EBV-miRs调控STAT3信号通路介导EB病毒相关胃癌干细胞免疫抑制性的作用及分子机制

Cancer stem cells-mediated immunosuppression have been reported to be associated with the development and immunotherapy resistance of several human cancers. Our previous study have elucidated that Epstein-Barr virus-associated gastric carcinoma (EBVaGC) stem cells could induce immunosuppression by the STAT3 pathway. However, the exact mechanism of STAT3 overexpression in human EBVaGC is largely unknown. EBV was the first virus that is found to encode microRNAs. EBV miRNAs could regulate both cellular and viral targets and thus contribute to immune evasion. Our preliminary study found that the expression of EBV-miR-BART4-5p was increased in EBVaGC stem cells; the target sequences of EBV-miR-BART4-5p were the mRNA 3’-UTRs (untranslated regions) of SOCS3, a key inhibitor of STAT3 signaling pathway; and EBV-miR-BART4-5p could down-regulate the activity of luciferase report gene of SOCS3. In this study, we tried to to investigate the influences of EBV-miR-BART4-5p on SOCS3 expression and STAT3 signaling pathway, to observe the impact of the EBV-miRNA on EBVaGC stem cells-mediated immunosuppression, and to explore the correlation between the EBV-miRNA expression and the clinicopathological features and prognosis of the EBVaGC patients. The major goal of this work was to investigate the contribution of EBV to the modulation of EBVaGC stem cells-mediated immunosuppression, and to provide some scientific basis for clinical treatment of EBVaGC in the future.

肿瘤干细胞的免疫抑制性与肿瘤进展和肿瘤免疫逃逸密切相关。课题组前期研究发现EBVaGC干细胞通过STAT3信号通路发挥免疫抑制性，但STAT3在EBVaGC干细胞中过表达的机理尚未阐明。EBV是首个被发现编码miRNA的病毒，EBV-miRs可对病毒和细胞基因表达调控，从而参与细胞免疫逃逸。本项目预实验发现：EBV-miR-BART4-5p在EBVaGC干细胞中高表达，且在STAT3信号通路的负性调控蛋白SOCS3 mRNA 3’-UTR存在靶序列，能下调SOCS3荧光素酶报告基因活性。本课题拟从基因表达调控，细胞实验，动物模型及人EBVaGC组织标本，探讨EBV-miR-BART4-5p对SOCS3及STAT3通路的影响；对EBVaGC干细胞免疫抑制性的影响；对人EBVaGC临床病理特征和预后的影响。旨在揭示EBV调控EBVaGC干细胞免疫抑制性的分子机制，为治疗EBVaGC奠定基础。