Abstract
Identification of regulatory mechanisms underlying the poor prognosis of ovarian cancer is necessary for diagnostic and therapeutic implications. Here we show that endothelin A receptor (ETAR) and ZEB1 expression is upregulated in mesenchymal ovarian cancer and correlates with poor prognosis. Notably, the expression of ETAR and ZEB1 negatively correlates with miR-200b/c. These miRNAs, besides targeting ZEB1, impair ETAR expression through the 3'UTR binding. ZEB1, in turn, restores ETAR levels by transcriptionally repressing miR-200b/c. Activation of ETAR drives the expression of ZEB1 integrating the miR-200/ZEB1 double negative feedback loop. The ETAR-miR-200b/c-ZEB1 circuit promotes epithelial-mesenchymal transition, cell plasticity, invasiveness and metastasis. Of therapeutic interest, ETAR blockade with macitentan, a dual ETAR and ETBR antagonist, increases miR-200b/c and reduces ZEB1 expression with the concomitant inhibition of metastatic dissemination. Collectively, these findings highlight the reciprocal network that integrates ETAR and ZEB1 axes with the miR-200b/c regulatory circuit to favour metastatic progression in ovarian cancer.