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

我们之前报道过EBV感染胃上皮细胞导致胰岛素样生长因子(IGF)-1的诱导，IGF-1通过自分泌机制促进EBV感染细胞的生长。我们还发现ebv编码的小RNA （EBER）是IGF-1诱导的负责基因。在本研究中，我们分析了EBER如何诱导IGF-1，以阐明ebv介导的胃癌发生机制。我们发现，EBER激活视黄酸诱导基因(RIG)- 1，这是胞质双链RNA （ds RNA）传感器，通过激活IRF3和NF-κB在伯基特淋巴瘤（BL）细胞中诱导干扰素的产生。此外，我们发现eber介导的rig -1激活诱导IL-10， IL-10是BL细胞的生长因子。这些新发现表明，EBER激活先天免疫信号有助于促进ebv阳性癌细胞的生长。另一方面，我们发现ebv阳性胃癌细胞的细胞外释放出EBER，从而诱导tlr3介导的信号转导。我们的研究结果表明，tlr3介导的信号是组成性激活的，因此可能有助于EBER在EBV阳性胃癌细胞中诱导IGF-1。

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.