Abstract
5290
Bmi-1 is a polycomb group oncogene highly overexpressed in premalignant and malignant oral lesions. Exogenous Bmi-1 can enhance the replicative capacity of normal human oral keratinocytes (NHOK) although it alone fails to immortalize the cells. To determine the mechanisms underlying the extension of replicative life span mediated by Bmi-1 overexpression, we performed microarray analysis to identify the cellular target genes differentially expressed by exogenous Bmi-1. Among the differentially regulated genes, we confirmed the downregulation of nuclear factor in high endothelial venule (NF-HEV, also called C9ORF26) by overexpression of Bmi-1 in NHOK by reverse transcription (RT)-PCR. We also found that NF-HEV expression was notably induced in NHOK during replicative senescence, which is in keeping with the decreased expression of endogenous Bmi-1 in senescent cells. Survey of NF-HEV expression levels in 10 independent oral squamous cell carcinoma (OSCC) cell lines showed complete lack of its expression in eight of the 10 OSCC cell lines and expression of the mutant forms in the other two cell lines. To determine the cellular function of NF-HEV, we constructed a retroviral vector capable of expressing full-length, wild-type NF-HEV. When NF-HEV was overexpressed by retroviral infection in SCC4 cells, an OSCC cell line lacking endogenous NF-HEV expression, the cells underwent rapid alteration in cellular morphology and apparent cell death. Infection of normal human oral fibroblasts (NHOF) with the retrovirus expressing NF-HEV also led to notable retardation of cellular replication. These results indicate that (1) NF-HEV is negatively regulated by Bmi-1, (2) aberration of NF-HEV expression is associated with OSCC, and (3) NF-HEV demonstrates growth suppressive activity. This work was supported in part by the grants from NIDCR/NIH and from Oral and Maxillofacial Surgery Foundation.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA