NADPH oxidases-associated transition from Barrett's esophagus to adenocarcinoma

NADPH 氧化酶相关的巴雷特食管向腺癌的转变

基本信息

批准号：
7229819
负责人：
WEIBIAO CAO
金额：
$ 21.85万
依托单位：
RHODE ISLAND HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-01 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7229819
关键词：
Acids Adenocarcinoma Adenocarcinoma Cell Adult Affect Age-Years Apoptosis Barrett Esophagus Calcium Cell Line Cell Proliferation Cells Cyclic AMP-Responsive DNA-Binding Protein Cyclin D1 Cyclins DNA DNA Damage Data Development Dysplasia Enzymes Epithelium Esophageal Esophageal Adenocarcinoma Esophageal mucous membrane Free Radicals Gastroesophageal reflux disease Hydrogen Peroxide Intestinal Metaplasia Intestines Lead Lipids Mediating Metaplasia Metaplastic Metaplastic Cell Mutation NADP NADPH Oxidase Oxidases PTGS2 gene Patients Peptic Esophagitis Physiologic pulse Play Prevention approach Production Prostaglandin-Endoperoxide Synthase Protein Isoforms Protein Overexpression Proteins Pulse taking Reactive Oxygen Species Reflux Risk Risk Factors Role Signal Transduction Pathway Small Interfering RNA Source Squamous Epithelium Testing Up-Regulation cyclooxygenase 1 cyclooxygenase 2

项目摘要

DESCRIPTION (provided by applicant): Gastroesophageal reflux disease (GERD) affects more than 1 in 10 adults over 40 years of age and 1 in 4 adults over 60. Approximately 10% of GERD patients develop Barrett's esophagus (BE) where esophageal squamous epithelium damaged by reflux esophagitis is replaced by a metaplastic, intestinal- type epithelium. The specialized intestinal metaplasia of BE is associated with nearly a 30-125-fold increased risk for the development of esophageal adenocarcinoma. However, the mechanisms of progression from Barrett's esophagus (intestinal metaplasia) to dysplasia and to adenocarcinoma are not known. We propose that reactive oxygen species (ROS), which are elevated in BE and in adenocarcinoma, play a key role in the progression from BE to adenocarcinoma. Preliminary data demonstrate that the NADPH oxidase isoform NOX5 is overexpressed in an adenocarcinoma cell line (SEG1) where it may overproduce ROS. We will therefore test the central hypothesis that acid exposure upregulates NADPH oxidases in Barrett's intestinal metaplastic cells, causing production of free radicals, which in turn may upregulate cyclooxygenase 2 (COX-2) and cyclin D1. Upregulation of COX-2 and cyclin-D1 will increase cell proliferation and decrease apoptosis in these metaplastic cells. Persistent acid reflux present in BE patients may cause continuous changes including high levels of ROS, increased cell proliferation and decreased apoptosis, which may lead to DNA damage and increased mutations contributing to the progression from metaplasia to dysplasia and to esophageal adenocarcinoma. To test this hypothesis we will: 1) Examine whether NADPH oxidases, in particular NOX5, are upregulated by acid exposure in Barrett's metaplastic cells and SEG1 cells; 2) Examine whether calcium and cyclic AMP response element binding protein (CREB) mediates acid-induced expression of NADPH oxidases (in particular NOX5) in a Barrett's cell line and in SEG1 cells; 3) Define the role of NADPH oxidases-generated ROS in upregulating COX-2 and cyclin-D1. A better understanding of the signal transduction pathway of acid induced upregulation of NADPH oxidases, in particular NOX5, leading to increased cell proliferation and decreased apoptosis, may provide a rational approach to the prevention of development of esophageal adenocarcinoma.

描述（由申请人提供）：胃食管反流病 (GERD) 影响超过十分之一的 40 岁以上成年人和四分之一以上的 60 岁以上成年人。大约 10% 的 GERD 患者会出现食管鳞状上皮受损的巴雷特食管 (BE)反流性食管炎被化生的肠型上皮所取代。 BE 的特殊肠化生与食管腺癌发生风险增加近 30-125 倍相关。然而，从巴雷特食管（肠化生）进展为不典型增生和腺癌的机制尚不清楚。我们认为，活性氧 (ROS) 在 BE 和腺癌中升高，在 BE 向腺癌的进展中发挥关键作用。初步数据表明，NADPH 氧化酶同工型 NOX5 在腺癌细胞系 (SEG1) 中过度表达，可能会过度产生 ROS。因此，我们将检验中心假设，即酸暴露上调 Barrett 肠化生细胞中的 NADPH 氧化酶，导致自由基产生，进而可能上调环氧合酶 2 (COX-2) 和细胞周期蛋白 D1。 COX-2 和细胞周期蛋白-D1 的上调将增加这些化生细胞的细胞增殖并减少细胞凋亡。 BE患者中持续的胃酸反流可能会导致持续的变化，包括高水平的ROS、细胞增殖增加和细胞凋亡减少，这可能导致DNA损伤和突变增加，从而导致从化生进展到不典型增生和食管腺癌。为了检验这一假设，我们将： 1) 检查 Barrett 化生细胞和 SEG1 细胞中的 NADPH 氧化酶（特别是 NOX5）是否因酸暴露而上调； 2) 检查Barrett细胞系和SEG1细胞中钙和环AMP反应元件结合蛋白（CREB）是否介导酸诱导的NADPH氧化酶（特别是NOX5）的表达； 3) 定义 NADPH 氧化酶产生的 ROS 在上调 COX-2 和细胞周期蛋白-D1 中的作用。更好地了解酸诱导 NADPH 氧化酶（特别是 NOX5）上调，导致细胞增殖增加和细胞凋亡减少的信号转导途径，可能为预防食管腺癌的发展提供合理的方法。