Inactivation of RUNX3 by Helicobacter pylori and gastric cancer

描述（由申请人提供）：Runt相关转录因子3或RUNX3是胃癌中的肿瘤抑制因子。RUNX3的失活与胃癌的发生有因果关系，因为RUNX3在胃癌中经常失活。幽门螺杆菌感染是胃癌发生的最大危险因素。最近 研究表明，H. pylori感染在RUNX3失活中起重要作用，这种失活有助于H.幽门。我们最近证明了H. pylori通过在感染的早期阶段以毒力因子CagA依赖的方式诱导其泛素化和降解来抑制RUNX3。然而，这种失活在胃癌发生发展中的详细分子机制和生理功能仍不清楚。这个建议的总体目标是调查如何H。幽门螺杆菌利用CagA使RUNX3失活以及这种失活对胃癌形成的贡献。 在具体目标1中，我们将确定H。pylori CagA诱导RUNX3的泛素化和降解。我们将研究RUNX3的核输出是否是其降解的先决条件，并确定RUNX3的CagA相关泛素E3连接酶。在具体目标2中，我们将确定H。pylori CagA与RUNX3的相互作用以及阻断这种相互作用是否能阻止H.幽门诱发胃癌这些基于细胞和体内动物实验将为H. pylori CagA在H. pylori，并更好地理解RUNX3作为胃癌肿瘤抑制因子的作用。 公共卫生相关性：H. pylori感染是胃腺癌发生的最强危险因素，RUNX3表达缺失与胃癌的发生、发展有因果关系，与胃癌的分化、转移及预后不良有关。我们最近的研究表明，H。幽门螺杆菌以毒力因子CagA依赖的方式灭活RUNX3，但这种灭活的详细机制和生理功能仍不清楚。了解H. pylori的研究将增加我们对RUNX3的肿瘤抑制活性以及病原体和细胞分子之间的相互作用的理解，并可能导致鉴定可用于治疗H.幽门引发的癌症

DESCRIPTION (provided by applicant): Runt-related transcription factor 3, or RUNX3, is a tumor suppressor in gastric cancer. Inactivation of RUNX3 is causally associated with the genesis of gastric cancer, since RUNX3 is frequently inactivated in gastric cancers. Infection with Helicobacter pylori is the strongest risk factor for the development of gastric cancer. Recent studies have indicated that H. pylori infection plays an important role in the inactivation of RUNX3, and that this inactivation contributes to the pathogenesis of H. pylori. We recently demonstrated that H. pylori inactivate RUNX3 by inducing its ubiquitination and degradation during an early stage of the infection in a virulence factor CagA-dependent manner. However, the detailed molecular mechanism and the physiological function of this inactivation in the development of gastric cancer remain unclear. The overall goal of this proposal is to investigate how H. pylori utilize CagA to inactivate RUNX3 and the contribution of this inactivation to the formation of gastric cancer. In Specific Aim 1, we will determine how H. pylori CagA induce the ubiquitination and degradation of RUNX3. We will investigate whether nuclear export of RUNX3 is a prerequisite for its degradation and identify the CagA-associated ubiquitin E3 ligase for RUNX3. In Specific Aim 2, we will determine how H. pylori CagA interact with RUNX3 and whether blocking the interaction could prevent the formation of H. pylori-induced gastric cancer. These cell-based and in vivo animal experiments will provide new insights into the role of H. pylori CagA in the pathogenesis of H. pylori and give a better understanding of the role RUNX3 plays as a tumor suppressor in gastric cancer. PUBLIC HEALTH RELEVANCE: H. pylori infection is the strongest risk factor for the development of gastric adenocarcinoma, and loss of expression of RUNX3 is causally related to the genesis and progression of gastric cancer and also correlates with differentiation, metastasis, and poor prognosis of gastric cancer. Our recent studies have shown that H. pylori inactivates RUNX3 in a virulence factor CagA-dependent manner, but the detailed mechanism and the physiological function of this inactivation remain unclear. Understanding the inactivation of RUNX3 by H. pylori will increase our understanding of the tumor suppressor activity of RUNX3 and the interaction between pathogens and cellular molecules, and may lead to the identification of specific inhibitors which could be used therapeutically for the treatment of H. pylori-initiated cancer.