肿瘤微环境中成纤维细胞高表达GORAB促进胃癌发展的分子机制研究

Epithelial mesenchymal transition (EMT) and inflammation in the tumor microenvironment influence the development and progression of gastric cancer . Therefore the study on the molecular mechanism is essential. In our preliminary studies, we showed that GORAB was highly expressed in gastric tumor stroma, and its expression level was closely associated with the fibroblast activation and inflammatory cytokine secretion, gastric cancer cell EMT and tumorgenesis. By simulating the fibroblasts dependent gastric cancer microenvironment, we will investigate the molecular mechanism of fibroblast activation and inflammatory cytokine secretion stimulated by GORAB combined with real-time quantitative PCR, dual-luciferase reporter assay, ELISA and other cellular and molecular biology techniques. Furthermore, using immunodeficient mice model by orthotopic transplantation or intravenous injection, we will study how GORAB promotes EMT and metastasis of gastric cancer cell. In addition, with antibody blockade technique. it will be determined whether the promotion of gastric cancer development and progression by GORAB is mediated through inflammatory factors secreted by fibroblasts. Eventually, the promotion of gastric cancer development and progression by GORAB in tumor microenvironment will be clarified systematically to provide a new theoretical and experimental basis for repression and intervention on the development, progression and metastasis of gastric cancer in clinical trial.

胃癌微环境中上皮间质转化（EMT）及炎症反应都影响着胃癌的发生发展，对其分子机制的研究和探索十分重要。基于本课题组前期研究工作所发现的GORAB高表达于胃癌肿瘤基质中，且其表达量与成纤维细胞活化、炎症因子分泌、胃癌细胞EMT以及成瘤能力密切相关，我们模拟建立成纤维细胞依赖的胃癌微环境模型，通过实时荧光定量、双荧光报告系统及ELISA等细胞分子生物学方法研究GORAB促进成纤维细胞活化及炎症因子分泌的分子机制，进一步结合免疫缺陷鼠原位移植和尾静脉注射实验研究GORAB促进胃癌细胞EMT及胃癌发展转移的分子机制，通过抗体封闭阻断的方法，研究GORAB对胃癌发生发展的促进是否由成纤维细胞所分泌的炎症因子所介导，系统地阐释GORAB在胃癌微环境中促进胃癌发生发展的肿瘤分子学机制；为临床阻遏和干预胃癌发生发展以及转移提供新的理论与实验依据。

炎症肿瘤微环境和表观调控机制影响着胃癌的发生发展，对其分子机制的研究和探索十分重要。基于本课题组前期研究工作所发现的重要候选基因和micrRNAs其表达量与成纤维细胞活化、炎症因子分泌、胃癌细胞EMT以及成瘤能力密切相关，我们模拟建立成纤维细胞依赖的胃癌微环境模型，通过实时荧光定量、双荧光报告系统及ELISA等细胞分子生物学方法研究促进成纤维细胞活化及炎症因子分泌的分子机制，进一步结合免疫缺陷鼠原位移植和尾静脉注射实验研究候选基因和microRNAs促进胃癌细胞EMT及胃癌发展转移的分子机制，研究其对胃癌发生发展的促进是否由成纤维细胞所分泌的炎症因子所介导，系统地阐释胃癌发生发展的肿瘤分子学机制；为临床阻遏和干预胃癌发生发展以及转移提供新的理论与实验依据。