi China
| | - Yaochun Wang
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,The Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi China
| | - Juan Li
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,The Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi China
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Shohat S, Vol E, Shifman S. Gene essentiality in cancer cell lines is modified by the sex chromosomes. Genome Res 2022; 32:1993-2002. [PMID: 36418059 PMCID: PMC9808629 DOI: 10.1101/gr.276488.121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 11/16/2022] [Indexed: 11/27/2022]
Abstract
Human sex differences arise from gonadal hormones and sex chromosomes. Studying the direct effects of sex chromosomes in humans is still challenging. Here we studied how the sex chromosomes can modulate gene expression and the outcome of mutations across the genome by exploiting the tendency of cancer cell lines to lose or gain sex chromosomes. We inferred the dosage of the sex chromosomes in 355 female and 408 male cancer cell lines and used it to dissect the contributions of the Y and X Chromosomes to sex-biased gene expression. Furthermore, based on genome-wide CRISPR screens, we identified genes whose essentiality is different between male and female cells depending on the sex chromosomes. The most significant genes were X-linked genes compensated by Y-linked paralogs. Our sex-based analysis identifies genes that, when mutated, can affect male and female cells differently and reinforces the roles of the X and Y Chromosomes in sex-specific cell function.
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48
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Li L, Liu ZP. Detecting prognostic biomarkers of breast cancer by regularized Cox proportional hazards models. J Transl Med 2021; 19:514. [PMID: 34930307 PMCID: PMC8686664 DOI: 10.1186/s12967-021-03180-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 12/03/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The successful identification of breast cancer (BRCA) prognostic biomarkers is essential for the strategic interference of BRCA patients. Recently, various methods have been proposed for exploring a small prognostic gene set that can distinguish the high-risk group from the low-risk group. METHODS Regularized Cox proportional hazards (RCPH) models were proposed to discover prognostic biomarkers of BRCA from gene expression data. Firstly, the maximum connected network with 1142 genes by mapping 956 differentially expressed genes (DEGs) and 677 previously BRCA-related genes into the gene regulatory network (GRN) was constructed. Then, the 72 union genes of the four feature gene sets identified by Lasso-RCPH, Enet-RCPH, [Formula: see text]-RCPH and SCAD-RCPH models were recognized as the robust prognostic biomarkers. These biomarkers were validated by literature checks, BRCA-specific GRN and functional enrichment analysis. Finally, an index of prognostic risk score (PRS) for BRCA was established based on univariate and multivariate Cox regression analysis. Survival analysis was performed to investigate the PRS on 1080 BRCA patients from the internal validation. Particularly, the nomogram was constructed to express the relationship between PRS and other clinical information on the discovery dataset. The PRS was also verified on 1848 BRCA patients of ten external validation datasets or collected cohorts. RESULTS The nomogram highlighted that the importance of PRS in guiding significance for the prognosis of BRCA patients. In addition, the PRS of 301 normal samples and 306 tumor samples from five independent datasets showed that it is significantly higher in tumors than in normal tissues ([Formula: see text]). The protein expression profiles of the three genes, i.e., ADRB1, SAV1 and TSPAN14, involved in the PRS model demonstrated that the latter two genes are more strongly stained in tumor specimens. More importantly, external validation illustrated that the high-risk group has worse survival than the low-risk group ([Formula: see text]) in both internal and external validations. CONCLUSIONS The proposed pipelines of detecting and validating prognostic biomarker genes for BRCA are effective and efficient. Moreover, the proposed PRS is very promising as an important indicator for judging the prognosis of BRCA patients.
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Affiliation(s)
- Lingyu Li
- Department of Biomedical Engineering, School of Control Science and Engineering, Shandong University, Jinan, 250061, China
| | - Zhi-Ping Liu
- Department of Biomedical Engineering, School of Control Science and Engineering, Shandong University, Jinan, 250061, China.
