A Regulatory Loop Involving miR-200c and NF-κB Modulates Mortalin Expression and Increases Cisplatin Sensitivity in an Ovarian Cancer Cell Line Model

Abstract

Ovarian cancer is currently the most lethal gynecological cancer. At present, primary debulking surgery combined with platinum-based chemotherapy is the standard treatment strategy for ovarian cancer. Although cisplatin-based chemotherapy has greatly improved the prognosis of patients, the subsequent primary or acquired drug resistance of cancer cells has become an obstacle to a favorable prognosis. Mortalin is a chaperone that plays an important role in multiple cellular and biological processes. Our previous studies have found that mortalin is associated with the proliferation and migration of ovarian cancer cells and their resistance to cisplatin-based chemotherapy. In this study, microRNA (miR)-200b/c downregulated mortalin expression and inhibited the proliferation and migration of the paired cisplatin-sensitive (A2780S) and cisplatin-resistant (A2780CP) epithelial ovarian cancer cell lines. Moreover, miR-200c increased the sensitivity of ovarian cancer cells to cisplatin treatment by regulating mortalin levels. Nuclear factor (NF)-κB directly regulated mortalin and miR-200b/c expression levels, while NF-κB and miR-200b/c jointly regulated the expression of mortalin. The combination of cisplatin and miR-200c significantly enhanced the therapeutic effects on ovarian cancer in vivo, suggesting that miR-200c may serve as a potential therapeutic agent for ovarian cancer.

Drug resistance in ovarian cancer: from mechanism to clinical trial

“…Mechanistically, increased nuclear translocation of the p65 subunit and phosphorylation of inhibitor of IκB kinase subunits alpha and beta are markers of NFκB activation, which promotes chemoresistance [ 99 ]. Moreover, NF-κB p65 increases miR-200b/c expression by binding to its promoter, subsequently sensitizing ovarian cancer cells to cisplatin [ 100 ]. It also regulates the downstream miRNAs miR-452-5p and miR-335-5p through the NF-κB TFs RelA and RelB, preventing the recurrence of OC [ 101 ].…”