| Autor: |
Sestito R; Preclinical Models and New Therapeutic Agents Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy., Cianfrocca R; Preclinical Models and New Therapeutic Agents Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy., Tocci P; Preclinical Models and New Therapeutic Agents Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy., Rosanò L; Preclinical Models and New Therapeutic Agents Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy.; Institute of Molecular Biology and Pathology, National Research Council (CNR), Rome, Italy., Sacconi A; Oncogenomic and Epigenetic Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy., Blandino G; Oncogenomic and Epigenetic Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy., Bagnato A; Preclinical Models and New Therapeutic Agents Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy. annateresa.bagnato@ifo.gov.it. |
| Abstrakt: |
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 (ET A R) and ZEB1 expression is upregulated in mesenchymal ovarian cancer and correlates with poor prognosis. Notably, the expression of ET A R and ZEB1 negatively correlates with miR-200b/c. These miRNAs, besides targeting ZEB1, impair ET A R expression through the 3'UTR binding. ZEB1, in turn, restores ET A R levels by transcriptionally repressing miR-200b/c. Activation of ET A R drives the expression of ZEB1 integrating the miR-200/ZEB1 double negative feedback loop. The ET A R-miR-200b/c-ZEB1 circuit promotes epithelial-mesenchymal transition, cell plasticity, invasiveness and metastasis. Of therapeutic interest, ET A R blockade with macitentan, a dual ET A R and ET B R 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 ET A R and ZEB1 axes with the miR-200b/c regulatory circuit to favour metastatic progression in ovarian cancer. |
