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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.
Highlights
Ovarian cancer is the most lethal gynecologic malignancy, primarily for the advanced stage at diagnosis and the recurrence of chemotherapy-resistant tumors [1,2]
The miR-200 family plays an important role in down-regulation of ZEB1/ZEB2 expression, being in turn repressed by these factors, in a well described inihibitory feedforward loop [7]
The results indicated that the expression of the miRNAs of the family varied considerably within all the cell lines analyzed, supporting the notion of specific roles played by the different family members and the presence of a spectrum of epithelial-mesenchymal transition (EMT) phenotypes
Summary
Ovarian cancer is the most lethal gynecologic malignancy, primarily for the advanced stage at diagnosis and the recurrence of chemotherapy-resistant tumors [1,2]. The migration and invasiveness of the epithelial tumor cells depends on the activation of a reversible development process called epithelial-to-mesenchymal transition (EMT) [4]. Once the cells reach their new niche, they can activate the reverse program – mesenchymal-to-epithelial transition (MET) – to form metastasis, as described in ovarian cancer [5]. The transcriptional repressor ZEB2 was deeply studied proving to be an EMT activator and a key factor in promoting the initiation and development of different tumors [8,9,10,11,12,13]. ZEB2 gene expression was described to be regulated at post-transcriptional levels by the activity of several miRNAs, five of them corresponding to the miR-200 family [14,15,16, 7]. Expression of the miR-200 family is strongly associated with epithelial differentiation, and a reciprocal feedback loop between the miR-200-family and and the ZEB family tightly controls both EMT and MET
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