Role of Polycomb Group Gene Bmi-1 in the Development of Prostate Cancer

摘要

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.