Deoxycholic acid induces the overexpression of intestinal mucin, MUC2, via NF-kB signaling pathway in human esophageal adenocarcinoma cells

Jiantao Wu,Yinxue Song,Juan Geng,Jun Gong

doi:10.1186/1471-2407-8-333

Abstract

BackgroundMucin alterations are a common feature of esophageal neoplasia, and alterations in MUC2 mucin have been associated with tumor progression in the esophagus. Bile acids have been linked to esophageal adenocarcinoma and mucin secretion, but their effects on mucin gene expression in human esophageal adenocarcinoma cells is unknown.MethodsHuman esophageal adenocarcinoma cells were treated 18 hours with 50–300 μM deoxycholic acid, chenodeoxycholic acid, or taurocholic acid. MUC2 transcription was assayed using a MUC2 promoter reporter luciferase construct and MUC2 protein was assayed by Western blot analysis. Transcription Nuclear factor-κB activity was measured using a Nuclear factor-κB reporter construct and confirmed by Western blot analysis for Nuclear factor-κB p65.ResultsMUC2 transcription and MUC2 protein expression were increased four to five fold by bile acids in a time and dose-dependent manner with no effect on cell viability. Nuclear factor-κB activity was also increased. Treatment with the putative chemopreventive agent aspirin, which decreased Nuclear factor-κB activity, also decreased MUC2 transcription. Nuclear factor-κB p65 siRNA decreased MUC2 transcription, confirming the significance of Nuclear factor-κB in MUC2 induction by deoxycholic acid. Calphostin C, a specific inhibitor of protein kinase C (PKC), greatly decreased bile acid induced MUC2 transcription and Nuclear factor-κB activity, whereas inhibitors of MAP kinase had no effect.ConclusionDeoxycholic acid induced MUC2 overexpression in human esophageal adenocarcinoma cells by activation of Nuclear factor-κB transcription through a process involving PKC-dependent but not PKA, independent of activation of MAP kinase.

Highlights

Mucin alterations are a common feature of esophageal neoplasia, and alterations in MUC2 mucin have been associated with tumor progression in the esophagus
We find that bile acids induce MUC2 expression in human esophageal adenocarcinoma cells at the level of transcription through a process that involves protein kinase C (PKC)-dependent activation of Nuclear factor-κB (NF-κB), primarily a MAP kinase-independent
Effects of Bile Acids on MUC2 Expression and Transcription SEG-1 treated with deoxycholic acid (DCA), CDCA, and taurocholic acid (TCA)

Summary

Introduction

Mucin alterations are a common feature of esophageal neoplasia, and alterations in MUC2 mucin have been associated with tumor progression in the esophagus. Fractions of duodenogastricoesophageal reflux (DGER) have been detected in patients with extensive esophageal mucosal damage, have been reported to promote esophageal carcinogenesis[7,8]. These bile acids, primarily deoxycholic acid (DCA), are cytotoxic to esophageal cells[8], and are established tumor promoters in animal models[9]. Regulations of MUC1 and MUC4 mucin genes by bile acids, such as DCA, CDCA and TCA, in human oesophageal cancer cells have been the thorough extensive study [14,15,16], the mechanisms responsible for regulation of MUC2 expression in the esophageal adenocarcinoma cells remain unknown

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