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EBV infection is closely associated with nasopharyngeal carcinoma (NPC) and can be detected in early premalignant lesions of nasopharyngeal epithelium. The latent membrane protein 1 (LMP1) is an oncoprotein encoded by the Epstein-Barr virus and is believed to play a role in transforming premalignant nasopharyngeal epithelial cells into cancer cells. The RASSF1A is a tumour suppressor gene commonly inactivated in many types of human cancer including nasopharyngeal carcinoma. In this study, we report a novel function of LMP1 in down-regulating RASSF1A expression in human epithelial cells. Down-regulation of RASSF1A expression by LMP1 is dependent on the activation of intracellular signaling of NF-κB involving the C-terminal activating regions (CTARs) of LMP1. LMP1 expression also suppresses the transcriptional activity of the RASSF1A core promoter. RASSF1A stabilizes microtubules and regulates events in mitosis. Aberrant mitotic spindles and chromosome aberrations are reported phenotypes in RASSF1A inactivated cells. LMP1 expresson in human epithelial cells also induced aberrant mitotic spindles, unstable interphase microtubules and aneuploidy. LMP1 expression also suppresses microtubule dynamics as exemplified by tracking the movements of the growing tips of microtubules in live cells by transfecting EGFP-tagged EB1 into cells. The aberrant mitotic spindles and interphase microtubule structures in LMP1 expressing cells could be rescued by co-transfecting RASSF1A expressing plasmid into cells. Our results reveal a novel function of LMP1 in downregulation of RASSF1A expression resulting in disruption of microtubule function and induction of chromosome aberrations in human epithelial cells. Downregulation of RASSF1A by LMP1 may facilitate the tumorigenic transformation of EBV infected nasopharyngeal epithelial cells.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA