Loc101928316介导Wnt通路在致癌物MNNG诱发胃癌中的作用机制研究

Gastric cancer appears high incidence and a crowd gathered characteristic in Wuwei, Gansu province, meanwhile, its pathogenesis remains unclear. LncRNA generally participate in cancer development induced by environmental carcinogen through gene expression regulation. Our previous study has found that lncRNA Loc101928316, which were decreased expression in gastric cancer and specificity related with nitrite high exposure in Wuwei. Expand tissue samples study found that Loc101928316 has obviously changed in degree of differentiation in gastric cancer. Bioinformatics analysis results also suggest that Loc101928316 may regulation the Wnt pathway through target its key genes, and affects the nitrite induced to gastric cancer progression, but the mechanism remains to be further clarified. In this study, we construct the Loc101928316 regulation network of Wnt signaling pathway by cell experiments, and also combine the animal model experiments to clarify the Loc101928316 roles of regulate Wnt signaling pathway in the development of MNNG induced gastric cancer. Finally, we use population-based study in different nitrite exposure conditions to further investigate the Loc101928316 and Wnt related molecules as biomarkers for gastric cancer in Wuwei. The results will supply the evidence for further revealing the molecular mechanisms and provide a basis for prevention and treatment of nitrite induced gastric cancer in a high-risk area.

甘肃省武威地区胃癌发病呈现区域性高发和人群聚集性，但其病因和发病机制尚未阐明。lncRNA可通过调节基因表达参与环境致癌物所致肿瘤的发生，我们前期研究发现Loc101928316在武威地区亚硝酸盐高暴露胃癌患者癌组织中呈现特异性下调，且与胃癌的分化程度显著相关。生物信息学分析结果提示Loc101928316可能靶向Wnt通路关键基因的调节，影响亚硝酸盐致胃癌的发生，但作用机制有待深入研究。本项目应用细胞模型，构建Loc101928316对Wnt通路的调控网络，结合动物模型，阐明Loc101928316调控Wnt通路在甲基硝基亚硝基胍（MNNG）诱导大鼠胃癌进程中的作用，最后通过武威地区不同亚硝酸盐暴露条件下胃癌人群研究，验证Loc101928316及Wnt通路相关分子作为生物标志的可能。研究将为进一步揭示胃癌高发地区亚硝酸盐引发胃癌分子机制及其防治提供科学依据。

胃癌发病呈现区域性高发和人群聚集性，其病因和发病机制需深入探讨。lncRNA可通过调节基因表达参与环境致癌物所致肿瘤的发生，我们前期通过高通量筛选结合数据库比对分析，发现Loc101928316在亚硝酸盐高暴露胃癌患者癌组织中呈现特异性下调，且与胃癌的分化程度显著相关。生物信息学分析结果提示Loc101928316可能靶向Wnt通路关键基因的调节，影响亚硝酸盐致胃癌的发生，但作用机制有待深入阐明。本研究应用细胞模型，构建Loc101928316对Wnt通路的调控网络，结合动物模型，初步阐明Loc101928316调控Wnt通路在MNNG诱导大鼠胃癌进程中的作用，最后通过不同亚硝酸盐暴露条件下早期胃癌人群研究，验证Loc101928316及Wnt通路相关分子作为生物标志的可能。研究将为进一步揭示亚硝酸盐引发胃癌分子机制及其防治提供依据。本研究成功构建MNNG亚慢性暴露大鼠模型；MNNG亚慢性暴露可引起大鼠生胃粘膜炎症反应和胃上皮细胞凋亡，为MNNG亚慢性暴露对大鼠胃炎性损伤的调控机制研究提供基础。MNNG暴露可引起Loc101928316（LINC02859）基因表达水平明显降低，进而诱导正常胃上皮细胞发生恶性转化，为胃癌的早期诊断生物标志物和治疗靶点提供了新的线索。MNNG可通过激活Wnt/β-catenin信号通路促进胃癌的发生发展，在此过程中Loc101928316（LINC02859）可起到负向调节作用。通过Loc101928316（LINC02859）-过表达可显著抑制胃癌SGC-7901细胞的增殖、降低细胞迁移、侵袭、抑制裸鼠皮下成瘤进程；结果提示Loc101928316（LINC02859）发挥类似抑癌基因的功能并可能在胃癌进程中发挥重要调控功能。Loc101928316对于胃癌高发地区胃癌的筛查、诊断及治疗具有一定的潜在价值。