Mechanisms that Regulate Helicobacter pylori-Induced beta-catenin Activation

调节幽门螺杆菌诱导的 β-连环蛋白激活的机制

• 批准号: 8413057
• 负责人: RICHARD M. PEEK
• 金额: $ 23.13万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413057
• 关键词: Adherence; Binding; Biological; Cancer Etiology; Cessation of life; Development; Epithelial; Epithelial Cells; Epithelium; Event; Gastric Adenocarcinoma; Gastric Adenoma; Gastric Intraepithelial Neoplasia; Genes; Gerbils; Harvest; Helicobacter pylori; Histologic; In Vitro; Inflammation; Injury; Integration Host Factors; Malignant Neoplasms; Mediating; Microbe; Modeling; Molecular; Mucositis; Mus; Nuclear; Nuclear Translocation; Pathogenicity; Pathogenicity Island; Pathway interactions; Persons; Phenotype; Phosphorylation; Protein Export Pathway; Reporter; Risk; Risk Factors; Rodent; Signal Pathway; Signal Transduction; Specimen; Staging; Stomach; System; Transcriptional Activation; Transgenic Organisms; beta catenin; cancer risk; carcinogenesis; high risk; in vivo; malignant stomach neoplasm; mutant; prototype; receptor; response

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.

胃腺癌是世界上第二大癌症相关死亡原因。H.幽门螺杆菌是 这种恶性肿瘤的最强已知危险因素，但只有一小部分感染者会发展成癌症。 一个H pylori决定因素是cag致病岛，几个cag基因 编码IV型细菌分泌系统的组分，其功能是输出蛋白质（例如，CagA） nto host宿主epithelial上皮cell细胞.可能影响癌发生的宿主效应物是li-catenin，其下游是li-catenin。 Wnt途径的组成部分。当Wnt信号传导失活时，β-连环蛋白被组成性磷酸化， Wnt与其受体的结合抑制了G-连环蛋白磷酸化，导致其核 积累和影响致癌作用的基因的转录激活。核 在胃腺瘤和异型增生标本中， 胃腺癌前病变。我们的初步研究现在表明，啮齿动物适应H。幽门 Ag+菌株（7.13）在高胃泌素血症（INS-GAS）小鼠中迅速诱导胃癌24周， Vlongolian沙鼠4周，菌株7.13诱导G-连环蛋白核转位并激活 一个B-连环蛋白反应的报告在体外，表明li-catenin是功能上响应于这个原型 株IS-连环蛋白被H.幽门螺杆菌依赖于CagA易位到上皮细胞中， 在从cag+感染者获得的胃上皮中U-连环蛋白的核积累增加， 与携带CAG菌株的受试者或未感染的人相比。我们假设H.幽门螺杆菌cag* 菌株选择性地激活宿主信号传导途径，例如由R-连环蛋白介导的那些，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.确定H.幽门螺杆菌成分对S-连环蛋白激活的影响。 2.目的：研究真核生物中H. Py/或/-诱导的β-连环蛋白活化。 3.明确上皮细胞对致癌性H.幽门螺杆菌与突变株 使用胃癌的转基因小鼠模型。