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Induction of Interleukin-8 by Epstein-Barr Virus Latent Membrane Protein-1 and Its Correlation to Angiogenesis in Nasopharyngeal Carcinoma

Department of Otolaryngology, School of Medicine [T. Y., T. H., R. Q-C., N. W., H. T., M. F.] and Department of Molecular Oncology and Virology, Cancer Research Institute [R. Q-C., H. S.], Kanazawa University, Kanazawa 920-8641, Japan, and Department of Otolaryngology, School of Medicine, National Taiwan University, Taipei 10016, Taiwan, Republic of China [T-S. S., S-Y. L.]

Purpose: The EBV latent membrane protein-1 (LMP-1) is a multifunctional protein. Recently, the contribution of LMP-1 to the metastasis of nasopharyngeal carcinoma (NPC) has been suggested. Angiogenesis is a key step for metastasis. Thus, the association of LMP-1 to neovascularization of NPC was examined in this study.

Experimental Design: The association of LMP-1 to angiogenesis in 39 patients with NPC was evaluated by immunohistochemical study, and then induction of angiogenic factors by LMP-1 was examined by ELISA and luciferase reporter assay.

Results: In an immunohistochemical study, the expression of LMP-1 was significantly correlated to microvessel counts (P = 0.0003), suggesting that LMP-1 may induce some angiogenic factors. Therefore, we studied the relationship between LMP-1 expression and interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) expression by immunohistochemical analysis. IL-8, VEGF, and bFGF expression were correlated to microvessel counts, but only IL-8 expression was significantly correlated to LMP-1 expression (P < 0.0001). Transfection with LMP-1 expression plasmid induced IL-8 protein expression in C33A cells. The expression of LMP-1 transactivated IL-8 promoter, as demonstrated by IL-8 promoter luciferase reporter assay. Mutation of the nuclear factor B responsive element in the IL-8 promoter region completely abolished transactivation by LMP-1, whereas mutation of the activator protein responsive element did not affect promoter activity.

Conclusion: These results suggested that LMP-1 induces expression of IL-8 through the nuclear factor B binding site, which may contribute in part to angiogenesis in NPC.

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