Project 2: EGFR, ODC, and the Hypusome in H. pylori-induced Gastric Cancer

项目2：幽门螺杆菌诱导的胃癌中的EGFR、ODC和Hypusome

• 批准号: 10581609
• 负责人: Keith T. Wilson
• 金额: $ 31.38万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10581609
• 关键词: Address; Amino Acids; Animal Model; Antibiotics; Award; Bacteria; Biological Models; Cancer Etiology; Cancer Model; Carcinoma; Cell model; Cells; Cessation of life; Chemopreventive Agent; Chronic; Chronic Gastritis; Clinical; Collaborations; Data; Development; Disease Progression; Dysplasia; Ensure; Enzymes; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epithelial Cells; Epithelium; Equilibrium; Exhibits; Gases; Gastric Adenocarcinoma; Gastritis; Gefitinib; Gene Deletion; Genetic Transcription; Gerbils; Goals; Helicobacter Infections; Helicobacter Pylori-Related Malignant Neoplasm; Helicobacter pylori; Helicobacter pylori induced gastric cancer; Human; Immigration; Immune; Immune response; Immunosuppression; Infection; Inflammation; Inflammatory; Intervention; Intestinal Metaplasia; Link; MAPK1 gene; Macrophage; Macrophage Activation; Malignant Neoplasms; Modeling; Molecular; Mus; Myelogenous; Organoids; Ornithine Decarboxylase; Pathway interactions; Pattern; Persons; Phosphorylation; Polyamines; Population; Prevention approach; Prevention strategy; Program Research Project Grants; Proteins; Proteomics; Putrescine; Receptor Activation; Receptor Signaling; Regulatory T-Lymphocyte; Research; Risk Factors; Role; Signal Transduction; Spermidine; Stomach; Stomach Carcinoma; System; Tissue Sample; Translating; Validation; Work; attenuation; burden of illness; cancer risk; carcinogenesis; chemokine; deoxyhypusine synthase; design; gastric carcinogenesis; histone modification; human tissue; hypusine; inhibitor; innovation; insight; mRNA Translation; malignant stomach neoplasm; metabolomics; novel; novel chemoprevention; pathogen; phosphoproteomics; programs; response; risk stratification

PROJECT 2 SUMMARY Half of the global population harbors H. pylori infection, the strongest known risk factor for gastric cancer, which is the third leading cause of cancer deaths worldwide. Continued immigration of infected persons ensures that H. pylori infection will remain a major disease burden in the U.S. Antibiotics do not uniformly eradicate the infection, and exert only a modest effect on cancer risk. H. pylori-induced cancer development is driven by chronic active gastritis. Project 2 will elucidate novel mechanisms underlying gastric inflammation and downstream carcinogenesis, and will translate these results to humans. During the award period we collaborated with the other Projects and the Cores to address why the host immune response fails to eliminate the pathogen, and, instead, causes gastritis and cancer. Key discoveries included: 1) Epidermal growth factor receptor (EGFR) activation (phosphorylation) occurs in gastric epithelial cells (GECs) during chronic gastritis and intestinal metaplasia, while pEGFR in gastric macrophages is elevated from gastritis to the endpoint of cancer; 2) EGFR signaling regulates macrophage activation patterns: mice that we generated with myeloid- specific deletion of Egfr exhibited marked attenuation of M1 macrophage responses, MyD88, MAPK1/3, and NF-κB activation, chemokine expression, and Th1 and Th17 responses, but enhanced Treg response; 3) The EGFR inhibitor, gefitinib, reduces gastric cancer in H. pylori-infected INS-GAS mice or gerbils; 4) Inhibition of ornithine decarboxylase (ODC), the rate-limiting enzyme for polyamine synthesis, blocks gastric cancer in gerbils, and mice we generated with myeloid-specific deletion of Odc had increased M1 macrophage responses to H. pylori and reduced colonization; this was due to elimination of immunosuppressive effects of the polyamine putrescine, which blocks transcription through histone modifications; 5) Formation of hypusine from the polyamine spermidine by deoxyhypusine synthase (DHPS) is upregulated by H. pylori and leads to targeted translation of mRNAs encoding for pro-inflammatory proteins specifically in macrophages, constituting what we have termed “The Hypusome”; 6) EGFR signaling is linked to ODC levels during H. pylori infection, providing substrate for hypusination. These insights reveal previously unknown effects of macrophages in gastric carcinogenesis. Our hypothesis is that EGFR, ODC, and hypusination form an inter-related axis in gastric macrophages that leads to H. pylori-induced immune dysregulation, inflammation, and gastric carcinoma. We will benefit from the tight integration in this PPG to address our Aims, which are to determine the role of the following in H. pylori-induced inflammation-associated gastric carcinogenesis: 1) EGFR activation and downstream signaling; 2) ODC; 3) Hypusination/DHPS. This will be accomplished with cell- specific gene deletion and inhibitors in mouse and gerbil cancer models with validation in human tissues, and innovative use of proteomics/phosphoproteomics, metabolomics, and organoid models. We will break new ground regarding macrophages in gastric carcinogenesis, leading to novel chemoprevention approaches.

