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Reflux-Induced Oxidative DNA Damage Repair Early in Barrett's Carcinogenesis

Barrett 癌变早期回流诱导的氧化 DNA 损伤修复

基本信息

批准号：
10405516
负责人：
Kerry Brandt Dunbar
金额：
--
依托单位：
VA NORTH TEXAS HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10405516
关键词：
Acids Acute Address Barrett Epithelium Barrett Esophagus Barrett&apos s carcinogenesis Base Excision Repairs Bile Acids Bile Acids and Salts Biopsy Specimen Cell Line Cells Chronic Complication DNA Damage DNA Repair DNA-(apurinic or apyrimidinic site) lyase Data Development Disease Disease susceptibility Epithelial Cells Esophageal Adenocarcinoma Esophagus Event Frequencies Gastric Acid Gastroesophageal reflux disease Genes Genome Stability Genomic Instability Genomics Impairment In Vitro Incidence Inflammation Intestines Knowledge Lead Left Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of esophagus Medical Metaplasia Modernization Molecular Mucositis Mucous Membrane Nuclear Oxidative Stress Pathway interactions Patients Peptic Esophagitis Perfusion Pharmaceutical Preparations Preventive Production Proteins Proton Pump Inhibitors Reactive Oxygen Species Reflux Risk Factors Role Site Stomach TP53 gene Tissues Veterans Work base bile salts carcinogenesis cell type design endonuclease genome integrity improved in vivo nucleophosmin oxidative DNA damage oxidative damage p38 Mitogen Activated Protein Kinase prevent repaired response tumor progression

项目摘要

Project Summary Gastroesophageal reflux disease (GERD) can be complicated by Barrett’s esophagus, the condition in which a metaplastic, intestinal-type mucosa replaces esophageal squamous mucosa that has been damaged by GERD. Both GERD and Barrett’s esophagus are risk factors for esophageal adenocarcinoma, a deadly cancer whose incidence has been increasing rapidly for decades. Chronic GERD contributes to the malignant transformation of Barrett’s esophagus by causing inflammation, oxidative stress and oxidative DNA damage in the metaplastic mucosa. The modern medical treatment of GERD is directed almost exclusively at decreasing gastric acid production with medications such as proton pump inhibitors (PPIs), which are very effective in controlling reflux esophagitis. However, the PPIs do not eliminate gastric acid secretion, they merely decrease it, and they do nothing to correct the underlying reflux diathesis. Thus, PPIs do not prevent the reflux of weakly acidic material and bile salts, both of which can inflict oxidative injury on the esophagus. This might explain why the frequency of esophageal adenocarcinoma continues to rise despite the widespread use of PPIs. To prevent Barrett’s cancers, new treatments are needed to minimize reflux-induced, oxidative genomic damage. Recent data suggest that esophageal adenocarcinomas develop as a direct consequence of GERD- induced oxidative DNA damage in Barrett’s metaplasia. Left unrepaired, this DNA damage leads to genomic instability and carcinogenesis. Maintenance of genomic integrity requires an appropriate cellular response to oxidative injury, which normally is provided by the p53 gene. This gene is inactivated frequently during carcinogenesis in Barrett’s esophagus, however. In some p53-deficient cell types, p38 can assume the role of “guardian” of genomic stability. In earlier studies, we showed that esophageal acid perfusion specifically activated p38 in the non-dysplastic Barrett’s mucosa of patients in vivo, and that Barrett’s cells in vitro were uniquely susceptible to bile acid-induced DNA damage. We also have established Barrett’s epithelial cell lines that faithfully recapitulate molecular events induced by acid and bile salts in primary tissues. We have inactivated p53 in some of these unique cell lines, which we propose to use in studies that recapitulate the early stages of Barrett’s carcinogenesis. We have preliminary data demonstrating that weakly acidic bile salts induce Barrett’s epithelial cells to generate reactive oxygen species (ROS) that cause oxidative DNA damage. This oxidative injury results in a modest, brief increase in phospho-p38 in p53-intact Barrett’s cells, while oxidative DNA damage triggers a strong, sustained phospho-p38 increase in p53-deficient Barrett’s cells. We show that inhibition of p38 impairs the ability of Barrett’s cells to remove apurinic/apyrimidinic (AP) sites, the early manifestations of oxidative DNA damage that ordinarily are eliminated by AP endonuclease-1 (APE-1), a base-excision-repair protein. We have found that acidic bile salts cause Barrett’s cells to increase their expression and nuclear localization of nucleophosmin 1 (NPM1), a protein that enhances the functional efficiency of APE-1; these events also are impaired by p38 inhibition. Based on these findings, we hypothesize that activation of the p38 pathway in Barrett’s cells by reflux-induced oxidative stress is an important cancer-preventive mechanism that works by upregulating NPM1 to enhance the efficiency of APE-1 in repairing oxidative DNA damage. Our proposed studies are designed to elucidate mechanisms whereby p38 activation regulates NPM1 to enhance APE-1 efficiency in repairing reflux-induced oxidative DNA damage in Barrett’s cells, and to demonstrate that acute reflux esophagitis in Barrett’s patients is associated with p38 activation and with markers of enhanced efficiency of APE-1 in their Barrett’s metaplasia. These studies will elucidate early cellular and molecular events that drive neoplastic progression in Barrett’s esophagus, thereby providing the basis for development of new medical treatments to prevent deadly Barrett’s cancers in our Veteran patients.

项目总结