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 总结 全球一半人口感染幽门螺杆菌，这是已知最强的胃癌危险因素， 这是全球癌症死亡的第三大原因。感染者的持续移民。 确保幽门螺杆菌感染仍将是美国的主要疾病负担。抗生素并不统一 根除感染，对幽门螺杆菌诱发的癌症发展仅产生有限的影响。 项目 2 将阐明胃炎症的新机制。 和下游致癌作用，并将在奖励期间将这些结果转化为人类。 与其他项目和核心合作，解决宿主免疫反应无法消除的原因 主要发现包括：1）表皮生长因子。 慢性胃炎期间胃上皮细胞 (GEC) 中发生受体 (EGFR) 激活（磷酸化） 和肠化生，而胃巨噬细胞中的pEGFR从胃炎升高到终点 癌症；2) EGFR 信号调节巨噬细胞激活模式：我们用骨髓- Egfr 的特异性删除显示 M1 巨噬细胞反应、MyD88、MAPK1/3 和 NF-κB 激活、趋化因子表达以及 Th1 和 Th17 反应，但增强 Treg 反应 3) EGFR 抑制剂吉非替尼可降低幽门螺杆菌感染的 INS-GAS 小鼠或沙鼠的胃癌发生率 4) 抑制； 鸟氨酸脱羧酶 (ODC) 是多胺合成的限速酶，可阻止胃癌 沙鼠和我们产生的骨髓特异性删除 Odc 的小鼠的 M1 巨噬细胞增加 对幽门螺杆菌的反应和定植减少；这是由于消除了幽门螺杆菌的免疫抑制作用 多胺腐胺，通过组蛋白修饰阻断转录 5) hypusine 的形成； 幽门螺杆菌上调脱氧亚精胺合成酶 (DHPS) 产生的多胺亚精胺，并导致 编码巨噬细胞中促炎蛋白的 mRNA 的靶向翻译，构成 我们称之为“Hypusome”；6) EGFR 信号传导与幽门螺杆菌感染期间的 ODC 水平相关， 这些见解揭示了巨噬细胞以前未知的作用。 我们的假设是 EGFR、ODC 和 hypusination 形成一个相互关联的轴。 胃巨噬细胞导致幽门螺杆菌诱导的免疫失调、炎症和胃病 我们将从该 PPG 的紧密整合中受益，以实现我们的目标，即确定目标。 以下因素在幽门螺杆菌诱导的炎症相关胃癌发生中的作用：1) EGFR 激活和下游信号传导；2) ODC；3) Hypusination/DHPS。 小鼠和沙鼠癌症模型中的特定基因删除和抑制剂，并在人体组织中进行验证，以及 蛋白质组学/磷酸化蛋白质组学、代谢组学和类器官模型的创新应用我们将突破新的。 巨噬细胞在胃癌发生中的作用，从而产生新的化学预防方法。