MyD88-dependent mechanisms of Helicobacter pylori-induced gastric cancer progression

幽门螺杆菌诱导胃癌进展的 MyD88 依赖性机制

• 批准号: 9303180
• 负责人: MARYGORRET OBONYO
• 金额: $ 20.23万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-03 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303180
• 关键词: Acceleration; Acute; Adaptor Signaling Protein; African American; Asians; Bacteria; Biological; CD44 gene; Cancer Burden; Cancer Etiology; Carcinogens; Caucasians; Cell Culture System; Cell Proliferation; Cell Survival; Cessation of life; Chronic; Cyclin D1; Death Rate; Development; Disease; Disease Progression; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Exhibits; Future; Gastric Intraepithelial Neoplasia; Gene Targeting; Genes; Helicobacter; Helicobacter Infections; Helicobacter pylori; Hispanics; Histopathology; Human; Immune response; Immune signaling; Infection; Inflammation; Inflammatory Response; Innate Immune Response; Intervention; Knowledge; Label; Lead; Malignant - descriptor; Malignant Neoplasms; Measures; Mediator of activation protein; Modeling; Mus; Myelogenous; NF-kappa B; Native Americans; Oncogenic; Organoids; Outcome; Pacific Island Americans; Pathway interactions; Population; Predisposition; Prevention; Preventive therapy; Reporter; Risk Factors; Signal Pathway; Signal Transduction; Stomach; Stomach Neoplasms; System; Time; WNT Signaling Pathway; Wild Type Mouse; Work; Xenograft Model; beta catenin; c-myc Genes; cancer health disparity; cancer type; carcinogenesis; gastrointestinal; insight; malignant stomach neoplasm; mortality; mouse model; novel; pathogen; response; tumor progression; tumor xenograft

Abstract Gastric cancer ranks high among the leading causes of cancer-related deaths worldwide, with 989,600 new cases and 738,000 deaths each year. The majority of human stomach tumors are associated with chronic infection with the bacterial pathogen Helicobacter pylori. It is therefore critical to understand mechanisms that regulate and facilitate malignant progression to efficiently identify potential targets for preventative therapies. In the USA, death rates from gastric cancer follow ethnic divisions with the highest mortality rates among African Americans, followed by Asian/Pacific Islanders, Native Americans, Hispanics, and Caucasians. The cause of this disparity is unknown. There is now considerable amount of confirmatory evidence that the host response to H. pylori is crucial in determining susceptibility to gastric cancer. Furthermore, it is well established that inappropriate activation of Wnt/β-catenin signaling has an important function in gastric cancer development. The central objective of our proposed project is to identify accelerating factors by investigating the interaction of MyD88 signaling and a known gastric oncogenic pathway, Wnt/β-catenin and to elucidate the biological significance of these interactions in cancer progression. We recently showed using a Helicobacter-induced mouse model of gastric cancer that a key immune signal transduction adaptor protein, myeloid differentiation primary response gene 88 (MyD88), regulates Helicobacter-induced gastric cancer progression. However, the mediators of this cancer progression are unknown. We hypothesize that MyD88 deficiency leads to increased Wnt/β-catenin signaling in response to Helicobacter infection, which promotes gastric cancer development. It is known that Wnt/β-catenin signaling regulates gastrointestinal epithelial cell proliferation. However, the extent to which interactions between MyD88 and Wnt/β-catenin signaling pathways impact H. pylori-associated gastric carcinogenesis is unknown and has not been investigated. Our overall hypothesis is that the dramatic -/- acceleration in progression to gastric cancer found in Myd88 mice is due to interactions with oncogenic pathways, such as Wnt/β-catenin. Herein using a novel ex vivo gastric organoid culture system and a well- established Helicobacter-induced model of gastric cancer we will pursue the following specific aims: Specific aim 1: Investigate the effect of MyD88 on Wnt/β-catenin activity in H. pylori-induced epithelial cell proliferation using a gastric organoid culture system; Specific aim 2: Examine the function of Wnt/β- catenin signaling during acute inflammatory response and chronic inflammation in the absence and presence of MyD88 in a gastric cancer mouse model. First, this work first seeks to show that deficiency in MyD88 results in increased Wnt/β-catenin signaling. Second, this work will inform for the first time on the crosstalk between the MyD88 and Wnt/β-catenin signaling pathways and its significance in initiation and progression of gastric cancer.

摘要 胃癌在全球癌症相关死亡的主要原因中名列前茅，新增989,600人 每年有738,000人死亡。大多数人的胃肿瘤与慢性胃病有关 感染幽门螺杆菌。因此，重要的是要了解 调节和促进恶性进展，以有效地确定预防性治疗的潜在靶点。在……里面 在美国，胃癌死亡率遵循种族划分，在非洲死亡率最高 其次是亚洲/太平洋岛民、美洲原住民、西班牙裔和高加索人。的起因 这种差距是未知的。现在有大量确凿的证据表明，宿主的反应 对幽门螺杆菌的敏感性是决定对胃癌易感性的关键。此外，众所周知， Wnt/β-catenin信号的异常激活在胃癌的发生发展中起着重要作用。 我们提议的项目的中心目标是通过调查相互作用来确定加速因素 MYD88信号转导途径与已知的胃癌变途径Wnt/β-catenin的关系及其生物学意义 这些相互作用在癌症进展中的意义。我们最近展示了使用幽门螺杆菌诱导的 小鼠胃癌模型中的一种关键免疫信号转导适配蛋白，髓系分化 初级反应基因88(MyD88)调节幽门螺杆菌诱导的胃癌进展。然而， 癌症进展的中介物尚不清楚。我们假设MyD88缺乏会导致 Wnt/β-连环蛋白信号转导系统对幽门螺杆菌感染的反应，促进胃癌的发生。它是 已知Wnt/β-catenin信号调节胃肠上皮细胞增殖。然而，到目前为止， MyD88和Wnt/β-catenin信号通路的哪些相互作用影响幽门螺杆菌相关性胃 致癌机制尚不清楚，也没有被研究过。我们的总体假设是戏剧性的 -/- 在MyD88小鼠中发现胃癌进展加速是由于与致癌因素的相互作用 途径，如Wnt/β-catenin。在此，使用一种新的体外胃类器官培养系统和一种良好的 建立幽门螺杆菌诱导的胃癌模型我们将追求以下特定目标： 目的1：探讨MyD88对幽门螺杆菌诱导的上皮细胞Wnt/β-catenin活性的影响 利用胃器官培养系统进行增殖；特异性目标2：检测Wnt/β的功能。 急性炎症反应和慢性炎症中的连环蛋白信号转导 MyD88在小鼠胃癌模型中的表达。首先，这项工作首先试图表明 MyD88导致Wnt/β-catenin信号增强。第二，这项工作将首次在 MyD88和Wnt/β-catenin信号通路之间的串扰及其在启动和恢复中的意义 胃癌的进展。