The miR‐200 family differentially regulates sensitivity to paclitaxel and carboplatin in human ovarian carcinoma OVCAR‐3 and MES‐OV cells

Abstract

We studied the role of miRNA‐200 family members in cellular sensitivity to paclitaxel and carboplatin, using two ovarian cancer cell lines, OVCAR‐3 and MES‐OV, and their paclitaxel resistant variants OVCAR‐3/TP and MES‐OV/TP. Both resistant variants display a strong epithelial‐mesenchymal transition (EMT) phenotype, with marked decreases in expression of miR‐200c and miR‐141 in OVCAR‐3/TP, and down‐regulation of all five members of the miR‐200 family in MES‐OV/TP. Lentiviral transfection of inhibitors of miR‐200c or miR‐141 in parental OVCAR‐3 triggered EMT and rendered the cells resistant to paclitaxel and carboplatin. Conversely, the infection of OVCAR‐3/TP cells with retroviral particles carrying the miR‐200ab429 and 200c141 clusters triggered a partial mesenchymal to epithelial transition (MET). This partial MET was not sufficient to re‐sensitize OVCAR‐3/TP cells to paclitaxel. However, the miR‐200c/miR‐141 cluster transfectants became 6–8x resistant to carboplatin, an unexpected result, whereas miR‐200a/miR‐200b/miR‐429 had no effect. Transfecting the OVCAR‐3/TP GFP cells with specific miRNA mimics confirmed these data. MiR‐200c and miR‐141 mimics conferred resistance to carboplatin in MES‐OV/TP cells, similar to OVCAR‐3/TP, but sensitized MES‐OV to paclitaxel. Several genes involved in balancing oxidative stress were altered in OVCAR‐3/TP 200c141 cells compared to controls. The miR‐200 family plays major, cell‐context dependent roles in regulating EMT and sensitivity to carboplatin and paclitaxel in OVCAR‐3 and MES‐OV cells.

Profiles and Bioinformatics Analysis of Differentially Expressed Circrnas in Taxol-Resistant Non-Small Cell Lung Cancer Cells

“…The annotations of all circRNAs in the circRNA/ miRNA network were not fully unveiled, but several circRNA-associated miRNAs are involved in taxol-resistant cancers. The overexpression of miR-141 increases the response of resistant [31]. MiR-34c-5p conferred the notable resistance of lung cancer to taxol-mediated apoptosis via p53 downregulation, silencing its target genes Bcl-2-modifying factor (Bmf) and c-myc [32].…”

miR-200c: a versatile watchdog in cancer progression, EMT, and drug resistance

“…Similarly in pancreatic CSCs, decrease in chemoresistance has been attributed to overexpression of miR-200c [79]. In addition, miR-200c together with other miRNAs from the miR-200 family has been shown to sensitize ovarian cancer cell lines with strong EMT phenotype to anti-cancer drugs paclitaxel and carboplatin [80].…”

Clinical validation of chemotherapy predictors developed on global microRNA expression in the NCI60 cell line panel tested in ovarian cancer

“…However, miR-200c and miR-141 mimics did sensitize MES-OV/TP cells to paclitaxel. They therefore concluded that restoration of sensitivity, by upregulation and mimics of the miR-200 family members, depended on cell context, as the different cell lines had different expression levels of the miR-200 family members [35]. In our study miR-200a, miR-200b and miR-200c showed to be negatively correlated to Carboplatin sensitivity.…”