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Induction of Receptor for Advanced Glycation End Products by EBV Latent Membrane Protein 1 and Its Correlation with Angiogenesis and Cervical Lymph Node Metastasis in Nasopharyngeal Carcinoma

Authors' Affiliation: Division of Otolaryngology Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Ishikawa, Japan

Requests for reprints: Tomokazu Yoshizaki, Division of Otolaryngology, Graduate School of Medicine, Kanazawa University, Takara-machi 13-1, Kanazawa, 920-8640, Japan. Phone: 81-76-265-2413; Fax: 81-76-234-4265; E-mail: tomoy{at}med.kanazawa-u.ac.jp.

Purpose: The EBV oncoprotein, latent membrane protein 1 (LMP1), contributes to the metastasis of nasopharyngeal carcinoma (NPC) by inducing factors to promote tumor invasion and angiogenesis. The receptor for advanced glycation end products (RAGE) is associated with abnormal angiogenesis in diabetic microangiopathies. Moreover, some papers have suggested the association of RAGE overexpression with tumor metastasis; thus, the associations of RAGE with LMP1 and angiogenesis in NPC were examined.

Experimental Design: Forty-two patients with NPC were evaluated for expressions of LMP1, RAGE, and S100 proteins and for microvessel counts by immunohistochemistry. Then, the RAGE induction by LMP1 was examined with Western blotting and luciferase reporter assay.

Results: The microvessel counts were significantly higher in patients with high LMP1 expression or high RAGE expression compared with cases with low expressions (P = 0.0049 and P < 0.0001), respectively. Patients with advanced N classification were also significantly increased in these groups (P = 0.0484 and P = 0.0005). The expressions of LMP1 and RAGE proteins were clearly correlated in NPC tissues (P = 0.0093). Transient transfection with LMP1 expression plasmid induced RAGE protein in Ad-AH cells. The expression of LMP1 transactivated the RAGE promoter as shown by luciferase reporter assay. Mutation of the reporter at nuclear factor-B binding site (–671 to –663) abolished transactivation of the RAGE promoter by LMP1.

Conclusion: These results suggest that LMP1-induced RAGE enhances lymph node metastasis through the induction of angiogenesis in NPC. Nuclear factor-B binding site (–671 to –663) is essential for transactivation of the RAGE promoter by LMP1.