Elevated Bmi-1 expression is associated with dysplastic cell transformation during oral carcinogenesis and is required for cancer cell replication and survival

Bmi-I is a polycomb group protein that was identified as c-myc cooperating oncogene in murine lymphomagenesis. The current study was undertaken to determine the role of Bmi-I in human oral carcinogenesis. Bmi-I protein and RNA expression levels were markedly enhanced in the cells of oral squamous cell carcinomas (OSCC) compared with that of normal human oral keratinocytes (NHOK). Enhanced-Bmi-I expression was also detected in situ in the archived oral mucosal tissues with cancerous and precancerous histopathology, including that of mild epithelial dysplasia. Thus, Bmi-I expression occurs at a very early stage in oral carcinogenesis. To determine the biological role of Bmi-I in cell proliferation, endogenous Bmi-I was knocked down in actively proliferating SCC4 cells and NHOK by RNA interference. After Bmi-I knockdown, cell replication was severely retarded. However, the expression of p16(INK4A), a known cellular target of Bmi-I, was not changed in cells with or without Bmi-I knockdown. Furthermore, Bmi-I knockdown in HOK-16B-BaP-T cells, in which the p16(INK4A)/pRb pathway was abrogated, led to immediate arrest of replication and loss of viable cells. Thus, our data suggest that Bmi-I may act through p16(INK4A)-independent pathways to regulate cellular proliferation during oral cancer progression.