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

摘要 胃癌是全球癌症相关死亡的主要原因之一， 每年有738，000人死亡。大多数人类胃肿瘤与慢性肿瘤有关。 幽门螺杆菌感染。因此，理解以下机制至关重要： 调节和促进恶性进展，以有效地识别预防性治疗的潜在靶点。在 在美国，胃癌的死亡率遵循种族划分，非洲人的死亡率最高 美国人，其次是亚洲/太平洋岛民，美洲原住民，西班牙裔和高加索人。事业 这种差异是未知的。现在有相当多的确凿证据表明宿主的反应 到H.幽门螺杆菌是决定胃癌易感性的关键。此外，众所周知， Wnt/β-catenin信号通路的不适当激活在胃癌发生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 MyD 88信号传导和已知的胃致癌通路Wnt/β-连环蛋白的结合，并阐明MyD 88信号传导的生物学机制。 这些相互作用在癌症进展中的重要性。我们最近展示了使用螺旋杆菌诱导的 小鼠胃癌模型中一种关键的免疫信号转导衔接蛋白，髓样分化 主要反应基因88（MyD 88）调节螺杆菌诱导的胃癌进展。但 这种癌症进展的介质是未知的。我们假设MyD 88缺陷导致增加 Wnt/β-catenin信号对螺杆菌感染的反应，其促进胃癌的发展。是 已知Wnt/β-catenin信号调节胃肠上皮细胞增殖。然而，程度 MyD 88和Wnt/β-catenin信号通路之间的相互作用影响H.幽门相关性胃 致癌作用是未知的，也没有研究过。我们的总体假设是， -/- 在Myd 88小鼠中发现的胃癌进展的加速是由于与致癌基因的相互作用。 例如Wnt/β-catenin。本文使用新的离体胃类器官培养系统和良好的 建立幽门螺杆菌诱导的胃癌模型，我们将追求以下具体目标： 目的1：研究MyD 88对H.幽门诱导上皮细胞 使用胃类器官培养系统进行增殖;具体目的2：检查Wnt/β- 在急性炎症反应和慢性炎症中， 在胃癌小鼠模型中MyD 88的存在。首先，这项工作首先试图表明， MyD 88导致Wnt/β-连环蛋白信号传导增加。第二，这项工作将首次通报 MyD 88和Wnt/β-catenin信号通路之间的串扰及其在启动和 胃癌的进展。

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.