Role of inflammatory microenvironment in Helicobacter-induced gastric cancer

 描述（由申请人提供）：胃癌是全球癌症相关死亡的主要原因之一，每年有989，000例新发病例和738，000例死亡。大多数人类胃肿瘤与细菌病原体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，螺杆菌感染对全球胃癌负担有显著贡献。关键是要了解导致从炎症性疾病到胃肠道疾病转变的因素。 癌感染H. pylori感染时，由细菌引起的炎症反应被认为是胃恶性肿瘤发展的主要决定因素。然而，螺杆菌诱导的炎症的调节机制仍然没有很好地理解。此外，幽门螺杆菌诱导胃癌发生的机制尚不清楚。我们最近使用小鼠胃癌模型表明，一个关键的信号转导衔接蛋白，髓样分化初级反应基因88（MyD 88），调节螺杆菌诱导的胃癌进展。我们的总体假设是，在MyD 88缺陷小鼠中发现的胃癌进展的急剧增加是由于替代TRIF介导的信号通路的过度激活，导致胃组织中一组特定的TRIF调节的促肿瘤炎性因子的过度产生。为了验证这一假设，我们将使用我们最近发表的胃癌加速小鼠模型来研究MyD 88/TRIF信号转导在螺杆菌刺激的炎症微环境中的作用。在拟定的研究中将讨论以下具体目标：具体目标1：研究过度活化的TRIF通路在螺杆菌诱导的胃肿瘤形成中的作用;具体目标2：确定参与螺杆菌诱导的胃癌加速进展的基因。这项工作首先试图在螺杆菌诱导的慢性炎症过程中发现一个新的胃癌进展危险因素。其次，这项工作将确定在胃癌的发展和进展中重要的关键胃癌候选基因。

 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.