title: 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 (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.
authors.affiliation: School of Biological Sciences, University of Hong Kong, Pokfulam Road, Pokfulam, Hong Kong.
authors.forename: Sophia Sn
authors.initials: SS
authors.lastname: Lam
authors.affiliation: School of Biological Sciences, University of Hong Kong, Pokfulam Road, Pokfulam, Hong Kong.
authors.forename: Abby Sc
authors.initials: AS
authors.lastname: Mak
authors.affiliation: Department of Pathology, University of Hong Kong, Sassoon Road, Pokfulam, Hong Kong.
authors.forename: Judy Wp
authors.initials: JW
authors.lastname: Yam
authors.affiliation: Department of Pathology, University of Hong Kong, Sassoon Road, Pokfulam, Hong Kong.
authors.forename: Annie Ny
authors.initials: AN
authors.lastname: Cheung
authors.affiliation: Department of Obstetrics and Gynecology, University of Hong Kong, Sassoon Road, Pokfulam, Hong Kong.
authors.forename: Hextan Ys
authors.initials: HY
authors.lastname: Ngan
authors.affiliation: School of Biological Sciences, University of Hong Kong, Pokfulam Road, Pokfulam, Hong Kong.
authors.forename: Alice St
authors.initials: AS
authors.lastname: Wong
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012908:Snails / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor