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

Oral Oncol. 2008 Sep;44(9):891-7. doi: 10.1016/j.oraloncology.2007.11.005. Epub 2008 Mar 4.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology*
  • Carcinoma, Squamous Cell / virology
  • Down-Regulation
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Imidazoles / pharmacology
  • Nasopharyngeal Neoplasms / metabolism
  • Nasopharyngeal Neoplasms / pathology*
  • Nasopharyngeal Neoplasms / virology
  • Neoplasm Invasiveness
  • Promoter Regions, Genetic / genetics
  • Pyridines / pharmacology
  • Tissue Inhibitor of Metalloproteinase-3 / antagonists & inhibitors
  • Tissue Inhibitor of Metalloproteinase-3 / genetics
  • Tissue Inhibitor of Metalloproteinase-3 / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Cells, Cultured
  • Viral Matrix Proteins / genetics
  • Viral Matrix Proteins / physiology*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors

Substances

  • EBV-associated membrane antigen, Epstein-Barr virus
  • Enzyme Inhibitors
  • Imidazoles
  • Pyridines
  • Tissue Inhibitor of Metalloproteinase-3
  • Transcription Factors
  • Viral Matrix Proteins
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580