MicroRNA 376c enhances ovarian cancer cell survival by targeting activin receptor-like kinase 7: implications for chemoresistance
- 1 February 2011
- journal article
- Published by The Company of Biologists in Journal of Cell Science
- Vol. 124 (3), 359-368
- https://doi.org/10.1242/jcs.072223
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.Keywords
This publication has 49 references indexed in Scilit:
- miR-199a*, a Bone Morphogenic Protein 2-responsive MicroRNA, Regulates Chondrogenesis via Direct Targeting to Smad1Online Journal of Public Health Informatics, 2009
- Antiangiogenic drugs in ovarian cancerBritish Journal of Cancer, 2008
- Distinct microRNA expression profiles in acute myeloid leukemia with common translocationsProceedings of the National Academy of Sciences of the United States of America, 2008
- MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer (Retracted article. See vol. 175, pg. 192, 2023)Gynecologic Oncology, 2008
- SMAD proteins control DROSHA-mediated microRNA maturationNature, 2008
- miR‐15b and miR‐16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cellsInternational Journal of Cancer, 2008
- Mullerian Inhibiting Substance enhances subclinical doses of chemotherapeutic agents to inhibit human and mouse ovarian cancerProceedings of the National Academy of Sciences of the United States of America, 2006
- microRNAs exhibit high frequency genomic alterations in human cancerProceedings of the National Academy of Sciences of the United States of America, 2006
- TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencingNature, 2005
- Smad-dependent and Smad-independent pathways in TGF-β family signallingNature, 2003