p27 & apoptosis resistance in gastric cancer

描述(申请人提供)：胃癌是世界范围内死亡的主要原因。可悲的是，这种疾病通常出现在晚期，此时对化疗辐射激活细胞死亡途径具有抵抗力。对胃癌细胞获得凋亡抵抗的分子机制的深入研究可能为该病的治疗提供更合理的靶点。大多数情况下，胃癌发生在幽门螺杆菌感染之前，并可归因于幽门螺杆菌感染。幽门螺杆菌慢性感染可增加胃上皮细胞的周转，并可导致与慢性感染的胃上皮细胞中p27抑癌蛋白低表达有关的凋亡抵抗。我们最近在共培养实验中证明，幽门螺杆菌通过加速p27蛋白的蛋白酶体降解来降低胃上皮细胞中p27的表达，并在幽门螺杆菌定植的患者的内窥镜活检组织中发现类似的翻译后p27蛋白表达下调。此外，我们还发现p27基因缺失的小鼠在幽门螺杆菌感染后经常发生胃癌。基于这些发现，我们建议通过加速蛋白酶体p27蛋白降解导致胃癌易感性增加的新机制来检验幽门螺杆菌降低胃上皮细胞p27的假设，并将幽门螺杆菌感染的p27缺陷小鼠表征为用于临床前研究的胃癌模型。具体来说，我们会： 1.确定幽门螺杆菌如何促进p27蛋白的蛋白酶体降解我们将利用无细胞和共培养系统来研究我们已经确定的幽门螺杆菌激活的泛素非依赖性p27降解途径的分子机制。 2.研究p27基因缺陷小鼠幽门螺杆菌相关性胃癌模型的组织学、细菌学和免疫学特征。 3.利用p27基因缺陷小鼠作为临床前工具，检测根除幽门螺杆菌对胃癌易感性的影响。 这些研究集中在p27在幽门螺杆菌相关性胃癌发生中的作用，有助于加深对幽门螺杆菌相关胃癌发生机制的理解，并为临床前检测提供一种新的幽门螺杆菌相关性胃癌的小鼠模型。由于世界卫生组织将幽门螺杆菌列为全球第二大癌症死亡原因的病因学中的I类(明确)致癌物，我们的发现对一个重大的全球公共卫生问题具有重要意义。我们的总体长期目标是为制定新的预防、诊断和治疗胃癌的临床策略做出贡献。

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.