Inactivation of RUNX3 by Helicobacter pylori and gastric cancer

幽门螺杆菌导致 RUNX3 失活与胃癌

基本信息

批准号：
8485602
负责人：
Lin-Feng Chen
金额：
$ 18.32万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2015-06-30
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：与RUNT相关的转录因子3（Runx3）是胃癌的肿瘤抑制剂。 Runx3的灭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展的最强危险因素。最近的研究表明，幽门螺杆菌感染在Runx3失活中起着重要作用，并且这种失活有助于幽门螺杆菌的发病机理。我们最近证明了幽门螺杆菌通过以毒力因子CAGA依赖性方式在感染的早期阶段诱导其泛素化和降解来诱导其泛素化和降解。但是，这种灭活在胃癌发展中的详细分子机制和生理功能尚不清楚。该提案的总体目标是研究幽门螺杆菌如何利用CAGA灭活Runx3以及这种失活对胃癌形成的贡献。在特定的目标1中，我们将确定幽门螺杆菌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，并确定与Runx3相关的CAGA相关的泛素E3连接酶。在特定的目标2中，我们将确定幽门螺杆菌CAGA如何与Runx3相互作用，以及阻断相互作用是否可以防止幽门螺杆菌诱导的胃癌的形成。这些基于细胞的和体内动物的实验将为幽门螺杆菌在幽门螺杆菌发病机理中的作用提供新的见解，并更好地了解Runx3在胃癌中的肿瘤抑制作用。