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Regulation of Matrix Metalloproteinase-1 by Epstein-Barr Virus Proteins¹

Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan

Matrix metalloproteinases (MMPs) play crucial roles in tumor progression. To investigate the roles of MMPs in the progression of nasopharyngeal carcinoma (NPC), the expression of MMP-1, MMP-2, MMP-3, MMP-7, MMP-12, MMP-13, MMP-14, and MMP-19 was explored by microarray assay. Among them, MMP-1 was significantly up-regulated in NPC biopsies. These results were confirmed further by real-time quantitative PCR in additional NPC biopsies and comparison with normal tissues and other head and neck cancers. Moreover, the use of RNA from different cellular constituents of NPC biopsies revealed that MMP-1 was detected predominantly in epithelial cells. Immunohistochemical staining of paraffin-fixed NPC sections confirmed that MMP-1 protein was expressed in the epithelial tumor cells. Because EBV is strongly associated with NPC formation, we sought a correlation between viral gene expression and MMP-1 up-regulation. The results showed clearly that the amounts of transcripts, proteins, and enzyme activities of MMP-1 were increased in cells expressing EBV proteins, LMP1 (latent membrane protein 1) and Zta (Z transactivator; also named as BZLF1 or ZEBRA) but not EBNA-1 (EBV nuclear antigen-1). Additionally, the mobility of LMP1 and Zta transfectants was increased in scrape-wound migration assays. The invasiveness and ability to survive in a three-dimensional collagen gel also were enhanced in LMP1- and Zta-expressing cells. Furthermore, anti-MMP-1 antibody and peptide inhibitors could block the invasiveness and survival properties of LMP1 and Zta transfectants, suggesting a real contribution of MMP-1 to cell mobility and survival. Taken together, our data show that the viral LMP1 and Zta proteins regulate the expression and activity of MMP-1, and thereby confer the invasive properties of the cells. This study presents the first evidence that viral proteins are capable of regulating MMP-1 and also provides clues for the role of EBV in NPC progression.

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