p27 & apoptosis resistance in gastric cancer

p27

• 批准号: 7671383
• 负责人: STEVEN F MOSS
• 金额: $ 19.03万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7671383
• 关键词: Apoptosis; Binding; Cancer Model; Carcinogens; Cell Cycle; Cell Death; Cells; Chronic; Clinical; Coculture Techniques; Degradation Pathway; Development; Diagnosis; Disease; Down-Regulation; Endoscopic Biopsy; Epithelial; Epithelial Cells; Etiology; Frequencies; Gastric Intraepithelial Neoplasia; Goals; Helicobacter Infections; Helicobacter pylori; Human; Immune response; Incidence; Intervention; Intestinal Metaplasia; Lead; Link; Malignant Neoplasms; Modeling; Molecular; Mosses; Mus; Nuclear; Pathogenesis; Pathway interactions; Patients; Phase; Pre-Clinical Model; Preclinical Testing; Predisposition; Prevention strategy; Public Health; Pylorus; Radiation; Research Personnel; Resistance; Role; Staging; Stomach; Stomach Neoplasms; System; Testing; Time; Tumor Suppressor Proteins; Ubiquitin; Ubiquitination; Wild Type Mouse; World Health Organization; base; cancer cell; cancer therapy; carcinogenesis; cell growth; cyclin-dependent kinase inhibitor 1B; density; improved; in vitro Model; insight; malignant stomach neoplasm; mortality; mouse model; multicatalytic endopeptidase complex; novel; outcome forecast; pre-clinical; preclinical study; prevent; programs; protein degradation; protein expression; research study; response; tool; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Gastric cancer is a major cause of worldwide mortality. Sadly, the disease usually presents at an advanced stage, when resistant to the activation of cell death pathways by chemo-radiation. Insights into the molecular pathogenesis whereby gastric cancer cells acquire resistance to apoptosis may provide more rational targets for therapy in this disease. Gastric cancer is in most cases preceded by and attributable to gastric infection by Helicobacter pylori. Chronic H. pylori infection increases gastric epithelial cell turnover and can lead to apoptosis-resistance associated with low expression of the p27 tumor suppressor protein in chronically-infected gastric epithelial cells. We have recently demonstrated in co-culture experiments that H. pylori decreases the expression of p27 in gastric epithelial cells through accelerated proteasomal degradation of p27 protein and found similar post-translational down-regulation of p27 protein expression in endoscopic biopsies from H. pylori-colonized patients. In addition, we found that mice deficient in p27 frequently develop gastric cancer following H. pylori infection. Based on these findings, we propose to test the hypothesis that H. pylori decreases p27 in gastric epithelial cells by a novel mechanism involving accelerated proteasomal p27 protein degradation resulting in increased susceptibility to gastric cancer, and to characterize the H. pylori-infected p27-deficient mouse as a gastric cancer model for preclinical studies. Specifically, we shall: 1. Determine how H. pylori increases the proteasomal degradation of p27 protein Cell-free and co-culture systems will be utilized to examine the molecular mechanisms of the novel ubiquitin-independent p27 degradative pathway activated by H. pylori that we have identified. 2. Characterize the histological, bacterial and immunological features of our novel model of H. pylori-associated gastric cancer in p27-deficient mice. 3. Utilize the p27-deficient mouse as a preclinical tool to test the effects of H. pylori eradication on gastric cancer susceptibility. These studies focused on the role of p27 in gastric carcinogenesis associated with H. pylori should lead to improved understanding of the mechanisms of gastric carcinogenesis associated with H. pylori infection and provide a novel mouse model of H. pylori-associated gastric carcinogenesis for preclinical testing. Because of the designation of H. pylori by the World Health Organization as a class I (definite) carcinogen in the etiology of the second most frequent cause of worldwide cancer mortality, our findings have important implications for a major global public health problem. Our overall long-term goal is to contribute to the development of new clinical strategies for the prevention, diagnosis and treatment of gastric cancer.

描述（由申请人提供）：胃癌是全球死亡率的主要原因。可悲的是，这种疾病通常出现在晚期，当抵抗化学辐射激活细胞死亡途径时。深入了解胃癌细胞获得抗凋亡的分子机制，可能为胃癌的治疗提供更合理的靶点。在大多数情况下，胃癌发生之前或可归因于幽门螺杆菌的胃感染。慢性H.幽门螺杆菌感染增加胃上皮细胞更新，并可导致与慢性感染的胃上皮细胞中p27肿瘤抑制蛋白低表达相关的结肠癌抗性。我们最近在共培养实验中证明，H。pylori通过加速p27蛋白的蛋白酶体降解降低胃上皮细胞中p27的表达，并且在来自H.幽门定植患者。此外，我们发现p27缺陷的小鼠在H.幽门感染基于这些发现，我们提出了测试的假设，H。pylori通过一种新的机制降低胃上皮细胞中p27的表达，该机制涉及蛋白酶体p27蛋白降解加速，导致胃癌易感性增加，并描述了H. p27缺陷小鼠作为胃癌模型用于临床前研究。具体而言，我们将： 1.确定H。pylori激活的p27蛋白酶体降解增加无细胞和共培养系统将被用于研究新的泛素非依赖性p27降解途径的分子机制。pylori幽门螺杆菌。 2.描述我们新的H. p27缺陷小鼠中幽门相关性胃癌。 3.利用p27缺陷小鼠作为临床前工具来测试H.幽门螺杆菌根除对胃癌易感性的影响。 这些研究集中在p27在胃癌发生中的作用与H。pylori的研究有助于我们更好地理解与H. pylori感染，并提供了一种新的H.幽门相关胃癌的临床前试验。由于H.幽门螺杆菌被世界卫生组织列为I类（明确）致癌物，是全球癌症死亡率的第二大最常见病因，我们的研究结果对全球重大公共卫生问题具有重要意义。我们的总体长期目标是为预防、诊断和治疗胃癌的新临床策略的发展做出贡献。