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Lee J, Chen X, Wang Y, Nishimura T, Li M, Ishikawa S, Daikoku T, Kawai J, Tojo A, Gotoh N. A novel oral inhibitor for one-carbon metabolism and checkpoint kinase 1 inhibitor as a rational combination treatment for breast cancer. Biochem Biophys Res Commun 2021; 584:7-14. [PMID: 34753066 DOI: 10.1016/j.bbrc.2021.11.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 10/27/2021] [Accepted: 11/01/2021] [Indexed: 11/27/2022]
Abstract
Patients with triple-negative breast cancer have a poor prognosis as only a few efficient targeted therapies are available. Cancer cells are characterized by their unregulated proliferation and require large amounts of nucleotides to replicate their DNA. One-carbon metabolism contributes to purine and pyrimidine nucleotide synthesis by supplying one carbon atom. Although mitochondrial one-carbon metabolism has recently been focused on as an important target for cancer treatment, few specific inhibitors have been reported. In this study, we aimed to examine the effects of DS18561882 (DS18), a novel, orally active, specific inhibitor of methylenetetrahydrofolate dehydrogenase (MTHFD2), a mitochondrial enzyme involved in one-carbon metabolism. Treatment with DS18 led to a marked reduction in cancer-cell proliferation; however, it did not induce cell death. Combinatorial treatment with DS18 and inhibitors of checkpoint kinase 1 (Chk1), an activator of the S phase checkpoint pathway, efficiently induced apoptotic cell death in breast cancer cells and suppressed tumorigenesis in a triple-negative breast cancer patient-derived xenograft model. Mechanistically, MTHFD2 inhibition led to cell cycle arrest and slowed nucleotide synthesis. This finding suggests that DNA replication stress occurs due to nucleotide shortage and that the S-phase checkpoint pathway is activated, leading to cell-cycle arrest. Combinatorial treatment with both inhibitors released cell-cycle arrest, but induced accumulation of DNA double-strand breaks, leading to apoptotic cell death. Collectively, a combination of MTHFD2 and Chk1 inhibitors would be a rational treatment option for patients with triple-negative breast cancer.
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Affiliation(s)
- Jin Lee
- Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa City, Ishikawa, 920-1192, Japan
| | - Xiaoxi Chen
- Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa City, Ishikawa, 920-1192, Japan
| | - Yuming Wang
- Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa City, Ishikawa, 920-1192, Japan
| | - Tatsunori Nishimura
- Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa City, Ishikawa, 920-1192, Japan
| | - Mengjiao Li
- Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa City, Ishikawa, 920-1192, Japan
| | - Satoko Ishikawa
- Department of Gastroenterological Surgery, Kanazawa University, Kanazawa City, Ishikawa, 920-1192, Japan
| | - Takiko Daikoku
- Research Center for Experimental Modeling of Human Disease, Institute for Experimental Animals, Kanazawa University, Kanazawa City, Ishikawa, 920-1192, Japan
| | - Junya Kawai
- R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan
| | - Arinobu Tojo
- Division of Molecular Therapy, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, 108-8639, Japan
| | - Noriko Gotoh
- Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa City, Ishikawa, 920-1192, Japan.
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Chung LH, Liu D, Liu XT, Qi Y. Ceramide Transfer Protein (CERT): An Overlooked Molecular Player in Cancer. Int J Mol Sci 2021; 22:13184. [PMID: 34947980 PMCID: PMC8705978 DOI: 10.3390/ijms222413184] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/02/2021] [Accepted: 12/05/2021] [Indexed: 12/26/2022] Open
Abstract
Sphingolipids are a class of essential lipids implicated in constructing cellular membranes and regulating nearly all cellular functions. Sphingolipid metabolic network is centered with the ceramide-sphingomyelin axis. Ceramide is well-recognized as a pro-apoptotic signal; while sphingomyelin, as the most abundant type of sphingolipids, is required for cell growth. Therefore, the balance between these two sphingolipids can be critical for cancer cell survival and functioning. Ceramide transfer protein (CERT) dictates the ratio of ceramide to sphingomyelin within the cell. It is the only lipid transfer protein that specifically delivers ceramide from the endoplasmic reticulum to the Golgi apparatus, where ceramide serves as the substrate for sphingomyelin synthesis. In the past two decades, an increasing body of evidence has suggested a critical role of CERT in cancer, but much more intensive efforts are required to draw a definite conclusion. Herein, we review all research findings of CERT, focusing on its molecular structure, cellular functions and implications in cancer. This comprehensive review of CERT will help to better understand the molecular mechanism of cancer and inspire to identify novel druggable targets.
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Affiliation(s)
- Long Hoa Chung
- Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Camperdown, NSW 2050, Australia; (D.L.); (X.T.L.)
| | | | | | - Yanfei Qi
- Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Camperdown, NSW 2050, Australia; (D.L.); (X.T.L.)
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