miR-205 Exerts Tumor-Suppressive Functions in Human Prostate through Down-regulation of Protein Kinase C

Departments of ¹Experimental Oncology and Laboratories, ²Pathology, ³Urology, and ⁴Prostate Program, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico Istituto Nazionale dei Tumori and ⁵Institute of Endocrinology, University of Milan, Milan, Italy

^* To whom correspondence should be addressed. E-mail: nadia.zaffaroni{at}istitutotumori.mi.it.

	Abstract

Limited information is available concerning the expression and role of microRNAs in prostate cancer. In this study, we investigated the involvement of miR-205 in prostate carcinogenesis. Significantly lower miR-205 expression levels were found in cancer than in normal prostate cell lines as well as in tumor compared with matched normal prostate tissues, with a particularly pronounced reduction in carcinomas from patients with local-regionally disseminated disease. Restoring the expression of miR-205 in prostate cancer cells resulted in cell rearrangements consistent with a mesenchymal-to-epithelial transition, such as up-regulation of E-cadherin and reduction of cell locomotion and invasion, and in the down-regulation of several oncogenes known to be involved in disease progression (i.e., interleukin 6, caveolin-1, EZH2). Our evidence suggests that these events are driven by the concurrent repression of specific predicted miR-205 targets, namely N-chimaerin, ErbB3, E2F1, E2F5, ZEB2, and protein kinase C. Strikingly, the latter seemed to play a direct role in regulating epithelial-to-mesenchymal transition. In fact, its down-regulation led to a cell phenotype largely reminiscent of that of cells ectopically expressing miR-205. Overall, we showed for the first time that miR-205 exerts a tumor-suppressive effect in human prostate by counteracting epithelial-to-mesenchymal transition and reducing cell migration/invasion, at least in part through the down-regulation of protein kinase C. [Cancer Res 2009;69(6):OF1–9]

Key Words: prostate cancer, microRNA, miR-205, epithelial-to-mesenchymal transition, PKC

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