长链非编码RNA通过JAK2调控环境因素诱导胃上皮细胞恶性转化的作用机制

环境-基因交互作用驱动胃癌发生。长期暴露N-亚硝基化合物（NOC）和感染幽门螺杆菌（Hp）被认为是诱发胃癌发生最主要的两大环境危害因素，但其作用机制仍不明确。长链非编码RNA（lncRNA）在多种疾病包括胃癌发生中发挥重要作用，但其在NOC和Hp诱导胃上皮细胞恶性转化过程中的作用机制研究报道甚少。课题组已建立了N-甲基亚硝基脲（MNU）诱导胃GES-1细胞恶性转化模型，并通过lncRNA芯片筛选结合RNA沉淀技术发现lncRNA-Lnc-GT通过结合激酶JAK2调节MNU诱导的细胞损伤和Hp介导的炎症反应。在此基础上，本项目拟通过细胞，类组织和动物模型结合人群研究，利用分子细胞生物学相关技术和分子流行病学相关方法进一步探讨Lnc-GT-JAK2信号通路在MNU和Hp单独和联合暴露诱导胃上皮细胞恶性转化的作用机制，为环境致癌物诱导胃癌发生的早期监测和有效干预提供理论依据。

Environment-gene interaction drives gastric carcinogenesis. Long-time exposure of N-nitroso compound (NOC) and infection of Helicobacter pylori (Hp) are two main environmental risk factor in gastric tumorigenesis, but the molecular mechanism is needed to be further investigated. The evidences have shown that long non-coding RNA (lncRNA) plays key role in some diseases including gastric cancer, but its function in NOC and Hp induced gastric malignant transformation is still not clear. We have constructed malignant transformation of GES-1 cell model induced by N-methyl-N-nitrosourea (MNU). Then lncRNA array and RNA pulldown methods were used, we found LncRNA-Lnc-GT could bind tyrosine kinase JAK2, which modulates MNU-induced cellular damage and Hp-mediated inflammation. Based on these, we will use cellular, gastric organoid, animal models and cohort study with molecular and cellular biological skills and epidemiology methods to identify the mechanisms of Lnc-GT-JAK2 signaling in regulating MNU and Hp induced gastric malignant transformation. These efforts may facilitate elucidation of biological mechanisms and to provide new strategies for early screening and intervention for gastric cancer.