Abstract
Epithelial ovarian cancer is a highly lethal and aggressive gynecological malignancy. The high mortality rate is due in part to the fact that many advanced cancer patients become refractory to current chemotherapeutic agents, leading to tumor recurrence and death. However, the underlying mechanisms leading to chemoresistance remain obscure. Here, we report that the loss of miR-199b-5p due to progressive epigenetic silencing leads to the activation of the JAG1-mediated Notch1 signaling cascade, thereby leading to the development of acquired chemoresistance in ovarian cancer. Using miRCURY LNA™ microRNA array and Q-PCR analyses of two pairs of cisplatin-sensitive and -resistant ovarian cancer cell lines, we identified miR-199b-5p as significantly down-regulated in cisplatin-resistant ovarian cancer cells and confirmed that miR-199b-5p is clinically associated with advanced and poor survival ovarian cancers. Interestingly, the loss of miR-199b-5p could be restored by 5-Aza-dC-mediated demethylation, and methylated specific PCR (MS-PCR), bisulfite-sequencing and pyrosequencing revealed that the promoter region of miR-199b-5p was hypermethylated. Computational and mechanistic analyses identified JAG1 as a primary target of miR-199b-5p. Notably, the reduced expression of miR-199b-5p was found to be inversely correlated with the increased expression of JAG1 using an ovarian cancer tissue array. Enforced expression of miR-199b-5p sensitized ovarian cancer cells to cisplatin-induced cytotoxicity both in vitro and in vivo. Conversely, re-expression of miR-199b-5p and siRNA-mediated JAG1 knockdown or treatment with Notch specific inhibitor γ-secretase (GSI) attenuated JAG1-Notch1 signaling activity, thereby enhancing cisplatin-mediated cell cytotoxicity. Taken together, our study suggests that the epigenetic silencing of miR-199b-5p during tumor progression is significantly associated with acquired chemoresistance in ovarian cancer through the activation of JAG1-Notch1 signaling.
Highlights
Epithelial ovarian cancer is one of the most lethal malignancies in females worldwide
We identified that the loss of miR-199b-5p, mediated by increased DNA methylation, is associated with acquired cisplatin resistance via aberrant activation of JAG1-Notch1 signaling in ovarian cancer
Mounting evidence has suggested that the dysregulation of miRNAs causes aberrant upregulation of oncogenes or the downregulation of tumor suppressor genes which in turn leads to cancer initiation and progression [34,35,36]
Summary
Epithelial ovarian cancer is one of the most lethal malignancies in females worldwide. Chemotherapy combined with surgical cytoreduction is the standard initial management for ovarian cancer patients at advanced stages [1, 2]. Platinum-based chemotherapy is the standard first-line regimen for advanced ovarian cancer [3, 4]. The clinical response rate is initially high, but the subsequent relapse www.impactjournals.com/oncotarget and repetitive challenges of chemotherapeutic agents leads to the development of acquired chemoresistance [5]. Such acquired chemoresistance is the major obstacle to the clinical management of ovarian cancer [6, 7]. The molecular mechanisms underlying acquired chemoresistance remain largely unknown, underlying the urgent need to identify the associated molecular mechanisms to explore alternative therapeutic strategies
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