Role of Iron and B-Catenin Activation in Gastric Carcinogenesis

铁和 B-连环蛋白激活在胃癌发生中的作用

• 批准号: 9274160
• 负责人: RICHARD M. PEEK
• 金额: $ 28.23万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9274160
• 关键词: Address; Adherence; Cancer Etiology; Cells; Cessation of life; Collaborations; Core Facility; Data; Development; Dimensions; Disease Outcome; Environmental Risk Factor; Epithelial; Epithelial Cells; Event; Exhibits; Gastric Adenocarcinoma; Gerbils; Harvest; Helicobacter Infections; Helicobacter pylori; Histopathology; Homeostasis; Human; In Vitro; Inflammation; Inflammatory Response; Injury; Integration Host Factors; Iron; Journals; Knowledge; Laboratories; Link; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Neoplasms; Oncoproteins; Organ; Organoids; Pathogenesis; Pathogenicity; Patients; Persons; Population; Positioning Attribute; Pre-Clinical Model; Proteins; Proteomics; Publishing; Risk Factors; Rodent; Rodent Model; Role; Stem cells; Stomach; Structure; System; Testing; Type IV Secretion System Pathway; Virulence; base; beta catenin; cancer risk; carcinogenesis; carcinogenicity; clinical investigation; cytokine; deprivation; differential expression; high risk; iron deficiency; malignant stomach neoplasm; microbial; monolayer; mutant; novel; pathogen; response; tumorigenesis; two-dimensional

H. pylori is the strongest known risk factor for gastric adenocarcinoma, the second leading cause of cancer-related death worldwide, yet only a fraction of infected persons ever develop this malignancy. One H. pylori determinant that augments cancer risk is the cag type IV secretion system (T4SS), which translocates the microbial oncoprotein GagA into epithelial cells. Our preliminary data generated with Project 2 demonstrate that intracellular delivery of GagA activates B-catenin and that a consequence of Beta catenin activation within H. pylori-infected epithelial cells is hyperproliferation. Our studies have also demonstrated that iron depletion augments the ability of H. pylori to activate Beta-catenin. We have now shown with Gastric Histopathology Core A that iron depletion accelerates the development of H. pylori induced cancer in gerbils in a cagA-dependent manner. Two-dimensional (20) DIGE/mass spectrometry performed by Proteomics Core B identified 33 differentially abundant proteins among H. pylori strains isolated from iron-depleted versus iron-replete gerbils, several of which mediate microbial adherence and function of the cag T4SS. These results directly informed provocative new studies performed with Project 3 demonstrating that H. pylori strains harvested from iron-depleted gerbils or grown under iron-depleted conditions in vitro exhibit an enhanced capacity to assemble the cag T4SS, translocate GagA, and induce expression of proinflammatory cytokines. We have also developed new models of H. pylori infection that more closely recapitulate events occurring within the gastric niche. Gastric organoids are three dimensional, single-layered epithelial organ-like structures, and provide a unique opportunity to study host H. pylori interactions in a pre-clinical model. We have now successfully grown, maintained, characterized, and infected gastric organoids with H. pylori. Our hypothesis is that iron depletion augments H. pylori cag� dependent oncogenesis. We will test this via the following Aims: 1. Define mechanisms that regulate oncogenesis in response to iron deprivation and H. pylori. 2. Define H. pylori-induced carcinogenic responses using a novel ex vivo organoid system. 3. Define differences in epithelial molecular responses to carcinogenic H. pylori versus a cagA- mutant strain using a gerbil model of gastric cancer within the context of iron depletion.

H.幽门螺杆菌是胃腺癌的最强已知危险因素，胃腺癌是全世界癌症相关死亡的第二大原因，然而只有一小部分感染者发展成这种恶性肿瘤。一个H增加癌症风险的幽门螺杆菌决定因子是cag IV型分泌系统（T4 SS），其将微生物癌蛋白GagA易位到上皮细胞中。我们的项目2产生的初步数据表明，细胞内GagA的传递激活B-连环蛋白，并且在H.幽门感染的上皮细胞过度增殖。我们的研究还表明，铁缺乏增强了H。pylori以激活β-连环蛋白。我们现在已经用胃组织学核心A表明铁缺乏加速了H的发展。pylori以cagA依赖的方式诱导沙鼠的癌症。蛋白质组学核心B进行的二维（20）DIGE/质谱鉴定了H.幽门螺杆菌菌株分离自铁缺乏与铁充满沙鼠，其中几个介导微生物粘附和功能的cag T4 SS。这些结果直接通知挑衅性的新研究与项目3表明，H。从铁缺乏的沙鼠收获的或在铁缺乏的条件下体外生长的幽门螺杆菌菌株表现出增强的组装cag T4 SS、易位GagA和诱导促炎细胞因子表达的能力。我们还开发了H.幽门螺杆菌感染，更密切地重演发生在胃龛内的事件。胃类器官是三维的单层上皮样器官结构，为研究宿主H。幽门螺杆菌的相互作用在临床前模型。我们现在已经成功地培养，维持，表征和感染了H。幽门。我们的假设是铁的缺乏增加了H。pylori cag依赖性肿瘤发生。我们将通过以下目标进行测试： 1.定义响应铁剥夺和H调节肿瘤发生的机制。幽门。 2.定义H幽门诱导的致癌反应，使用一种新的离体类器官系统。 3.定义上皮细胞对致癌性H的分子反应的差异。幽门螺杆菌与cagA突变株使用沙土鼠胃癌模型的背景下，铁耗竭。