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: 9248619
• 负责人: RICHARD M. PEEK
• 金额: $ 20.26万
• 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/9248619
• 关键词: Address; Adherence; Cancer Etiology; Cells; Cessation of life; Collaborations; Core Facility; Data; Development; 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; Oncogenes; Organ; Organoids; Pathogenesis; Patients; Persons; Population; Positioning Attribute; Pre-Clinical Model; Proteins; Proteomics; Publishing; Pylorus; Risk Factors; Rodent; Rodent Model; Role; Stem cells; Stomach; Structure; System; Testing; Type IV Secretion System Pathway; Virulence; base; beta catenin; cancer risk; carcinogenesis; 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.

幽门螺杆菌是已知的最强的胃腺癌危险因素，胃腺癌是全球癌症相关死亡的第二大原因，但只有一小部分感染者会患上这种恶性肿瘤。 幽门螺杆菌增加癌症风险的一个决定因素是 cag IV 型。我们通过项目 2 生成的初步数据表明，GagA 的细胞内递送可激活 B-连环蛋白。我们的研究还表明，幽门螺杆菌感染的上皮细胞内β连环蛋白激活的结果是过度增殖，我们现在用胃组织病理学核心A证明了这一点。铁耗竭以 cagA 依赖性方式加速沙鼠中幽门螺杆菌诱导的癌症的发展。 二维 (20) DIGE/质量。 Proteomics Core B 进行的光谱分析确定了从缺铁沙鼠和富铁沙鼠中分离出的幽门螺杆菌菌株中存在 33 种差异丰富的蛋白质，其中一些蛋白质介导 cag T4SS 的微生物粘附和功能。这些结果直接为 Project 进行的挑衅性新研究提供了信息。图3证明从贫铁沙鼠收获的幽门螺杆菌菌株或在体外贫铁条件下生长的幽门螺杆菌菌株表现出增强的组装cag的能力T4SS，易位 GagA，并诱导促炎细胞因子的表达。我们还开发了幽门螺杆菌感染的新模型，更准确地概括了胃微环境中发生的事件。胃类器官是三维、单层上皮器官样结构，并且为在临床前模型中研究宿主幽门螺杆菌相互作用提供了独特的机会，我们现在已经成功地用幽门螺杆菌培养、维持、表征和感染胃类器官。假设铁耗竭会增加幽门螺杆菌依赖性肿瘤发生，我们将通过以下目标进行测试： 1. 定义响应缺铁和幽门螺杆菌而调节肿瘤发生的机制。 2. 使用新型离体类器官系统定义幽门螺杆菌诱导的致癌反应。 3. 使用铁耗竭背景下的胃癌沙鼠模型，确定上皮分子对致癌性幽门螺杆菌与 cagA 突变株的反应差异。