Induction of c-Met proto-oncogene by Epstein-Barr virus latent membrane protein-1 and the correlation with cervical lymph node metastasis of nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is distinctive in head and neck carcinomas f or its close association with Epstein-Barr virus and Its highly metastatic nature. Up-regulation of cell motility Is essential for enhancement of meta static potential. The expression of c-Met proto-oncogene, a high-affinity r eceptor for hepatocyte growth factor/scatter factor, has been reported to c orrelate with metastatic ability of the tumor cell We observed close associ ation of c-Met expression with cervical lymph node metastasis (P = 0.0272) In 39 NPC specimens studied immunohistochemically, Epstein-Barr virus-encod ing latent membrane protein-1 (LMP-1) is a primary oncogene and is suggeste d to enhance the metastatic property of NPC, Previously, we reported that L MP-1 enhanced the motility of Madin-Darby canine kidney (MDCK) epithelial c ells that was mediated by activation of Ets-1 transcription factor. Therefo re, we examined the interrelationships of LMP-1, Ets-1, and c-Met. In immun ohistochemical studies, the expression of LMP-1, Ets-1, and c-Met correlate d significantly with each other in NPC (LMP-1 versus Ets-1, P < 0.0001; Ets -1 versus c-Met, P = 0.0012; LMP-1 versus Met, P 0.0005). Transfection of L MP-1-expressing plasmid in MDCK cells induced c-Met protein expression, The c-Met protein was also induced by Ets-1 expression, and induction of c-Met by LMP-1 was suppressed by introducing a dominant-negative form of Ets-1 i n LMP-1-expressing MDCK cells. These results suggest that LMP-1 induces c-M et through the activation of Ets-1, which may contribute in part to the hig hly metastatic potential of NPC.