Targeting estrogen-related receptor alpha inhibits epithelial-to-mesenchymal transition and stem cell properties of ovarian cancer cells.

ABSTRACT: Epithelial-mesenchymal transition represents a key event in cancer progression and has emerged as a promising anticancer target. Estrogen-related receptor alpha (ERR?) is frequently elevated in advanced-stage ovarian cancer, but its potential role in tumor progression is not known. Here we show that ERR? functions in epithelial-mesenchymal transition and in subsequent stem cell traits responsible for the acquisition of high degree of aggressiveness and potential for metastasis that are characteristic of ovarian cancer. Importantly, targeted inhibition of ERR? also inhibited the expression of Snail, a repressor of E-cadherin and an inducer of epithelial-mesenchymal transition. Interestingly, induction of Snail resulted from not only changes in mRNA transcription rate but also mRNA stability. We thus identified the miR-200 family as a new player in the ERR?-mediated posttranscriptional regulation of Snail, and antagonism of miR-200a/b could revert the decreased expression of Snail and reversal of epithelial-mesenchymal transition and stem cell characteristics due to ERR? depletion. Finally, we showed that RNA interference-mediated inhibition of ERR? significantly reduced tumor burden, ascites formation, and metastatic peritoneal nodules in vivo in an orthotopic model of ovarian cancer. These results suggest ERR? activation as a mechanism of tumor aggressiveness and imply that targeting ERR? may be a promising approach in ovarian cancer treatment.

SUBMITTER: Lam SS 

PROVIDER: S-EPMC3982489 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature