Identification of Epstein-Barr Virus-mediated Decoy Receptor 3 upregulation and its effect on nasopharyngeal carcinoma metastasis

• Main Authors: Cheng-Hsun Ho, 何政勳
• Other Authors: Chi-Ju Chen
• Format: Others
• Language: zh-TW
• Online Access: http://ndltd.ncl.edu.tw/handle/s74x9j

博士 === 國立陽明大學 === 微生物及免疫學研究所 === 97 === Epstein-Barr virus (EBV) belongs to human γ-herpesvirus and its infection is known to be associated with various malignancies. However, how EBV escapes host immune surveillance and promotes tumorigenesis are not well elucidated. Decoy receptor 3 (DcR3) is a soluble tumor necrosis factor receptor found to be overexpressed in several tumor types and its overexpression has been implicated in tumor cells surviving through inhibiting apoptosis and interfering immunity. A previous study reported that amplification of DcR3 is detected in EBV-associated lymphomas but rare in non-EBV associated lymphomas, suggesting the role of EBV in DcR3 upregulation. After screening serial EBV genes, we found EBV latent membrane protein 1 (LMP1) and lytic transactivator Rta are responsible for upregulating DcR3 in EBV latent and lytic stages, respectively. Overexpression of Rta or LMP1 into EBV-negative cell lines enhanced DcR3 expression in a dose-dependent manner. Additionally, the amounts of Rta or LMP1 was correlated with DcR3 expression levels in EBV-infected cell lines. Further dissection revealed that C-terminal activation domain of Rta or LMP1 was essential for DcR3 stimulation. Rta induced DcR3 expression mainly through binding to Rta-responsive element (RRE) on DcR3 promoter, while LMP1-mediated DcR3 elicitation was via triggering diverse signaling pathways. Functionally, DcR3 was shown to enhance cell motility and invasiveness in nasopharyngeal carcinoma (NPC) cells, implicating the importance of DcR3 on promoting tumor metastasis. Finally, we showed the co-expression of DcR3 and LMP1 in NPC biopsies. Taken together, EBV may enhance DcR3 expression by LMP1 or Rta, which contributes to NPC metastasis.