Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Carcinoma, Squamous Cell / metabolism
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Carcinoma, Squamous Cell / pathology*
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Carcinoma, Squamous Cell / virology
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Down-Regulation
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Neoplastic / genetics
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Humans
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Imidazoles / pharmacology
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Nasopharyngeal Neoplasms / metabolism
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Nasopharyngeal Neoplasms / pathology*
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Nasopharyngeal Neoplasms / virology
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Neoplasm Invasiveness
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Promoter Regions, Genetic / genetics
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Pyridines / pharmacology
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Tissue Inhibitor of Metalloproteinase-3 / antagonists & inhibitors
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Tissue Inhibitor of Metalloproteinase-3 / genetics
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Tissue Inhibitor of Metalloproteinase-3 / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Tumor Cells, Cultured
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Viral Matrix Proteins / genetics
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Viral Matrix Proteins / physiology*
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
Substances
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EBV-associated membrane antigen, Epstein-Barr virus
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Enzyme Inhibitors
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Imidazoles
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Pyridines
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Tissue Inhibitor of Metalloproteinase-3
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Transcription Factors
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Viral Matrix Proteins
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p38 Mitogen-Activated Protein Kinases
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SB 203580