Inactivation of RUNX3 by Helicobacter pylori and gastric cancer

幽门螺杆菌导致 RUNX3 失活与胃癌

• 批准号: 8385337
• 负责人: Lin-Feng Chen
• 金额: $ 21.48万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8385337
• 关键词: Address; Animal Experiments; Biological Models; Cancer Etiology; Cells; Cessation of life; Complex; Cultured Cells; Cytosol; Data; Development; Developmental Process; Down-Regulation; Elements; Epithelial Cells; Event; Gastric Adenocarcinoma; Gene Expression; Gerbils; Goals; Helicobacter Infections; Helicobacter pylori; In Vitro; Infection; Lead; Malignant Neoplasms; Mediating; Molecular; Neoplasm Metastasis; Nuclear Export; Pathogenesis; Physiological; Play; Prevention; Recruitment Activity; Risk Factors; Role; Second Primary Cancers; Staging; Stomach; Stomach Diseases; Transcription Factor 3; Tumor Suppressor Proteins; Ubiquitination; Virulence Factors; base; cancer diagnosis; carcinogenesis; in vivo; inhibitor/antagonist; insight; malignant stomach neoplasm; mutant; outcome forecast; pathogen; prevent; response; transcription factor; ubiquitin-protein ligase

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.

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 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失活中发挥重要作用，这种失活有助于幽门螺杆菌的发病机制。我们最近证明，幽门螺杆菌在感染早期以毒力因子 CagA 依赖性方式诱导 RUNX3 泛素化和降解，从而使 RUNX3 失活。然而，这种失活在胃癌发生过程中的详细分子机制和生理功能仍不清楚。该提案的总体目标是研究幽门螺杆菌如何利用 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，我们将确定幽门螺杆菌 CagA 如何诱导 RUNX3 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，并鉴定 RUNX3 的 CagA 相关泛素 E3 连接酶。在具体目标 2 中，我们将确定幽门螺杆菌 CagA 如何与 RUNX3 相互作用，以及阻断这种相互作用是否可以预防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，并更好地了解RUNX3作为胃癌肿瘤抑制因子的作用。 公共卫生相关性：幽门螺杆菌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和进展有因果关系，也与胃癌的分化、转移和不良预后相关。我们最近的研究表明H. pylori以毒力因子CagA依赖性方式灭活RUNX3，但这种灭活的详细机制和生理功能仍不清楚。了解幽门螺杆菌对 RUNX3 的灭活将增加我们对 RUNX3 肿瘤抑制活性以及病原体与细胞分子之间相互作用的理解，并可能导致鉴定可用于治疗幽门螺杆菌引发的癌症的特异性抑制剂。