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.

幽门螺杆菌是胃腺癌的已知危险因素，这是全球与癌症相关死亡的第二大原因，但只有一小部分受感染者发展出这种恶性肿瘤。幽门螺杆菌确定增加癌症风险是CAG IV型分泌系统（T4SS），它将微生物癌蛋白GAGA转移到上皮细胞中。我们使用项目2生成的初步数据表明，GAGA的细胞内递送激活B-catenin，并且在幽门螺杆菌感染的上皮细胞内激活β链球菌激活的结果是高增殖。我们的研究还表明，铁部署增强了幽门螺杆菌激活β-catenin的能力。现在，我们已经使用胃组织病理学核心A展示了铁的部署以CAGA依赖性方式加速了幽门螺杆菌在沙犬中诱导的癌症的发展。由蛋白质组学核心B进行的二维（20）挖掘/质谱法鉴定了33种从铁耗尽的幽门螺杆菌菌株中的33种不同丰富的蛋白质，这些蛋白质是从铁耗尽的与铁重复的晶状体中分离出来的，其中几种CAG T4SS的介质微生物粘附和功能。这些结果直接通过项目3进行的新型新研究，表明幽门螺杆菌菌株是从铁耗尽的沙犬菌收获或在铁耗尽条件下在体外生长的，具有增强的能力，可以组装CAG T4SS，转化型GAGA，并影响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，这些模型更紧密地概括了胃位内发生的事件。胃癌是三个维度，单层上皮器官样结构，并提供了一个独特的机会，可以在临床前模型中研究宿主幽门螺杆菌相互作用。现在，我们已经成功地使用了幽门螺杆菌种植，维护，表征和感染的胃癌。我们的假设是铁依赖幽门螺杆菌cag依赖性肿瘤发生。我们将通过以下目标进行测试： 1。定义对铁剥夺和幽门螺杆菌的响应调节肿瘤发生的机制。 2。使用新型的离体器官系统定义幽门螺杆菌诱导的致癌反应。 3。使用胃癌的胃癌模型来定义对幽门螺杆菌与幽门螺杆菌的差异的差异。