Polycomb repressor complex 1 member, BMI1 contributes to urothelial tumorigenesis through p16-independent mechanisms

Urothelial carcinoma (UC) causes significant morbidity and remains the most expensive cancer to treat due to the need for repeated resections and life-long monitoring for patients with non-muscle-invasive bladder cancer (NMIBC). Novel therapeutics and stratification approaches are needed to improve the outlook for both NMIBC and muscle-invasive bladder cancer (MIBC). We investigated the expression and effects of B Lymphoma Mo-MLV Insertion Region 1 (BMI1) in UC. BMI1 was found to be over-expressed in most UC cell lines and primary tumors by quantitative-real-time-PCR and immunohistochemistry. In contrast to some previous reports, no association with tumor stage or grade was observed in 2 independent tumor panels. Furthermore, up-regulation of BMI1 was detected in premalignant bladder lesions, suggesting a role early in tumorigenesis. BMI1 is not located within a common region of genomic amplification in UC. The CDKN2A locus (which encodes the p16 tumor suppressor gene) is a transcriptional target of BMI1 in some cellular contexts. In UC cell lines and primary tissues, no correlation between BMI1 and p16 expression was observed. Retroviral-mediated over-expression of BMI1 immortalized normal human urothelial cells (NHUC) in vitro and was associated with induction of telomerase activity, bypass of senescence and repression of differentiation. The effects of BMI1 on gene expression were identified by expression microarray analysis of NHUC-BMI1. MetacoreTM analysis of the gene expression profile implicated downstream effects of BMI1 on α4/β1 integrin-mediated adhesion, cytoskeleton remodelling and CREB1-mediated transcription.