Role of inflammatory microenvironment in Helicobacter-induced gastric cancer

 描述(申请人提供)：胃癌在全球癌症相关死亡的主要原因中排名很高，每年有98.9万新病例和73.8万人死亡。大多数人的胃肿瘤与幽门螺杆菌的慢性感染有关。由于世界上大约一半的人口被感染，幽门螺杆菌感染对世界范围内的胃癌造成了很大的负担。了解导致炎症性疾病向胃部疾病转变的因素是至关重要的。 癌症。在感染幽门螺杆菌的患者中，对细菌的反应引起的炎症被认为是胃恶性肿瘤发生的主要决定因素。然而，幽门螺杆菌诱导的炎症的调控机制仍不是很清楚。此外，幽门螺杆菌诱导胃癌发生的机制尚不清楚。我们最近用小鼠的胃癌模型证明了一种关键的信号转导适配蛋白，髓系分化主要反应基因88(MyD88)，调节幽门螺杆菌诱导的胃癌的进展。我们的总体假设是，在MyD88缺陷小鼠中发现的胃癌进展的急剧增加是由于替代的TRIF介导的信号通路过度激活，导致胃组织中一组特定的TRIF调节的促癌性炎症因子过度产生。为了验证这一假设，我们将使用我们最近发表的加速胃癌小鼠模型来研究MyD88/TRIF信号在幽门螺杆菌刺激的炎症微环境中的作用。在拟议的研究中将涉及以下特定目标：特定目标1：研究高激活的TRIF通路在幽门螺杆菌诱导的胃肿瘤中的作用；特定目标2：确定与加速的幽门螺杆菌诱导的胃癌进展相关的基因。这项工作首先寻求在幽门螺杆菌诱导的慢性炎症过程中发现一种新的胃癌进展风险因素。其次，这项工作将确定在胃癌的发生和发展中重要的关键候选胃癌基因。

 DESCRIPTION (provided by applicant): Gastric cancer ranks high among the leading causes of cancer-related deaths worldwide, with 989,000 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. As approximately half of the world's population is infected, Helicobacter infection contributes significantly to the worldwide gastric cancer burden. It is critical to understand the factors that lead to the transition from inflammatory disease to gastric cancer. In patients infected with H. pylori, it is thought that the inflammation induced in respons to the bacteria is the major determinant in the development of gastric malignancy. However, the regulatory mechanisms of Helicobacter-induced inflammation are still not well understood. In addition, the mechanisms of Helicobacter-induced gastric carcinogenesis are still unclear. We recently showed using a mouse model of gastric cancer that a key signal transduction adaptor protein, myeloid differentiation primary response gene 88 (MyD88), regulates Helicobacter-induced gastric cancer progression. Our overall hypothesis is that the dramatic increase in progression to gastric cancer found in MyD88 deficient mice is due to overactivation of the alternative TRIF-mediated signaling pathway, leading to overproduction of a specific set of TRIF-regulated pro-neoplastic inflammatory factors in the gastric tissue. To test this hypothesis, we will use our recently published accelerated mouse model of gastric cancer to investigate the role of MyD88/TRIF signaling in Helicobacter-stimulated inflammatory microenvironment. The following specific aims will be addressed in the proposed study: Specific aim 1: Investigate the role of hyperactivated TRIF pathway in Helicobacter-induced gastric neoplasia; Specific aim 2: Determine genes involved in accelerated Helicobacter-induced gastric cancer progression. This work first seeks to discover a new gastric cancer progression risk factor during Helicobacter-induced chronic inflammation. Second, this work will identify key gastric cancer gene candidates that are important in the development and progression of gastric cancer.