The Role of Polycomb Group Gene BMI-1 in the Development of Prostate Cancer
Annual rept. 1 Sep 2009-31 Aug 2010
MINNESOTA UNIV MINNEAPOLIS
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We proposed to investigate the role of Bmi-1 a member of polycomb gene family in human prostate cancer CaP development. Here, we present the work accomplished during the first year of the project. Immunohistochemical analysis of prostatic specimens of 125 human CaP patients showed that Bmi-1 protein levels are highly elevated in patients with advanced disease. To understand the mechanism of action of Bmi-1, we employed two-prong strategy. Firstly, Bmi-1 was knocked down in CaP cells LNCaP, DU145 and PC-3 by employing siRNA technique. Bmi-1-silenced CaP cells exhibited decreased proliferative and clonogenic potential. Secondly, Bmi-1 was over-expressed in CaP cells by transfecting Bmi-1 overexpressing plasmid pbabe-Bmi-1 in CaP cells. Bmi-1-overexpressing cells exhibited increased clonogenicity and rate of proliferation. Based on the outcome of micro-array analysis, we analyzed CaP cells for Cyclin D1 the cell cycle regulatory protein and Bcl-2 pro-survival protein. Silencing of Bmi-1 caused a decrease in the Cyclin D1 and Bcl-2, however an increase in p16 was observed. On the contrary, overexpression of Bmi-1 caused an increase in the levels of Cyclin D1, Bcl2- and a decrease in p16 levels. Since Cyclin D1 is a the target of Wnt signaling and Bcl-2 is the major target of Sonic Hedgehog SHH signaling, we hypothesize that the Bmi-1 regulates the expression of Cyclin D1 and Bcl-2 by interacting with Wnt SHH signaling in CaP cells. We have taken steps to understand this mechanism in CaP cells and in this regard further experiments are underway. The successful outcome of these studies will provide deepinsight into the mechanism of CaP cell proliferation and would identify novel molecular targets for CaP chemotherapy.
- Medicine and Medical Research