项目2概要 全球一半的人口携带H。幽门螺杆菌感染是胃癌最强的已知危险因素， 这是全球癌症死亡的第三大原因。感染者继续入境 确保H.幽门螺杆菌感染仍将是美国的主要疾病负担。 根除感染，对癌症风险只有适度的影响。H.幽门诱发的癌症发展是 由慢性活动性胃炎引起项目2将阐明胃炎症的新机制 和下游致癌作用，并将这些结果转化为人类。在颁奖期间，我们 与其他项目和核心合作，以解决为什么宿主免疫反应不能消除 病原体，而不是，导致胃炎和癌症。主要发现包括：1）表皮生长因子 在慢性胃炎期间，胃上皮细胞（GECs）中发生EGFR受体（EGFR）活化（磷酸化 和肠上皮化生，而胃巨噬细胞中的pEGFR从胃炎到肠上皮化生的终点升高， 癌症; 2）EGFR信号调节巨噬细胞活化模式：我们用骨髓- Egfr的特异性缺失表现出M1巨噬细胞应答、MyD 88、MAPK 1/3和 NF-κB活化、趋化因子表达以及Th 1和Th 17应答，但增强Treg应答; EGFR抑制剂吉非替尼可降低H.幽门螺杆菌感染的INS-GAS小鼠或沙鼠; 4）抑制 鸟氨酸脱羧酶（ODC）是多胺合成的限速酶，可阻断胃癌的发生。 沙鼠和我们产生的骨髓特异性缺失Odc的小鼠的M1巨噬细胞 回应H。幽门螺杆菌和减少定植;这是由于消除免疫抑制作用， 多胺腐胺，其通过组蛋白修饰阻断转录; 5）羟腐胺赖氨酸的形成 通过脱氧羟腐胺赖氨酸合酶（DHPS）从多胺亚精胺中的转化被H.幽门螺杆菌，并导致 在巨噬细胞中特异性地靶向翻译编码促炎蛋白的mRNA， 我们称之为“Hypusome”; 6）EGFR信号传导与H.幽门感染， 为羟腐胺赖氨酸化提供底物。这些见解揭示了巨噬细胞在细胞内以前未知的作用。 胃癌发生我们的假设是EGFR、ODC和羟腐胺酸形成了一个相互关联的轴， 导致H.幽门螺杆菌诱导的免疫失调、炎症和胃肠道 carcinoma.我们将受益于本PPG的紧密整合，以实现我们的目标，即确定 在H.幽门诱导的炎症相关胃癌发生：1）EGFR 激活和下游信号传导; 2）ODC; 3）Hypusination/DHPS。这将通过细胞- 小鼠和沙鼠癌症模型中的特异性基因缺失和抑制剂，并在人体组织中进行验证，以及 蛋白质组学/磷酸蛋白质组学、代谢组学和类器官模型的创新应用。我们将打破新的 关于胃癌发生中的巨噬细胞，导致新的化学预防方法。