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）：胃食管反流病（GERD）影响超过1/10的40岁以上成人和1/4的60岁以上成人。大约10%的GERD患者发展为巴雷特食管（BE），其中由反流性食管炎损伤的食管鳞状上皮被化生的肠型上皮替代。BE的特化肠上皮化生与食管腺癌发生的风险增加近30-125倍相关。然而，从巴雷特食管（肠化生）发展到异型增生和腺癌的机制尚不清楚。我们认为，活性氧（ROS），这是升高BE和腺癌，发挥了关键作用，从BE到腺癌的进展。初步数据表明，NADPH氧化酶亚型NOX 5在腺癌细胞系（SEG 1）中过表达，可能会过度产生ROS。因此，我们将测试的核心假设，酸暴露上调NADPH氧化酶在巴雷特肠化生细胞，导致产生的自由基，这反过来可能上调环氧合酶2（考克斯-2）和细胞周期蛋白D1。上调考克斯-2和cyclin-D1将增加这些化生细胞的细胞增殖和减少凋亡。BE患者中存在的持续性酸反流可能导致持续变化，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，从而导致从化生到异型增生和食管腺癌的进展。为了验证这一假设，我们将：1）检查NADPH氧化酶，特别是NOX 5，是否被巴雷特化生细胞和SEG 1细胞中的酸暴露上调; 2）检查钙和环AMP反应元件结合蛋白（CREB）是否介导酸诱导的NADPH氧化酶表达。（特别是NOX 5）; 3）确定NADPH氧化酶产生的ROS在上调考克斯-2和细胞周期蛋白-D1中的作用。更好地了解酸诱导的NADPH氧化酶，特别是NOX 5上调，导致细胞增殖增加和凋亡减少的信号转导途径，可能提供一个合理的方法来预防食管腺癌的发展。