期刊
CELL DISCOVERY
卷 3, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/celldisc.2017.29
关键词
chemotherapy resistance; hnRNPA1; K-RAS; microRNAs; ovarian cancer; RNA-binding proteins
类别
资金
- National Institutes of Health/National Cancer Institute [R44GM086937, P50 CA093459, U54 CA151668, P50 CA083639, P50 CA098258, R21 CA180145, UH2TR000943, U54CA96300]
- Cancer Prevention Research Institute of Texas [RP120214]
The regulation of microRNA (miRNA) biogenesis, function and degradation involves a range of mechanisms, including interactions with RNA-binding proteins. The potential contribution of regulatory miRNAs to the expression of these RNA interactor proteins that could control other miRNAs expression is still unclear. Here we demonstrate a regulatory circuit involving oncogenic and tumor-suppressor miRNAs and an RNA-binding protein in a chemotherapy-resistant ovarian cancer model. We identified and characterized miR-15a-5p and miR-25-3p as negative regulators of hnRNPA1 expression, which is required for the processing of miR-18a-3p, an inhibitor of the K-RAS oncogene. The inhibition of miR-25-3p and miR-15a-5p decreased the proliferation, motility, invasiveness and angiogenic potential and increased apoptosis when combined with docetaxel. Alteration of this regulatory circuit causes poor overall survival outcome in ovarian cancer patients. These results highlight miR-15a-5p and miR-25-3p as key regulators of miR-18a-3p expression and its downstream target K-RAS, through direct modulation of hnRNPA1 expression. Our results demonstrate the therapeutic potential of inhibiting miR-25-3p and miR-15a-5p and the use of miR-18a-3p/KRAS ratio as a prominent outcome prognostic factor.
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