miR-30a inhibits endothelin A receptor and chemoresistance in ovarian carcinoma

Drug resistance remains the major clinical barrier to successful treatment in epithelial ovarian carcinoma (EOC) patients, and the evidence of microRNA involvement in drug resistance has been recently emerging. Endothelin-1 (ET-1)/ET(A) receptor (ET(A)R) axis is aberrantly activated in chemoresistant EOC cells and elicits pleiotropic effects promoting epithelial-to-mesenchymal transition (EMT) and the acquisition of chemoresistance. However, the relationship between ET(A)R and miRNA is still unknown. Hence, in this study we evaluated whether dysregulation of miRNA might enhance ET(A)R expression in sensitive and resistant EOC cells. Based on bioinformatic tools, we selected putative miRNA able to recognize the 3′UTR of ET(A)R. An inverse correlation was observed between the expression levels of miR-30a and ET(A)R in both EOC cell lines and tumor samples. miR-30a was found to specifically bind to the 3′UTR of ET(A)R mRNA, indicating that ET(A)R is a direct target of miR-30a. Overexpression of miR-30a decreased Akt and mitogen activated protein kinase signaling pathway activation, cell proliferation, invasion, plasticity, EMT marker levels, and vascular endothelial growth factor release. Interestingly, ectopic expression of miR-30a re-sensitized platinum-resistant EOC cells to cisplatinum-induced apoptosis. Consistently, resistant EOC xenografts overexpressing miR-30a resulted in significantly less tumor growth than controls. Together our study provides a new perspective on the regulatory mechanism of ET(A)R gene. Interestingly, our findings highlight that blockade of ET(A)R regulatory axis is the mechanism underlying the tumor suppressor function of miR-30a in chemoresistant EOC cells.