title: MicroRNA 376c enhances ovarian cancer cell survival by targeting activin receptor-like kinase 7: implications for chemoresistance.
abstract: MicroRNAs (miRNAs) are small noncoding RNAs that have important roles in gene regulation. We have previously reported that activin receptor-like kinase 7 (ALK7) and its ligand, Nodal, induce apoptosis in human epithelial ovarian cancer cells. In this study, we examined the regulation of ALK7 by miRNAs and demonstrate that miR-376c targets ALK7. Ectopic expression of miR-376c significantly increased cell proliferation and survival, enhanced spheroid formation and blocked Nodal-induced apoptosis. Interestingly, overexpression of miR-376c blocked cisplatin-induced cell death, whereas anti-miR-376c enhanced the effect of cisplatin. These effects of miR-376c were partially compensated by the overexpression of ALK7. Moreover, in serous carcinoma samples taken from ovarian cancer patients who responded well to chemotherapy, strong ALK7 staining and low miR-376c expression was detected. By contrast, ALK7 expression was weak and miR-376c levels were high in samples from patients who responded poorly to chemotherapy. Finally, treatment with cisplatin led to an increase in expression of mRNA encoding Nodal and ALK7 but a decrease in miR-376c levels. Taken together, these results demonstrate that the Nodal-ALK7 pathway is involved in cisplatin-induced cell death in ovarian cancer cells and that miR-376c enhances proliferation, survival and chemoresistance by targeting, at least in part, ALK7.
authors.affiliation: Department of Biology, York University, 4700 Keel Street, Toronto ONM3J1P3, Canada.
authors.forename: Gang
authors.initials: G
authors.lastname: Ye
authors.forename: Guodong
authors.initials: G
authors.lastname: Fu
authors.forename: Shiying
authors.initials: S
authors.lastname: Cui
authors.forename: Sufen
authors.initials: S
authors.lastname: Zhao
authors.forename: Stefanie
authors.initials: S
authors.lastname: Bernaudo
authors.forename: Yin
authors.initials: Y
authors.lastname: Bai
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Ding
authors.forename: Yaou
authors.initials: Y
authors.lastname: Zhang
authors.forename: Burton B
authors.initials: BB
authors.lastname: Yang
authors.forename: Chun
authors.initials: C
authors.lastname: Peng
mesh_terms: D030201:Activin Receptors, Type I / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000235:genetics*; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D055457:Nodal Protein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D035683:MicroRNAs; C526007:NODAL protein, human; D055457:Nodal Protein; C424205:ACVR1C protein, human; D030201:Activin Receptors, Type I; D002945:Cisplatin