Transcriptional repression of tissue inhibitor of metalloproteinase-3 by Epstein-Barr virus latent membrane protein 1 enhances invasiveness of nasopharyngeal carcinoma cells.
Epstein-Barr virus latent membrane protein 1 (LMP1) has oncogenic and metastasis-promoting activity. We found that LMP1 down-regulated the anti-metastatic protein tissue inhibitor of metalloproteinase-3 (TIMP-3) in EBV-negative nasopharyngeal carcinoma (NPC) cells. Promoter assay demonstrated that LMP1 inhibited TIMP-3 via transcription repression and the response element is located at the -44/+28 region of the TIMP-3 promoter. Additionally, we found that repression of TIMP-3 by LMP1 was mediated by p38 kinase because SB203580 effectively reversed the inhibition of LMP1 whereas the inhibitors of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and AKT had little effect. Down-regulation of TIMP-3 by LMP1 enhanced the migration and invasive ability of NPC cells. Conversely, ectopic expression of TIMP-3 reduced the migration and invasion stimulated by LMP1. We conclude that LMP1 inhibits TIMP-3 via transcriptional repression and this repression is important for LMP1 to promote metastasis.
Chang
Shu-Hui
SH
Department of Pathology, Chang Gung Memorial Hospital - Kaohsiung Medical Center, Kaohsiung 833, Taiwan.
Chang
Hui-Chiu
HC
Hung
Wen-Chun
WC
D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014763:Viral Matrix Proteins / Q000235:genetics / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D019717:Tissue Inhibitor of Metalloproteinase-3; D014157:Transcription Factors; D014763:Viral Matrix Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580