Study of mechanism of Epstein-Barr virus-encoded small RNA-mediated gastric carcinogenesis

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We have previously reported that EBV infection of gastric epithelial cells leads to induction of insulin-like growth factor (IGF)-1 and IGF-1 promotes growth of EBV-infected cells by an autocrine mechanism. We have also identified that EBV-encoded small RNA (EBER) is the responsible gene for IGF-1 induction.In this study, we analyzed how EBER induced IGF-1 to clarify the mechanisms of EBV-mediated gastric carcinogenesis. We identified that EBER activates retinoic acid-inducible gene (RIG)-I, which is the cytosolic double stranded RNA (ds RNA) sensor, leading to induction of interferon via activation of IRF3 and NF-κB in Burkitt's lymphoma (BL) cells. Furthermore, we found that EBER-mediated RIG-I activation induces IL-10, which acts as a growth factor for BL cells. These are novel findings suggesting that activation of innate immune signals by EBER contributes to growth promotion of EBV-positive cancer cells.On the other hand, we identified that EBER is released extracellulary from EBV-positive gastric cancer cells leading to induction of TLR3-mediated signal transduction. Our findings indicate that TLR3-mediated signaling is constitutively activated, therefore may contribute to IGF-1 induction by EBER in EBV -positive gastric cancer cells.