Abstract 1451: MicroRNAs regulated by ESE3/EHF control important mediators of epithelial cell differentiation and stemness in prostate tumors
Authors: Dallavalle Cecilia , Albino Domenico , Civenni Gianluca , Ostano Paola , Genini Davide , Garcia-Escudero Ramon , Curti Laura , Pinton Sandra , Sarti Manuela , Chiorino Giovanna , Catapano Carlo V. , Carbone Giuseppina M. R. 
Published: May 2015

Abstract
Deregulated expression of ETS transcription factors has emerged as an important event in prostate cancer pathogenesis. We found that loss of the ETS factor ESE3/EHF induced a broad dedifferentiation program associated with epithelial-to-mesenchymal transition (EMT) and induction of metastatic and cancer stem-like cell properties. To understand the mechanism by which ESE3/EHF controls differentiation of prostate epithelial cells, we examined microRNA (miRNA) expression in a cohort of primary prostate tumors and prostate epithelial normal and cancer cells using miRNA gene arrays. A distinct set of miRNAs was specifically deregulated in cancer cells and tumors with low ESE3/EHF expression. Bioinformatic analysis indicated that the deregulated miRNAs controlled many genes involved in EMT and cell stemness. Interestingly, we found that miR-424 was at the top list of the miRNAs up-regulated in ESE3 low expressing tumors and cell lines. This finding was confirmed by qRT-PCR both in cells and human tumors. Functional assays showed that ESE3/EHF controlled directly miR-424 by binding to the pre-miRNA promoter and repressing its transcription. Inhibition of miR-424 using an antimiR reduced anchorage-independent growth and cell migration in cancer cells with low ESE3 expression and high miR-424 level. On the contrary, stable expression of pre-miR-424 in cells with low endogenous miR-424 level increased anchorage-independent growth and cell migration. Furthermore, modulation of miR-424 expression affected in vitro prostatosphere formation, a phenotype associated with cancer stem-like cell properties. Consistently, inhibition of miR-424 in DU145 prostate cancer cells reduced growth of tumor xenografts in immunodeficient mice. Integrating bioinformatic analyses of the predicted targets and gene profiling of cells with miR-424 overexpression we found that miRNA-424 controlled several factors involved in protein degradation. Collectively, these results show for the first time that ESE3/EHF controls a distinct network of miRNAs with both oncogenic and tumor suppressor functions. Loss of ESE3/EHF resulted specifically in increased expression of miR-424, which has oncogenic properties in prostate epithelial cells. This represents a novel mechanism by which deregulation of ESE3/EHF impact on prostate tumorigenesis. Thus, targeting miR-424 could be a novel therapeutic strategy for prostate cancer.
Citation Format: Cecilia Dallavalle, Domenico Albino, Gianluca Civenni, Paola Ostano, Davide Genini, Ramon Garcia-Escudero, Laura Curti, Sandra Pinton, Manuela Sarti, Giovanna Chiorino, Carlo V. Catapano, Giuseppina M. R. Carbone. MicroRNAs regulated by ESE3/EHF control important mediators of epithelial cell differentiation and stemness in prostate tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1451. doi:10.1158/1538-7445.AM2014-1451