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 for its close association with Epstein-Barr virus and its highly metastatic nature. Up-regulation of cell motility is essential for enhancement of metastatic potential. The expression of c-Met proto-oncogene, a high-affinity receptor for hepatocyte growth factor/scatter factor, has been reported to correlate with metastatic ability of the tumor cell. We observed close association of c-Met expression with cervical lymph node metastasis (P = 0.0272) in 39 NPC specimens studied immunohistochemically. Epstein-Barr virus-encoding latent membrane protein-1 (LMP-1) is a primary oncogene and is suggested to enhance the metastatic property of NPC. Previously, we reported that LMP-1 enhanced the motility of Madin-Darby canine kidney (MDCK) epithelial cells that was mediated by activation of Ets-1 transcription factor. Therefore, we examined the interrelationships of LMP-1, Ets-1, and c-Met. In immunohistochemical studies, the expression of LMP-1, Ets-1, and c-Met correlated 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 LMP-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 in LMP-1-expressing MDCK cells. These results suggest that LMP-1 induces c-Met through the activation of Ets-1, which may contribute in part to the highly metastatic potential of NPC.
Horikawa
T
T
Department of Otolaryngology, School of Medicine, Kanazawa University, Japan.
Sheen
T S
TS
Takeshita
H
H
Sato
H
H
Furukawa
M
M
Yoshizaki
T
T
D000818:Animals; D002460:Cell Line; D004285:Dogs; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000556:secondary*; D009333:Neck; D000090063:Proto-Oncogene Mas; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; C494041:ETS1 protein, human; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors; D014763:Viral Matrix Proteins; D019859:Proto-Oncogene Proteins c-met