Regulation of Matrix Metalloproteinase Genes by Epstein-Barr Virus

• Main Authors: Yu-YanLan, 藍宇彥
• Other Authors: Yao Chang
• Format: Others
• Language: en_US
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/77246155699486941278

博士 === 國立成功大學 === 基礎醫學研究所 === 103 === Both latent and lytic infection of Epstein-Barr virus (EBV) has been associated with development or progression of nasopharyngeal carcinoma (NPC), an epithelial malignancy with a propensity toward local invasion and distant metastasis. This study is to explore whether and how EBV proteins regulate expression of metastasis-associated matrix metalloproteinses (MMPs) to confer the invasive potential on NPC cells. First, we found that viral latent membrane protein 2A (LMP2A) upregulates MMP9 and promotes MMP9-dependent invasion of NPC cells. The underlying mechanism involves LMP2A-triggered ERK1/2 activation and its downstream induction of the Fra-1 transcription factor, thus transactivating the MMP9 promoter through two AP-1 elements. Interestingly, LMP2A physically interacts with a cellular protein WW domain-containing oxidoretuctase (WOX1), and endogenous WOX1 is required for LMP2A-induced ERK1/2-Fra-1-MMP9 signal transduction and cell invasion. In addition, we found a correlation of LMP2A not only with MMP9 expression in NPC biopsy specimens, but also with lymph node metastasis of the tumors. On the other hand, Zta, an immediate-early lytic protein of EBV, contributes to enhanced migration and invasion of EBV-infected NPC cells. In MMP array analysis, Zta upregulates expression of MMP9 and MMP3 in NPC cells. The underlying mechanism involves direct binding of Zta to the target promoter and triggering promoter activation through AP-1 elements. Furthermore, we found that Zta induces cell migration mainly through inducing MMP3 but not MMP9, while MMP3 and MMP9 cooperate synergistically for Zta-induced cell invasion. Our study reveals that both latent and lytic proteins of EBV promote NPC cell invasion through regulating MMP expression, providing a link how EBV contributes to NPC metastasis. Since MMPs are convergent metastasis-associated proteins regulated by EBV, they may serve as a potential therapeutic target for NPC treatment.