mir-200b and mir-200c co-contribute to the cisplatin sensitivity of ovarian cancer cells by targeting DNA methyltransferases

Abstract

Cisplatin is a first-line chemotherapy drug that is commonly used in the treatment of epithelial ovarian cancer (EOC). However, insensitivity to cisplatin markedly influences the outcomes of chemotherapy. MicroRNAs (miRNAs/miRs) have been demonstrated to modulate drug resistance in a number of types of cancer. The aim of the present study was to investigate the key miRNAs involved in modulating drug resistance in ovarian cancer cells. miR-200b and miR-200c were identified to be frequently deregulated in ovarian cancer. Upregulation of miR-200b and miR-200c promoted EOC cell death in the presence of cisplatin. Upregulation of miR-125b-5p significantly decreased tumor growth in combination with cisplatin in a mouse model. Significantly, miR-200b and miR-200c reversed cisplatin resistance by targeting DNA methyltransferases (DNMTs) (directly targeting DNMT3A/DNMT3B and indirectly targeting DNMT1 via specificity protein 1). These results indicate that miR-200b- and miR-200c-mediated regulation of DNMTs serves a crucial function in the cellular response to cisplatin. miR-200b- and miR-200c-mediated downregulation of DNMTs may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells and thus may have an impact on ovarian cancer therapy.