Role and prognostic significance of the epithelial-mesenchymal transition factor ZEB2 in ovarian cancer

// Silvia Prislei 1 , Enrica Martinelli 1 , Gian Franco Zannoni 1, 2 , Marco Petrillo 1 , Flavia Filippetti 1 , Marisa Mariani 3 , Simona Mozzetti 1 , Giuseppina Raspaglio 1 , Giovanni Scambia 1 , Cristiano Ferlini 1, 3 1 Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy 2 Department of Pathology, Catholic University of the Sacred Heart, Rome, Italy 3 Reproductive Tumor Biology Research, Biomedical Lab, Department of Obstetrics and Gynecology, Danbury Hospital, Danbury, CT, USA Correspondence to: Silvia Prislei, e-mail: silvia.prislei@rm.unicatt.it Keywords: ZEB2, EMT, HuR, ovarian cancer Received: December 09, 2014      Accepted: May 05, 2015      Published: May 15, 2015 ABSTRACT ZEB2 is a key factor in epithelial-mesenchymal transition (EMT), a program controlling cell migration in embryonic development and adult tissue homeostasis. We demonstrated a role of ZEB2 in migration and anchorage-independent cell growth in ovarian cancer, as shown by ZEB2 silencing. We found that the RNA-binding protein HuR bound the 3′UTR of ZEB2 mRNA, acting as a positive regulator of ZEB2 protein expression. In Hey ovarian cell line, HuR silencing decreased ZEB2 and ZEB1 nuclear expression and impaired migration. In hypoglycemic conditions ZEB2 expression decreased, along with ZEB1, vimentin and cytoplasmic HuR, and a reduced cellular migration ability was observed. Analysis of ZEB2 and HuR expression in ovarian cancers revealed that nuclear ZEB2 is localized in tumor leading edge and co-localizes with cytoplasmic HuR. In a series of 143 ovarian cancer patients high expression of ZEB2 mRNA significantly correlated with a poor prognosis in term of both overall survival and progression- free survival. Moreover, at immunohistochemical evaluation, we found that prognostic significance of ZEB2 protein relies on its nuclear expression and co-localization with cytoplasmic HuR. In conclusion our findings indicated that nuclear ZEB2 may enhance progression of EMT transition and acquisition of an aggressive phenotype in ovarian cancer.