MiRNAs frequently target 3’-UTRs and participate in numerous cellular events such as proliferation, differentiation, and apoptosis [
13‐
15]. Studies have shown that miRNAs play an important role in modulating the sensitivity of cancer cells to chemotherapeutic agents [
16,
17]. Thus, microRNAs can be promising diagnostic and prognostic molecular biomarkers as well as therapeutic targets in cancers [
18,
19].
MiR-186 has been reported to regulate glycolysis through
Glut1 during the formation of cancer-associated fibroblasts [
20]. Cui et al. reported that miR-186 targets
ROCK1 to suppress the growth and metastasis of non-small cell lung cancer cells [
21]. Cai et al. reported that miR-186 downregulation correlates with poor survival in lung adenocarcinoma [
22]. These studies suggest that miR-186 may function as a tumor suppressor gene. Our results showed that both A2780/DDP and A2780/Taxol cells expressed miR-186 at lower levels than A2780. MiR-186 overexpression increased the sensitivity of ovarian cancer cell lines to paclitaxel and cisplatin compared with the negative control or mock cells, miR-186 transfection induced cell apoptosis while anti-miR-186 transfection reduced cell apoptosis, suggesting that miR-186 may inhibit the development of drug resistance in ovarian cancer cells.
MDR (multi-drug resistance) is a major obstacle to the success of cancer chemotherapy, and it involves cancer stem cell regulation, ABC transporter family, miRNA regulation, hypoxia induction, DNA damage and repair, apoptosis induction, autophagy induction, and epigenetic regulation. The ABC transporter family is known to have 12 putative drug transporters [
23,
24], including MDR1 (encoded by
ABCB1) and MDR-associated protein-1 (MRP1, encoded by
ABCC1) [
25]. The predicted seed region in the 3’-UTR of
ABCB1 and
ABCC1 showed that both these genes are the direct targets of miR-186. However, our results showed that miR-186 overexpression downregulated both the mRNA and protein expression levels of MDR1 and GST-π in the ovarian cancer cell lines compared to the negative control cells or mock transfected cells, while there was no significant difference in the expression of MRP1. Therefore, we suggest that miR-186 may increase cell sensitivity of ovarian cancer cells lines to paclitaxel and cisplatin by targeting
ABCB1 but not
ABCC1. Studies have demonstrated the importance of increased MDR1 expression in the development of MDR, as this glycoprotein can help cells develop drug resistance by pumping drugs out of the cells and decreasing the intracellular drug concentration [
26‐
31]. Moreover, the π isoform of GST, which is a member of the GST family and has been shown to be responsible for the excessive intensity of detoxification of cytostatics, was shown to have functional polymorphisms that could potentially affect the metabolism of chemotherapeutic agents and influence the efficacy of chemotherapy and cancer survival [
32]. Studies have shown that GST dysfunction may improve ovarian cancer survival after postoperative chemotherapy; evaluation of the functional polymorphisms of GST may help arrive at a prognosis of ovarian cancer prognosis [
33,
34]. Based on these findings and our study results, we consider that miR-186 may inhibit the development of drug resistance by targeting
ABCB1 and regulating GST-π expression in ovarian cancer cells. Importantly, we find that combination of miR-186 with chemotherapeutic agents can increase the sensitivity of ovarian cancer cells to paclitaxel.
Ours is the first study to demonstrate that miR-186 overexpression may increase the sensitivity of ovarian cancer cells to paclitaxel by targeting ABCB1 and modulating GST-π. Further studies are required to determine the molecular mechanisms and its clinical manipulation in the future.