Mechanisms that Regulate Helicobacter pylori-Induced beta-catenin Activation

胃腺癌是世界上第二大癌症相关死亡原因。幽门螺杆菌是 这种恶性肿瘤的最大已知风险因素，然而只有一小部分感染者曾患上癌症。 一个增加癌症风险的幽门螺杆菌决定因素是CAG致病性岛和几个CAG基因 编码IV型细菌分泌系统的组成部分，该系统具有输出蛋白质的功能(例如，CagA) 不能寄生上皮细胞。一个可能影响癌症发生的宿主效应因子是下游的Li-catenin。 Wnt途径的组成部分。当Wnt信号不活跃时，(L-连环蛋白被结构性磷酸化 和降解；Wnt与其受体结合抑制G-catenin磷酸化，导致其核 影响癌症发生的基因的积累和转录激活。核子 FI-Catenin在胃腺瘤和不典型增生标本中积聚增加，组织学分期 先于胃腺癌。我们的初步研究表明，一种适应啮齿动物的幽门螺杆菌 Ag株(7.13)能在24周内快速诱导高胃泌素血症(INS-GAS)小鼠发生胃癌。 Vlong olian沙土鼠出生4周，该菌株7.13诱导G-连环蛋白的核转位并激活 一个B-连环蛋白反应的体外报告，表明Li-连环蛋白对这个原型有功能反应 紧张。幽门螺杆菌对IS-catenin的激活依赖于CagA转位到上皮细胞中，并且 从CAG感染者采集的胃上皮中U-连环蛋白的核积聚增加， 与携带CAG菌株的受试者或未感染的人相比。我们的假设是幽门螺杆菌CAG* 菌株选择性地激活宿主信号通路，例如由R-连环蛋白介导的信号通路，从而 调节细胞反应，有助于增加与这些相关的致癌风险 菌株。因此，我们的具体目标是： 1.明确幽门螺杆菌活性成分在体内外对S-连环蛋白激活的影响。 2.确定调控H.py/和/或H.py诱导FI-catenin活化的真核信号通路。 3.确定上皮细胞对致癌幽门螺杆菌和突变菌株的分子反应的差异 使用转基因小鼠的胃癌模型。

Gastric adenocarcinoma is the second leading cause of cancer-related death in the world. H. pylori is the strongest known risk factor for this malignancy, yet only a fraction of infected persons ever develop cancer. One H. pylori determinant that augments cancer risk is the cag pathogenicity island, and several cag genes encode components of a type IV bacterial secretion system which functions to export proteins (e.g., CagA) nto host epithelial cells. A host effector that may influence carcinogenesis is li-catenin, a downstream component of the Wnt pathway. When Wnt signaling is inactive, (l-catenin is constitutively phosphorylated and degraded; binding of Wnt to its receptor inhibits G-catenin phosphorylation, leading to its nuclear accumulation and the transcriptional activation of genes that influence carcinogenesis. Nuclear accumulation of fi-catenin is increased in gastric adenoma and dysplasia specimens, histologic stages that precede gastric adenocarcinoma. Our preliminary studies now demonstrate that a rodent-adapted H. pylori ¿ag+ strain (7.13) rapidly induces gastric cancer in hypergastrinemic (INS-GAS) mice by 24 weeks and in Vlongolian gerbils by 4 weeks and that strain 7.13 induces nuclear translocation of G-catenin and activates a B-catenin-responsive reporter in vitro, indicating that li-catenin is functionally responsive to this prototype strain. IS-catenin activation by H. pylori is dependent upon translocation of CagA into epithelial cells, and nuclear accumulation of U-catenin is increased in gastric epithelium harvested from cag+-infected persons, compared to subjects carrying cag strains or uninfected persons. Our hypothesis is that H. pylori cag* strains selectively activate host signaling pathways, such as those mediated by R-catenin, thereby regulating cellular responses that contribute to the augmentation in carcinogenic risk associated with these strains. Thus, our specific aims are: 1. To define the effects of H. pylori constituents on activation of S-catenin in vitro and in vivo. 2. To determine the eukaryotic signaling pathways that regulate H. py/or/-induced fi-catenin activation. 3. To define differences in epithelial molecular responses to carcinogenic H. pylori versus mutant strains using a transgenic murine model of gastric cancer.