Inactivation of RUNX3 by Helicobacter pylori and gastric cancer

描述(申请人提供)：RUNT相关转录因子3，或RUNX3，是胃癌中的一种肿瘤抑制因子。RUNX3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。近期 研究表明，幽门螺杆菌感染在RUNX3失活中起重要作用，这种失活在幽门螺杆菌的发病机制中起重要作用。我们最近证明，幽门螺杆菌通过在感染早期以毒力因子CagA依赖的方式诱导RUNX3泛素化和降解来灭活RUNX3。然而，这种失活在胃癌发生发展中的具体分子机制和生理功能仍不清楚。这项提议的总体目标是研究幽门螺杆菌如何利用CagA来灭活RUNX3，以及这种灭活在胃癌形成中的作用。在特定的目标1中，我们将确定Hp CagA如何诱导RUNX3的泛素化和降解。我们将调查RUNX3的核出口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。在特定的目标2，我们将确定幽门螺杆菌CagA如何与RUNX3相互作用，以及阻断这种相互作用是否可以防止幽门螺杆菌诱导的胃癌的形成。这些基于细胞和体内的动物实验将为了解幽门螺杆菌CagA在幽门螺杆菌发病机制中的作用提供新的见解，并使人们更好地理解RUNX3作为肿瘤抑制因子在胃癌中的作用。 公共卫生相关性：幽门螺杆菌感染是胃腺癌发生发展的最大危险因素，而RUNX3的表达缺失与胃癌的发生、发展有关，也与胃癌的分化、转移和预后不良有关。我们最近的研究表明，幽门螺杆菌以毒力因子CagA依赖的方式使RUNX3失活，但这种失活的具体机制和生理功能尚不清楚。了解幽门螺杆菌对RUNX3的失活作用将有助于我们更好地了解RUNX3的抑癌活性以及病原体与细胞分子之间的相互作用，并有可能发现可用于治疗幽门螺杆菌引发的癌症的特异性抑制剂。

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.