Targeting endothelin 1 receptor-miR-200b/c-ZEB1 circuitry blunts metastatic progression in ovarian cancer.

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 (ETR) and ZEB1 expression is upregulated in mesenchymal ovarian cancer and correlates with poor prognosis. Notably, the expression of ETR and ZEB1 negatively correlates with miR-200b/c. These miRNAs, besides targeting ZEB1, impair ETR expression through the 3'UTR binding. ZEB1, in turn, restores ETR levels by transcriptionally repressing miR-200b/c. Activation of ETR drives the expression of ZEB1 integrating the miR-200/ZEB1 double negative feedback loop. The ETR-miR-200b/c-ZEB1 circuit promotes epithelial-mesenchymal transition, cell plasticity, invasiveness and metastasis. Of therapeutic interest, ETR blockade with macitentan, a dual ETR and ETR 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 ETR and ZEB1 axes with the miR-200b/c regulatory circuit to favour metastatic progression in ovarian cancer.