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

> **NIH VA I01** · VA NORTH TEXAS HEALTH CARE SYSTEM · 2022 · —

## Abstract

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 e...

## Key facts

- **NIH application ID:** 10405516
- **Project number:** 5I01CX001668-05
- **Recipient organization:** VA NORTH TEXAS HEALTH CARE SYSTEM
- **Principal Investigator:** Kerry Brandt Dunbar
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405516

## Citation

> US National Institutes of Health, RePORTER application 10405516, Reflux-Induced Oxidative DNA Damage Repair Early in Barrett's Carcinogenesis (5I01CX001668-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10405516. Licensed CC0.

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