Bile acids inhibit Notch-1 expression in the development of Barrett’s esophagus

Abstract

Background: Barrett’s esophagus (BE) is the premalignant condition for the development of esophageal adenocarcinoma, and occurs when the stratified epithelium is replaced by an intestinal-type epithelium with goblet cells. Bile acids (BAs) may play a dominant role in esophageal metaplasia, which is characterized by the expression of intestine-specific nuclear transcription factor caudal type homeobox transcription factor 2 (CDX-2). Notch-1 is frequently downregulated in BE, and protects squamous epithelia from becoming malignant and inducing intestinal metaplasia. However, the molecular mechanisms of this pathway are unclear. Methods: We first investigated Notch-1 and CDX-2 in human BE epithelium. Then Wister rats were used to develope animal models to test the role of BAs in the pathogenesis of BE. Effects of deoxycholic acid (DCA) on Notch-1 and CDX-2, as well as Notch signaling pathway blockage with DATP or with si-Hes-1 in vitro were observed through RT–PCR and western blotting techniques in human EAC cells (OE-19) and esophageal epithelial cells (Het-1a). Results: We found that the Notch -1 gene was inhibited in human and rodent BE specimens and BAs induced Barrett’s-like metaplasia. DCA decreases Notch-1 in a time and concentration dependent manner in both EAC cells (OE-19) and esophageal epithelial cells (Het-1a). Notch signaling inhibition increased CDX-2 expression but also blocked the influence of DCA. Conclusions: These data imply that BAs induce BE by inhibiting Notch-1 in esophageal cells. Notch signal pathway inhibition presents a therapeutic strategy for premalignant conditions of the esophagus.