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

Rosanna Sestito,Anna Bagnato,Andrea Sacconi,Laura Rosanò,Roberta Cianfrocca,Piera Tocci,Giovanni Blandino

doi:10.1038/s42003-020-01404-3

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.

Highlights

Identification of regulatory mechanisms underlying the poor prognosis of ovarian cancer is necessary for diagnostic and therapeutic implications
Having demonstrated that ET-1/endothelin A receptor (ETAR) axis is a critical driver of epithelial–mesenchymal transition (EMT) in ovarian cancer[26,27], we sought to investigate whether ET-1/ETAR axis could be associated with the canonical EMTtranscription factors (EMT-TF) ZEB1
To confirm the association between ETAR and ZEB1, we performed an analysis from The Cancer Genome Atlas (TCGA) database of 535 miRNA/mRNA matched high-grade serous ovarian cancer (HG-SOC) patients, which are subdivided in four subtypes based on their specific gene expression profiles[4]

Summary

Introduction

Identification of regulatory mechanisms underlying the poor prognosis of ovarian cancer is necessary for diagnostic and therapeutic implications. We show that endothelin A receptor (ETAR) and ZEB1 expression is upregulated in mesenchymal ovarian cancer and correlates with poor prognosis. 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 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. High levels of ZEB1 correlate with loss of E-cadherin[11] and associate with advanced diseases, metastasis and poor prognosis of patients[12,13,14]. Forced expression of miR-200 family members represses ZEB1 expression and inhibits the capacity of ovarian cancer cells to undergo migration and invasion, implicating ZEB1 as a miR-200 target[16,17]. The knowledge of the complex ZEB1/miRNA interplay, established by functional links with other signaling pathways[23,24], may provide mechanistic insight into the regulatory networks controlling ovarian cancer aggressiveness and metastatic progression

Methods

Results

Conclusion