Abstract
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)/ETA receptor (ETAR) 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 ETAR and miRNA is still unknown. Hence, in this study we evaluated whether dysregulation of miRNA might enhance ETAR expression in sensitive and resistant EOC cells. Based on bioinformatic tools, we selected putative miRNA able to recognize the 3′UTR of ETAR. An inverse correlation was observed between the expression levels of miR-30a and ETAR in both EOC cell lines and tumor samples. miR-30a was found to specifically bind to the 3′UTR of ETAR mRNA, indicating that ETAR 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 ETAR gene. Interestingly, our findings highlight that blockade of ETAR regulatory axis is the mechanism underlying the tumor suppressor function of miR-30a in chemoresistant EOC cells.
Highlights
Epithelial ovarian carcinoma (EOC) accounts for the highest tumor-related mortality in women with gynecologic malignancy [1]
We evaluated the expression of miR-30a by quantitative real-time polymerase chain reaction (qPCR) in a cohort of 39 epithelial ovarian carcinoma (EOC) human tumor samples, whose clinical-pathological characteristics are summarized in Supplementary Table S1, and in which the ETA receptor (ETAR) expression has been previously examinated by immunohistochemistry (IHC) [8]
Because in EOC cells, ET-1 through ETAR induces the release of vascular endothelial growth factor (VEGF) [31], which has been reported to have important regulatory role in drug-sensitivity [22], we evaluated whether miR-30a was able to modulate the release of VEGF by EOC cells
Summary
Epithelial ovarian carcinoma (EOC) accounts for the highest tumor-related mortality in women with gynecologic malignancy [1]. The ET-1/ETAR interaction triggers the activation of the survival pathways, such as phosphoinositide-3-kinase www.impactjournals.com/oncotarget (PI-3K)/Akt and mitogen activated protein kinase (MAPK), protecting EOC cells from drug-induced apoptosis [4]. All these observations suggest that ETAR expression may be a predictor of chemoresistance, and that targeting ETAR could increase the sensitivity of EOC tumors to therapeutic agents. In this regard, we recently provide evidence that ETAR/β-arrestin-1 cooperates with Wnt signaling to acquire a chemoresistant phenotype through the amplification of ET-1 autocrine loop, sustaining EMT, stemness features, cell invasion and metastasis [8]. The dual receptor antagonist macitentan, interfering with ETAR, and microenvironmentassociated elements expressing ETBR [12,13,14,15], inhibited growth, vascularization, intravasation and progression in EOC xenografts [8]
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