Transcriptional repression of tissue inhibitor of metalloproteinase-3 by Epstein-Barr virus latent membrane protein 1 enhances invasiveness of nasopharyngeal carcinoma cells

SummaryEpstein-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.