Abstract
Mechanisms of the progression from Barrett’s esophagus (BE) to esophageal adenocarcinoma (EA) are not fully understood. We have shown that NOX5-S may be involved in this progression. However, how acid upregulates NOX5-S is not well known. We found that acid-induced increase in NOX5-S expression was significantly decreased by the Rho kinase (ROCK) inhibitor Y27632 in BE mucosal biopsies and FLO-1 EA cells. In addition, acid treatment significantly increased the Rho kinase activity in FLO-1 cells. The acid-induced increase in NOX5-S expression and H2O2 production was significantly decreased by knockdown of Rho kinase ROCK2, but not by knockdown of ROCK1. Conversely, the overexpression of the constitutively active ROCK2, but not the constitutively active ROCK1, significantly enhanced the NOX5-S expression and H2O2 production. Moreover, the acid-induced increase in Rho kinase activity and in NOX5-S mRNA expression was blocked by the removal of calcium in both FLO-1 and OE33 cells. The calcium ionophore A23187 significantly increased the Rho kinase activity and NOX5-S mRNA expression. We conclude that acid-induced increase in NOX5-S expression and H2O2 production may depend on the activation of ROCK2, but not ROCK1, in EA cells. The acid-induced activation of Rho kinase may be mediated by the intracellular calcium increase. It is possible that persistent acid reflux present in BE patients may increase the intracellular calcium, activate ROCK2 and thereby upregulate NOX5-S. High levels of reactive oxygen species derived from NOX5-S may cause DNA damage and thereby contribute to the progression from BE to EA.
Highlights
Gastroesophageal reflux disease (GERD) complicated by Barrett’s esophagus (BE) [1,2,3] is a major risk factor for esophageal adenocarcinoma (EA). 5–15% of GERD patients develop BE [3, 4] where esophageal squamous epithelium damaged by reflux esophagitis is replaced by a metaplastic intestinal-type epithelium
We found that a NADPH oxidase (NOX) isoform NOX5-S is overexpressed in Barrett’s mucosa with high grade dysplasia [12], EA cells lines and tissues [21], suggesting that NOX5-S present in the metaplastic cells may be a source of excess Reactive oxygen species (ROS)
In this paper we show that ROCK2 plays an important role in the acid-induced increase in NOX5-S expression and H2O2 production and that Rho kinase activation depends on the intracellular calcium increase
Summary
Gastroesophageal reflux disease (GERD) complicated by Barrett’s esophagus (BE) [1,2,3] is a major risk factor for esophageal adenocarcinoma (EA). 5–15% of GERD patients develop BE [3, 4] where esophageal squamous epithelium damaged by reflux esophagitis is replaced by a metaplastic intestinal-type epithelium. Gastroesophageal reflux disease (GERD) complicated by Barrett’s esophagus (BE) [1,2,3] is a major risk factor for esophageal adenocarcinoma (EA). 5–15% of GERD patients develop BE [3, 4] 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 30125-fold increased risk for the development of EA, with best estimates of cancer incidence of 0.12–0.8% per year, i.e. one cancer per 125–860 patients for each year of observation [3, 6,7,8,9,10]. There is a progression from BE to dysplasia and to EA. The mechanisms of this progression are not fully understood
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