Abstract 142: Novel tumor suppressor role of microRNA-205 in melanoma via regulation of E2F1

Abstract

Abstract MicroRNAs (miRNAs) regulate gene expression by repressing translation or directing sequence-specific degradation of complementary mRNA. Altered miRNA expression has been demonstrated in several human cancers. Limited information is available concerning the expression and role of miRNAs in melanoma. Here, we report that expression of miR-205 is significantly suppressed in melanoma tumor samples when compared with nevi, and is correlated inversely with melanoma progression. miR-205 expression was also significantly downregulated in a panel of melanoma cell lines when compared to a normal melanocyte line. miRNA target databases predicted a conserved target site for miRNA-205 in the 3’ untranslated region (UTR) of E2F1 and E2F5. The expression levels of E2F1 and E2F5 were inversely correlated with that of miR-205 in melanoma cell lines. miR-205 significantly suppressed the luciferase activity of reporter plasmids containing the 3’UTR sequences complementary to either E2F1 or E2F5, which was abolished by mutations in these 3’UTR regions. Overexpression of miR-205 in melanoma cells reduced E2F1 and E2F5 protein levels without alteration of mRNA expression. The proliferative ability of melanoma cells was suppressed by miR-205, mediated by E2F-regulated AKT phosphorylation. Transient overexpression of miR-205 in melanoma cells resulted in induction of apoptosis, as indicated by increases in cleaved caspase-3, poly-(ADP-ribose) polymerase (PARP) and release of cytochrome-c. Stable overexpression of miR-205 suppressed cell proliferation and colony formation, and resulted in inhibition of tumor cell growth in vivo and induction of a senescence phenotype accompanied by elevated p16INK4A expression and other markers for senescence. These results demonstrate a novel role for miR-205 as a tumor suppressor in melanoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 142. doi:10.1158/1538-7445.AM2011-142