TFF1/GKN2在H.pylori感染相关贲门腺癌发生中的作用及机制

Recently, the incidence of adenocarcinoma of gastric cardia has significantly increased. Evidences have demonstrated that cardia adenocarcinoma has many different features, such as etiological factors, tumor characteristics and biological behaviors, from noncardia tumors. Accordingly, it might belong to a special subtype of gastric cancer. H. pylori, a well-established risk factor for noncardia gastric cancer, is viewed as a controversial risk factor for cardia cancer. Our previous studies have shown that H. pylori plays important roles in the development of cardia cancer, as well as noncardia cancer. TFFs and GKNs are generally regarded as protecting factors in gastric mucosal epithelium since they could enhance epithelial repair immediately. Thus, in this study, we will detect the expression of Hp infection, TFFs and GKNs in human gastric cardia and distal cancers samples, and explore their role in the development of gastric cardia cancer. The effect of Hp on cell proliferation and differentiation in TFF1/GKN2 siRNA transfected cell lines is also studied in vitro. Additionally, the availability of TFF1/GKN2 knocked out mice will be applied to study the effects of long-term Hp infection in gastric epithelial damage in the absence of TFF1/GKN2. We are specifically interested in ascertaining whether the lack of TFF1/GKN2 affects the progression of cardia and distal cancer in this model. The study will provide another insight of cardia cancer in high incidence area, which may contribute to the prevention and treatment of gastric cancer in the future.

近年来，胃癌的发生部位发生明显变化，贲门腺癌发生率明显增高。而且在肿瘤发生、生物学行为等方面不同于非贲门胃癌，为一种独特的胃癌病理学亚型。Hp感染在贲门腺癌发生中的作用存在很大争议，然而本课题组发现Hp感染在胃癌高发区贲门腺癌发生中发挥重要作用。TFFs、GKNs为胃黏膜上皮保护因子,促进修复。Hp感染可影响胃黏膜上皮细胞TFFs、GKNs的表达。本项目拟在前期工作基础上，从整体角度比较Hp感染、TFFs、GKNs在贲门腺癌与远端胃腺癌发病中的作用及相关性；体外研究TFF1/GKN2复合物失活后，Hp感染对胃黏膜上皮细胞增殖、分化的影响；并采用动物实验，明确TFF1/GKN2失活是否加重Hp感染对胃黏膜的损伤。从而系统地阐明TFF1/GKN2在Hp感染相关贲门腺癌发生中的作用及机制，对高发区居民胃癌的防治具有重要意义。

近年来，胃癌的发生部位发生明显变化，贲门腺癌发生率明显增高。而且在肿瘤发生、生物学行为等方面不同于非贲门胃癌，为一种独特的胃癌病理学亚型。Hp感染在贲门腺癌发生中的作用存在很大争议，然而本课题组发现Hp感染在胃癌高发区贲门腺癌发生中发挥重要作用。TFFs为胃黏膜上皮保护因子,促进修复。本项目在前期工作基础上，从整体角度比较Hp感染、TFFs、GKNs在贲门腺癌与远端胃腺癌发病中的作用及相关性。结果发现，（1）不同部位胃癌患者Hp感染情况无明显差异，而GCA患者VacA+菌株及CagA+/VacA+感染率要高于DGA，表明Hp感染是GCA和DGA发病的危险因素。（2）不同部位胃癌中EBV检出率无明显差异，EBV是胃癌发生的危险因素，但与发病部位无明显相关。（3）贲门腺癌与远端胃腺癌组织中p16-Rb、SP1、Pim-3等表达存在差异，提示不同部位胃腺癌细胞增殖和分化能力存在差异。（4）胃癌肿瘤组织中TFFs表达比对照组胃黏膜组织明显降低，而不同部位胃癌中表达无明显差异。幽门螺杆菌感染可导致TFF1表达降低，降低TFF对胃黏膜的保护作用。（5）Hp蛋白作用细胞，小剂量可刺激细胞增生，剂量逐渐增大，细胞增生将受到抑制。本研究系统地比较了幽门螺杆菌感染、TFFs及多个信号通路关键蛋白在胃癌高发区不同部位胃癌中的发病中的作用及机制，对高发区居民胃癌的防治具有重要意义。