Molecular Pathobiology of Gastric Carcinogenesis

胃癌发生的分子病理学

• 批准号: 10253570
• 负责人: WAEL EL-RIFAI
• 金额: --
• 依托单位: MIAMI VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10253570
• 关键词: Address; Adult; Affect; Antioxidants; Binding; Bioinformatics; Biological; Biological Process; Biology; Cancer Biology; Cancer Etiology; Cancer Model; Cancer Patient; Carcinogens; Caring; Cell Proliferation; Cell Survival; Cells; Cellular Stress; Cessation of life; Chronic; Data; Development; Diagnosis; Diagnostic; Early Diagnosis; Epithelial; Epithelial Cells; Etiology; Event; FGF19 gene; FGFR4 gene; Far East; Fibroblast Growth Factor; Future; Gastric Adenocarcinoma; Gastric Intraepithelial Neoplasia; Goals; Helicobacter Infections; Helicobacter pylori; Histologic; Home; Human; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammatory; Intestinal Metaplasia; Knock-out; Knowledge; Ligands; Link; Malignant Neoplasms; Mediating; Middle East; Military Personnel; Molecular; National Cancer Institute; Oncogenic; Oncology; Organoids; Oxidative Stress; Pathology; Patients; Play; Population; Pre-Clinical Model; Preventive; Reactive Oxygen Species; Regulation; Reporting; Resistance; Risk; Risk Factors; Role; STAT3 gene; Signal Transduction; Soldier; Stimulus; Stomach; Survival Rate; TFF1 gene; Technology; The Cancer Genome Atlas; Therapeutic; Therapeutic Intervention; Tissue Sample; Tissues; Transcriptional Regulation; Treatment Efficacy; United States; Work; World Health Organization; base; cancer cell; cancer statistics; carcinogenicity; chemotherapy; clinically significant; design; epidemiologic data; experience; gastric carcinogenesis; gastric tumorigenesis; genotoxicity; global health; high risk; human tissue; improved; in vitro Model; in vivo; in vivo Model; malignant stomach neoplasm; member; mouse model; neoplastic cell; novel; novel therapeutic intervention; overexpression; patient derived xenograft model; prognostic; recruit; response; therapeutic target; therapy resistant; transcription factor; translational study; tumorigenesis; tumorigenic

Gastric cancer is the third leading cause of cancer-associated death worldwide. The global cancer statistics report indicated an estimated 1,033,701 new gastric cancer cases and 782,685 deaths occurred in 2018. Several studies have reported frequent association of gastric adenocarcinoma with Helicobacter pylori (H. pylori) infection. The World Health Organization has classified H. pylori as a class I carcinogen and the main risk factor for gastric cancer. Despite efforts to eradicate H. pylori, infection remains a global health problem with almost half of the world’s population infected. According to a recent study of U.S soldiers deployed to the Middle East and Far East, the incidence of H. pylori infection was 7.3 percent per year compared to 2.5 percent of U.S. military recruits living at home. This increase represents a major increase in risk. When epithelial cells lose their protective capacity, they become prone to the carcinogenic effects of H. pylori, leading to the development of intestinal metaplasia, gastric dysplasia and progression to cancer. Our recent preliminary data in this proposal, demonstrates frequent overexpression of oncogenic FGFR4 signaling in gastric cancer. Using in vitro and in vivo models as well as H. pylori infection, we demonstrated a novel link between pro-inflammatory signaling (STAT3) and overexpression and activation of FGFR4. Functionally, we found that FGFR4 plays a critical role in regulating the level and activity of NRF2, a major anti-oxidant transcription factor, in response to cellular stress induced by H. pylori or chemotherapy. The FGFR4-NRF2 signaling promoted cell survival and resistance to chemotherapeutics. Based on our novel findings, we hypothesize that the dynamic pro-inflammatory oncogenic cross-talk between STAT3, FGFR4 and cellular anti- oxidant capacity plays a critical role in gastric tumorigenesis. Our goal is to understand the molecular and functional consequences of FGFR4 in the multi-step gastric carcinogenesis cascade. In this proposal, we will investigate mechanisms of activation of FGFR4 in gastric tumorigenesis (Aim 1). We will determine the downstream molecular and biological functions of activation of FGFR4 and antioxidant response in gastric tumorigenesis in Aim 2. The translational significance of activation FGFR4 and NRF2 across stages of human gastric tumorigenesis will be investigated (Aim 3). In addition, Aim 3 will also determine the therapeutic significance of inhibiting FGFR4 as a single agent or in combinations with standards of care in pre-clinical models of gastric tumorigenesis. This proposal tackles etiology-based biologically-relevant questions to uncover novel information regarding the role of H. pylori, inflammation, oxidative stress, and tumorigenic signaling in the multi-step gastric tumorigenesis. A successful completion of this project will have a positive impact on understanding the biology and identification of diagnostic, prognostic and possibly therapeutic targets in gastric cancer.

胃癌是全球癌症相关死亡的第三主要原因。全球癌症统计 报告显示，2018年估计有1,033,701例新的胃癌病例和782,685例死亡。 几项研究报告了胃腺癌与幽门螺杆菌的经常关联（H. 幽门螺杆菌感染。世界卫生组织已将幽门螺杆菌归类为I类致癌物和主要 胃癌的危险因素。尽管促幽门螺氏菌，但感染仍然是一个全球健康问题 几乎有一半的世界人口感染。根据最近部署到美国士兵的研究 中东和远东地区，幽门螺杆菌感染的事件每年为7.3％，而2.5 美国军事新兵的百分比居住在家里。这增加代表了风险的重大增加。什么时候 上皮细胞失去了保护能力，它们易于幽门螺杆菌的致癌作用，领先 为了发展肠道化生，胃发育不全和癌症的发展。我们最近 该提案中的初步数据经常证明过度表达致癌性FGFR4信号传导 胃癌。使用体外和体内模型以及幽门螺杆菌感染，我们展示了一种新的联系 在促炎信号传导（STAT3）与FGFR4的过表达和激活之间。在功能上，我们 发现FGFR4在调节NRF2的水平和活性中起着至关重要的作用，NRF2是主要的抗氧化剂 转录因子，响应幽门螺杆菌或化学疗法诱导的细胞应激。 FGFR4-NRF2 信号传导促进了细胞的存活和对化学治疗剂的抗性。根据我们的小说发现，我们 假设STAT3，FGFR4和细胞抗 - 氧化能力在胃肿瘤发生中起关键作用。我们的目标是了解分子和 FGFR4在多步胃癌发生级联反应中的功能后果。在此提案中，我们将 研究FGFR4在胃肿瘤发生中激活的机制（AIM 1）。我们将确定 胃中FGFR4激活和抗氧化剂反应的下游分子和生物学功能 AIM 2中的肿瘤发生。激活FGFR4和NRF2的翻译意义跨越人类的阶段 将研究胃肿瘤发生（AIM 3）。此外，AIM 3还将确定疗法 抑制FGFR4作为单一药物或与临床前的护理标准组合的重要性 胃肿瘤发生的模型。该提议解决了基于病因的生物学问题的问题 发现有关幽门螺杆菌，感染，氧化应激和肿瘤的新信息 多步胃肿瘤发生中的信号传导。这个项目的成功完成将有一个积极的 对理解诊断，预后和可能疗法的生物学和鉴定的影响 胃癌的靶标。