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. ? ?
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