The number of patients suffering from gastro-esophageal reflux disease (GERD) is rising fast in the United States and several western countries. Chronic GERD is characterized by the increased exposure of epithelial cells to stress and generation of reactive oxygen species (ROS) which leads to the development of esophageal metaplasia, known as Barrett's esophagus (BE). BE is the main known risk factor for the development of gastro-esophageal and esophageal Barrett's associated adenocarcinomas (BACs). The incidence of these tumors is rising faster than any other malignancy in the United States. Unfortunately, the mortality rates for BACs approach incidence rate underscoring the need to understand its molecular pathobiology in order to develop better strategies for combating this deadly disease. Our genomic and epigenomic analysis of BACs has led to identification of several novel molecular alterations. Using integrated analysis approaches, we have identified silencing of glutathione peroxidase 7 (GPX7) in two-thirds of BACs. GPX7 is a recently identified member of the GPX family. We found that promoter DNA hypermethylation plays a critical role in silencing GPX7 expression. Our preliminary data indicate that GPX7 acts as anti-oxidant and can regulate the levels of ROS in the cell. In addition, we have shown that the re-constitution of the expression of GPX7 in esophageal adenocarcinoma cell lines suppresses their tumor growth in xenografted animal model. These data suggest that GPX7 can provide anti-oxidant and tumor growth suppressor properties to epithelia cells. In the first aim, we plan to determine and investigate the anti-oxidative functions of GPX7. In the second aim, we will investigate the interplay of genetic and epigenetic mechanisms in regulating GPX7 expression in Barrett's tumorigenesis. We will also examine the integrity of the methylation machinery and investigate the roles of DNA and histone methylation in the transcriptional regulation of GPX7.
Our third aim will investigate the tumor growth suppressor functions of GPX7 and its effect in regulating the cell cycle. We will also perform immunohistochemical analysis of GPX7 expression on tumor tissue microarrays to determine the histopathological and clinical values of loss of GPX7 expression. We expect that completion of this proposal will provide important molecular and pathobiological information that can have significant impact on the clinical management of patients with Barrett's associated adenocarcinomas.
We have recently characterized silencing of GPX7 expression as a frequent finding in Barrett's associated adenocarcinomas. In this proposal, we plan to characterize the mechanisms of silencing GPX7 expression and its role in Barrett's tumorigenesis in order to identify its biological, diagnostic, prognostic, and possibly therapeutic values.
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