Targeting Estrogen-Related Receptor Alpha Inhibits Epithelial-to-Mesenchymal Transition and Stem Cell Properties of Ovarian Cancer Cells

Epithelial–mesenchymal transition represents a key event in cancer progression and has emerged as a promising anticancer target. Estrogen-related receptor alpha (ERRα) is frequently elevated in advanced-stage ovarian cancer, but its potential role in tumor progression is not known. Here we show that...

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Bibliographic Details
Published in:Molecular therapy 2014-04, Vol.22 (4), p.743-751
Main Authors: Lam, Sophia SN, Mak, Abby SC, Yam, Judy WP, Cheung, Annie NY, Ngan, Hextan YS, Wong, Alice ST
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
Epithelial-Mesenchymal Transition - genetics
ERRalpha Estrogen-Related Receptor
Female
Genetic Therapy
Humans
Molecular Targeted Therapy
Neoplastic Stem Cells - metabolism
Original
Ovarian cancer
Ovarian Neoplasms - genetics
Ovarian Neoplasms - pathology
Ovarian Neoplasms - therapy
Receptors, Estrogen - antagonists & inhibitors
Receptors, Estrogen - genetics
Receptors, Estrogen - metabolism
Snails - genetics
Snails - metabolism
Transcription, Genetic
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Summary:Epithelial–mesenchymal transition represents a key event in cancer progression and has emerged as a promising anticancer target. Estrogen-related receptor alpha (ERRα) is frequently elevated in advanced-stage ovarian cancer, but its potential role in tumor progression is not known. Here we show that ERRα 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 ERRα 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 ERRα-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 ERRα depletion. Finally, we showed that RNA interference–mediated inhibition of ERRα significantly reduced tumor burden, ascites formation, and metastatic peritoneal nodules in vivo in an orthotopic model of ovarian cancer. These results suggest ERRα activation as a mechanism of tumor aggressiveness and imply that targeting ERRα may be a promising approach in ovarian cancer treatment.
ISSN:1525-0016
1525-0024
DOI:10.1038/mt.2014.1