Regulation of the Oncogenic Stress Response in Helicobacter pylori-infected cells

幽门螺杆菌感染细胞致癌应激反应的调节

• 批准号: 10192671
• 负责人: ALEXANDER I. ZAIKA
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-31 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192671
• 关键词: Affect; Animal Model; Animals; Apoptosis; Bacteria; Biogenesis; Biological; Bypass; CDKN2A gene; Cancer Etiology; Cell Cycle Arrest; Cells; Cessation of life; Chronic; Clinical; Colombia; Data; Development; Disease; Epithelial; Gastric Adenocarcinoma; Gastric Tissue; Gastric mucosa; Gene Expression; Geographic Locations; Gerbils; Helicobacter Infections; Helicobacter pylori; Human; Individual; Infection; Inflammatory Response; Innate Immune Response; Laboratories; Lead; Lesion; Link; Malignant Neoplasms; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Neoplasms; Oncogenic; Operative Surgical Procedures; Pathway interactions; Patients; Population; Prevention; Proteins; Regulation; Reporting; Research; Research Personnel; Ribosomes; Risk; Risk Factors; Role; Signal Transduction; South America; Specimen; Stimulus; Stomach; Stomach Neoplasms; Stress; TP53 gene; Testing; Tumor Suppression; Tumor Suppressor Proteins; Variant; Virulence Factors; base; beta catenin; biological adaptation to stress; cancer risk; clinical translation; clinically relevant; gastric carcinogenesis; gastric organoids; gastric tumorigenesis; in vivo; infection rate; innovation; insight; interest; malignant stomach neoplasm; mortality; novel; novel diagnostics; novel therapeutic intervention; novel therapeutics; p14ARF Protein; pathogenic bacteria; patient screening; premalignant; preneoplastic cell; prevent; public health relevance; response; tumor; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Gastric adenocarcinoma (GC) remains one of the most common forms of cancer and one of the leading causes of cancer-related death worldwide. Approximately six hundred thousand new cases of gastric cancer/year are attributable to Helicobacter pylori infection worldwide, making this bacterial pathogen the strongest known risk factor for gastric malignancy. However, only a percentage of infected individuals develop neoplasia, underscoring the importance of defining mechanisms that regulate tumorigenic interactions between bacteria and infected people. We have developed an innovative hypothesis that establishes a molecular link between the tumorigenic potential of H. pylori and inactivation of the Oncogenic Stress Response pathway (OSR), a major tumor suppressor mechanism that prevents tumorigenic transformation of gastric cells. This hypothesis is supported by strong preliminary data generated by studies of human individuals and animals infected with H. pylori. Our research revealed that suppression of the OSR by H. pylori is strongly linked to gastric carcinogenesis and that tumorigenic H. pylori strains are able to inhibit surveillance by the OSR. We will build on these findings to further investigate the OSR inhibition by H. pylori as a critical factor contributing to development of gastric adenocarcinoma. In aim 1, we will define the molecular underpinning of H. pylori signaling toward inhibition of the OSR. In aim 2, using the animal models and gastric organoids, we will investigate regulation of the OSR in the gastric niche in vivo. In aim 3, we will characterize how natural variability of bacterial virulence factors affects the OSR. We will also test human clinical specimens and H. pylori clinical isolates collected in geographical areas with high and low gastric cancer risk. Taken together, the proposed studies will provide novel insights into tumorigenesis associated with H. pylori infection, investigating the OSR regulation in condition of H. pylori infection. Thi will help to reveal the potential risk factors for gastric tumor development and lay the groundwork for translation of these clinically relevant data into novel therapeutic applications in H. pylori - infected patients.

描述（由申请人提供）：胃腺癌（GC）仍然是最常见的癌症形式之一，也是全球癌症相关死亡的主要原因之一。全世界每年约有60万新发胃癌病例可归因于幽门螺杆菌感染，使这种细菌病原体成为胃恶性肿瘤的最强已知风险因素。然而，只有一部分受感染的个体会发生肿瘤，这强调了定义调节细菌和受感染者之间的致瘤相互作用的机制的重要性。 我们提出了一个新的假说，建立了H.幽门螺杆菌和致癌应激反应途径（OSR）的失活，这是一种主要的肿瘤抑制机制，可防止胃细胞的致瘤性转化。这一假设得到了对感染H.幽门。我们的研究表明H. pylori与胃癌的发生密切相关，幽门螺杆菌菌株能够 阻止OSR的监视 我们将在这些发现的基础上进一步研究OSR 抑制作用。pylori是胃腺癌发生发展的关键因素。 在目标1中，我们将定义H的分子基础。pylori信号传导抑制 OSR。目的二，利用动物模型和胃类器官，研究OSR在体内胃小生境中的调控。在目标3中，我们将描述细菌毒力因子的自然变异性如何影响OSR。我们还将测试人类临床标本和H。幽门螺杆菌临床分离株收集的地理区域与高和低胃癌风险。 总之，拟议的研究将提供新的见解与H。pylori感染，探讨H.幽门感染这将有助于揭示胃肿瘤发展的潜在危险因素，并为将这些临床相关数据转化为H.幽门螺杆菌感染的病人。

项目成果

Glutathione peroxidase 7 protects against oxidative DNA damage in oesophageal cells.

• DOI: 10.1136/gutjnl-2011-301078
• 发表时间: 2012-09
• 期刊: Gut
• 影响因子: 24.5
• 作者: Peng D;Belkhiri A;Hu T;Chaturvedi R;Asim M;Wilson KT;Zaika A;El-Rifai W
• 通讯作者: El-Rifai W

Regulation of the p53 tumor suppressor by gastric pathogen Helicobacter pylori pathogen.

胃病原体幽门螺杆菌病原体对 p53 肿瘤抑制因子的调节。

• DOI: 10.18632/oncotarget.698
• 发表时间: 2012
• 期刊: Oncotarget
• 作者: Zaika,Alexander;Wei,Jinxiong;Noto,Jennifer;PeekJr,Richard
• 通讯作者: PeekJr,Richard

p53 Family: Role of Protein Isoforms in Human Cancer.

• DOI: 10.1155/2012/687359
• 发表时间: 2012
• 期刊: Journal of nucleic acids
• 影响因子: 2.3
• 作者: Wei J;Zaika E;Zaika A
• 通讯作者: Zaika A

Interactions of the p53 protein family in cellular stress response in gastrointestinal tumors.

• DOI: 10.1158/1535-7163.mct-09-0912
• 发表时间: 2010-03
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Vilgelm AE;Washington MK;Wei J;Chen H;Prassolov VS;Zaika AI
• 通讯作者: Zaika AI

Characterization of ΔNp73 expression and regulation in gastric and esophageal tumors.

• DOI: 10.1038/onc.2010.319
• 发表时间: 2010-10-28
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Vilgelm, A. E.;Hong, S-M;Washington, M. K.;Wei, J.;Chen, H.;El-Rifai, W.;Zaika, A.
• 通讯作者: Zaika, A.