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

Abstract

Bmi-1 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-1 in human oral carcinogenesis. Bmi-1 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-1 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-1 expression occurs at a very early stage in oral carcinogenesis. To determine the biological role of Bmi-1 in cell proliferation, endogenous Bmi-1 was knocked down in actively proliferating SCC4 cells and NHOK by RNA interference. After Bmi-1 knockdown, cell replication was severely retarded. However, the expression of p16 INK4A , a known cellular target of Bmi-1, was not changed in cells with or without Bmi-1 knockdown. Furthermore, Bmi-1 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-1 may act through p16 INK4A -independent pathways to regulate cellular proliferation during oral cancer progression.

Distinctive expression of the polycomb group proteins Bmi1 polycomb ring finger oncogene and enhancer of zeste homolog 2 in nonsmall cell lung cancers and their clinical and clinicopathologic significance

“…7,8 The oncogenic potential of Bmi1 is caused in part by its negative regulation of the Ink4a/Arf locus, which encodes 2 proteins (p16 INK4a and p19 ARF ) that suppress proliferation and promote apoptosis, 9,10 and its role in stem cell maintenance. 11,12 Elevated expression of Bmi1 has been reported in multiple types of cancers, including oral cancer, 13 lymphoma, 14,15 and breast cancer. 16,17 In previous studies on NSCLC, normal bronchial epithelial cells had abundant Bmi1 expression, whereas tumor cells had various expression patterns.…”

Knockdown of the Bmi-1 oncogene inhibits cell proliferation and induces cell apoptosis and is involved in the decrease of Akt phosphorylation in the human breast carcinoma cell line MCF-7

“…Bmi-1, the first identified PcG gene, has been documented to be involved in multiple biological processes, such as embryonic development, organ formation, tumorigenesis, stem cell stabilization and differentiation (5). With the rapid development of molecular biology and oncology, more and more evidence has shown that Bmi-1 is tightly associated with the development of tumors, including non-small cell lung cancer (6), colorectal cancer (7), nasopharyngeal carcinoma (8), oral cancer (9), esophageal squamous cell carcinoma (10), breast carcinoma (11,12). However, detailed molecular mechanism of Bmi-1 in occurrence and development of breast carcinoma remains to be elucidated.…”

Decreased expression of S100A6 in oral squamous cell carcinoma

“…Park et al (38) has established an in vitro multistep carcinogenesis model for OSCC from immortalized normal human oral keratinocytes. This model has been used for the in vitro investigation of gene expressions (39,40). However, no systematic study of the total protein expression is reported.…”