MiR-152 and miR-185 co-contribute to ovarian cancer cells cisplatin sensitivity by targeting DNMT1 directly: a novel epigenetic therapy independent of decitabine

Abstract

Epithelial ovarian cancer (EOC) is a highly lethal gynaecological malignancy. Cisplatin is the basal chemotherapeutic agent used to treat EOC, but resistance to cisplatin leads to chemotherapy failure. MicroRNAs are a novel class of regulators that function by controlling gene expression at the post-transcriptional level. Several recent reports have identified some microRNAs that are related to chemotherapy sensitivity. In this study, we found two microRNAs miR-152 and miR-185 that were significantly downregulated in the cisplatin-resistant ovarian cell lines SKOV3/DDP and A2780/DDP, compared with their sensitive parent line SKOV3 and A2780, respectively. Subsequently, the roles of miR-152 and miR-185 were evaluated in vitro and in vivo. The overexpression of miR-152 or miR-185 increased cisplatin sensitivity of SKOV3/DDP and A2780/DDP cells by inhibiting proliferation and promoting apoptosis, then we further confirmed that these miRNAs functioned through suppressing DNA methyltransferase 1 (DNMT1) directly. Concordantly, CD-1/CD-1 nude mice that were injected intraperitoneally with SKOV3/DDP cells transfected with miR-152 mimics exhibited upregulated cisplatin sensitivity in vivo. Interestingly, we found that there were no significant changes in the expression of these two microRNAs after treatment with decitabine (DAC), a traditional epigenetic therapeutic agent, suggesting these miRNAs represented two new regulators independent of DAC. Finally, the survival assay in A549 and HepG2 cells revealed that the two microRNAs involved in cisplatin sensitivity were related to cell types. Our results indicated that miR-152 and miR-185 were involved in ovarian cancer cisplatin resistance in vitro and in vivo by targeting DNMT1 directly. These molecules may serve as potential epigenetic therapeutic targets in other cancers.

Expression of Concern: miR‐145 sensitizes ovarian cancer cells to paclitaxel by targeting Sp1 and Cdk6

“…6,7 A second class modu-for drug transport or metabolism, including miR-24 (targets DHFR), 8 miR-451 and miR-27a (target MDR1), 9 miR-326 (targets ABCC1), 10 miR-328 and miR-519c (target ABCG2) 11 and miR-152 and miR-185 (target DNMT1). 12 All these findings suggest that miRNAs have emerged as a new platform for cancer therapeutics, and attempts to modify expression of selected miRNAs may lead to intriguing improvements in patient responses to chemotherapy.…”

MicroRNA-185 suppresses growth and invasion of colon cancer cells through inhibition of the hypoxia-inducible factor-2α pathway in vitro and in vivo

“…miR-185 was found to suppress glioma cell invasion, indicating that it may be a potential prognostic marker and therapeutic target (16). Previous studies have revealed that miR-185 impedes anchorage-independent growth, cell migration and invasion, in addition to suppressing tumor growth in vivo and increasing cisplatin sensitivity by promoting apoptosis, implicating it as a potent tumor suppressor (17)(18)(19). In the present study, overexpression of miR-185 repressed the growth and invasion of colon cancer cells in vitro and in vivo, which was consistent with the results of previous studies, indicating that miR-185 is a negative regulator of RhoA and Cdc42 and their cellular activities, and can inhibit the proliferation and invasion of CRC cells (20).…”

Downregulation of ATG14 by EGR1-MIR152 sensitizes ovarian cancer cells to cisplatin-induced apoptosis by inhibiting cyto-protective autophagy

“…Multiple mechanisms contribute to cisplatin resistance such as a defective DNA repair system, enhanced drug clearance and detoxification, epigenetic regulation, and abnormal signaling pathways. 23,24 A growing body of evidence indicates a role of autophagy as a prosurvival and resistance mechanism against chemotherapy. With regards to cisplatin, recent studies demonstrated that cisplatin can induce autophagy in ovarian cancer cells through the ubiquitinbinding protein SQSTM1 or HMGB1 (high mobility group box 1).…”