Abstract 2043: Inhibition of cervical carcinoma cells proliferation by miR-34c

Abstract

Abstract MicroRNAs (miRNAs) play central roles in controlling cell proliferation, differentiation, and apoptosis. Aberrant miRNA expression is recognized as an important molecular mechanism for human carcinogenesis. Infection with high-risk human papillomaviruses (HPVs) is causally associated with the onset of cervical dysplasia including cancer. Although high-risk HPV infection leads to hyperproliferation and immortalization, it is insufficient to produce a fully transformed phenotype. High-risk HPV E6 proteins (i.e. HPV-16 and 18) inactivate and destroy P53 protein leading to a p53-null phenotype and the subsequent repression of the p53 effector network including pro-apoptotic proteins and cell cycle inhibitors. Microarray analyses in normal and tumor cervical cells have linked only a few miRNAs to cervical cancer. However, no miRNAs have been established in the malignant process that may follow a high-risk HPV infection. Here, we analyze the function of miR-34c (a p53 effector) in HPV-positive cells. Steady-state miR-34c levels are very low in both immortal and tumor HPV-positive cells. Over-expression of miR-34c in cervical carcinoma cells caused inhibition of cell proliferation and anchorage independent growth resulting in G2/M arrest and significant apoptosis. Interestingly, no effect was noticed in HPV-negative tumor cells and HPV-immortalized keratinocytes suggesting a differential regulatory pathway of mi-34c in HPV-positive tumor cells. Analyses of miR-34c potential targets showed no significant effect on BCL-2 levels although it produced MAP-2 down-regulation. These results suggest that activation of miR-34c in the absence of functional p53 may play an important role in proliferation and apoptosis of HPV-positive cervical tumor cells that could be used as therapeutic or diagnostic/prognostic tool for cervical cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2043.