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.

抽象的 胃癌在全球癌症相关死亡的主要原因中名列前茅，新增死亡人数达 989,600 人 每年有 738,000 例病例和死亡。大多数人类胃肿瘤与慢性相关。 因此，了解幽门螺杆菌感染的机制至关重要。 调节和促进恶性进展，以有效识别预防性治疗的潜在靶点。 在美国，胃癌死亡率遵循种族划分，其中非洲人死亡率最高 美国人，其次是亚洲/太平洋岛民、美洲原住民、西班牙裔和白人。 这种差异是未知的，现在有大量确凿的证据表明宿主的反应。 幽门螺杆菌对于确定胃癌的易感性至关重要。此外，众所周知。 Wnt/β-连环蛋白信号传导的不当激活在胃癌的发展中具有重要作用。 我们提出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 信号传导和已知的胃致癌途径 Wnt/β-catenin 的研究，并阐明其生物学机制 我们最近使用螺杆菌诱导证明了这些相互作用在癌症进展中的重要性。 胃癌小鼠模型发现关键的免疫信号转导衔接蛋白、骨髓分化 初级反应基因 88 (MyD88) 调节螺杆菌诱导的胃癌进展。 这种癌症进展的介质尚不清楚，我们认为 MyD88 缺乏会导致癌症进展增加。 Wnt/β-连环蛋白信号传导响应螺杆菌感染，促进胃癌的发展。 已知 Wnt/β-连环蛋白信号传导调节胃肠道上皮细胞增殖，但其程度如何。 MyD88 和 Wnt/β-catenin 信号通路之间的相互作用影响幽门螺杆菌相关胃 致癌作用是未知的，也没有被研究过，我们的总体假设是，戏剧性的。 -/- Myd88 小鼠中发现加速进展为胃癌是由于与致癌基因的相互作用 途径，例如Wnt/β-连环蛋白，本文使用新型离体胃类器官培养系统和良好的- 建立螺杆菌诱导的胃癌模型，我们将追求以下具体目标： 目标 1：研究 MyD88 对幽门螺杆菌诱导的上皮细胞中 Wnt/β-catenin 活性的影响 使用胃类器官培养系统进行增殖；具体目标2：检查Wnt/β-的功能 急性炎症反应和慢性炎症期间连环蛋白信号传导 首先，这项工作首先试图证明 MyD88 的缺陷。 MyD88 导致 Wnt/β-catenin 信号传导增强 其次，这项工作将首次揭示 Wnt/β-catenin 信号传导。 MyD88 和 Wnt/β-catenin 信号通路之间的串扰及其在启动和启动中的意义 胃癌的进展。