The Role of Polycomb Group Gene Bmi-1 in the Development of Prostate Cancer
Annual rept. 1 Sep 2010-31 Aug 2011
TWIN STAR MEDICAL MINNEAPOLIS MN
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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 last 5 months after submitting the 1st annual report of the project. In 1st annual report we showed that Bmi-1 protein levels are highly elevated in human CaP patients and we investigated the mechanistic basis of the role of Bmi-1 in human CaP. We showed that Bmi-1-silenced CaP cells exhibit decreased proliferative and clonogenic potential. On the contrary, Bmi-1- overexpressing CaP cells exhibited the reverse. Based on the outcome of micro-array analysis, we showed that silencing of Bmi-1 caused a decrease in the cyclin D1 Wnt target and Bcl-2 Sonic Hedgehog-SHH target, however an increase in p16 was observed. Conversely, overexpression of Bmi-1 exhibited the reverse effects. We generated a hypothesis that the Bmi-1 regulates the expression of Cyclin D1 and Bcl-2 by interacting with Wnt SHH signaling in CaP cells. In the current report we provide novel findings about the transcriptional activation of Bcl-2 in CaP cells. Bcl-2 is known to be regulated by SHH signaling. However, we provide evidence showing that despite blocking SHH signaling, Bmi-1 induces the Bcl-2 expression in CaP cells suggesting the involvement of other pathway too in the regulation of Bcl-2 transcriptional activation. Another important finding of our report is that we identified those Bcl-2 acts as a novel Wnt target in CaP cells. Our investigations suggest that Bmi-1 regulates Bcl-2 through Wnt signaling. Finally, animal studies showed a significantly reduced growth in PC- 3-Bmi-1-supressing cell-originated tumors than PC-3-1-Bmi-overexpressing cell-originated tumors in xenograft mouse models.
- Anatomy and Physiology
- Medicine and Medical Research