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

• 批准号: 7013516
• 负责人: WEIBIAO CAO
• 金额: $ 18.75万
• 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: 2006-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7013516
• 关键词: Barretts esophagus; NAD(P)H dehydrogenase; adenocarcinoma; cAMP response element binding protein; cell line; clinical research; cyclins; enzyme induction /repression; esophagus neoplasm; free radical oxygen; gastric acid; human subject; metaplasia; patient oriented research; preneoplastic state; prostaglandin endoperoxide synthase; reflux esophagitis

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）：胃食管反流疾病（GERD）影响40岁以上的10名成年人中有1个以上，而40岁以上的4名成年人中有1名成年人。大约10％的GERD患者会出现Barrett的食管（BE），其中食管鳞状上皮受损了通过反流食管炎，被化生的肠道型上皮取代。 BE的专门肠道化生症与食管腺癌发育的风险增加了近30-125倍。然而，尚不清楚从巴雷特食管（肠道化生）到发育不良和腺癌的进展机制。我们提出，在BE和腺癌中升高的活性氧（ROS）在从BE到腺癌的发展中起着关键作用。初步数据表明，NADPH氧化酶同工型NOX5在腺癌细胞系（SEG1）中过表达，在该细胞系可能过度生产ROS。因此，我们将测试中心假设，即酸性暴露在Barrett的肠道化生细胞中上调了NADPH氧化酶，从而导致自由基的产生，这反过来又可能上调环氧酶2（COX-2）和细胞周期蛋白D1。 COX-2和Cyclin-D1的上调将增加细胞增殖并减少这些化生细胞的凋亡。 BE患者中存在的持续胃酸反流可能会导致持续变化，包括高水平的ROS，增加的细胞增殖和凋亡减少，这可能导致DNA损伤并增加突变，导致从化生症到发育不良和食管腺癌的发展。为了检验这一假设，我们将：1）检查NADPH氧化酶（尤其是NOX5）是否因Barrett的Metaplastic细胞和SEG1细胞中的酸暴露而上调； 2）检查钙和环状AMP响应元件结合蛋白（CREB）是否介导酸诱导的NADPH氧化酶（尤其是NOX5）在Barrett的细胞系和SEG1细胞中介导； 3）定义NADPH氧化酶生成的ROS在上调COX-2和Cyclin-D1中的作用。更好地理解酸诱导的NADPH氧化酶上调的信号转导途径，特别是NOX5，导致细胞增殖增加和凋亡减少，可能为预防食管腺癌的发展提供了合理的方法。