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
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
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DOI：
10.1158/1078-0432.ccr-08-0198
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发表时间：
2008-09-01
影响因子：
11.5
通讯作者：
Yoshizaki, Tomokazu
中科院分区：
文献类型：
--
作者：
Tsuji, Akira;Wakisaka, Naohiro;Yoshizaki, Tomokazu
目的：EB病毒的癌蛋白潜伏膜蛋白1（LMP 1）通过诱导因子促进肿瘤的侵袭和血管生成，从而参与鼻咽癌的转移。晚期糖基化终末产物受体（receptor for advanced glycation end products，RECEPTOR）与糖尿病微血管病变中的异常血管生成有关。此外，一些论文提出了关联的过表达与肿瘤转移，因此，关联的鼻咽癌与LMP1和血管生成npc examined.Experimental设计：42例鼻咽癌患者进行了评估LMP1，npc，和S100蛋白的表达和微血管计数免疫组化。结果：LMP1高表达组和LMP1低表达组的微血管计数均显著高于LMP1低表达组（P = 0.0049和P <0.0001）;在这些组中，晚期N分类的患者也显著增加（P = 0.0484和P = 0.0005）。LMP1和MMP-9蛋白在鼻咽癌组织中的表达呈明显相关性（P = 0.0093）。瞬时转染LMP1表达质粒可诱导Ad-AH细胞表达LMP1蛋白。荧光素酶报告基因检测显示LMP1的表达激活了LMP1启动子。核因子-κ B结合位点（-671~-663）的报告基因突变可抑制LMP 1对鼻咽癌细胞增殖和转移启动子的反式激活作用。结论：LMP 1诱导的鼻咽癌细胞增殖和转移可能通过诱导血管生成而增强淋巴结转移。核因子-κ B结合位点（-671至-663）对于LMP 1转录激活p53启动子是必需的。
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-kappa 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-kappa B binding site (-671 to -663) is essential for transactivation of the RAGE promoter by LMP1.