Expression, localization and polymorphisms of the nuclear receptor PXR in Barrett's esophagus and esophageal adenocarcinoma

Anouk van de Winkel,Herman van Dekken,Leon MG Moons,Ernst J Kuipers,Raymond GJ Pot,Peter D Siersema,Johannes G Kusters,Vivianda Menke,Luc JW van der Laan,Astrid Capello

doi:10.1186/1471-230x-11-108

Abstract

BackgroundThe continuous exposure of esophageal epithelium to refluxate may induce ectopic expression of bile-responsive genes and contribute to the development of Barrett's esophagus (BE) and esophageal adenocarcinoma. In normal physiology of the gut and liver, the nuclear receptor Pregnane × Receptor (PXR) is an important factor in the detoxification of xenobiotics and bile acid homeostasis. This study aimed to investigate the expression and genetic variation of PXR in reflux esophagitis (RE), Barrett's esophagus (BE) and esophageal adenocarcinoma.MethodsPXR mRNA levels and protein expression were determined in biopsies from patients with adenocarcinoma, BE, or RE, and healthy controls. Esophageal cell lines were stimulated with lithocholic acid and rifampicin. PXR polymorphisms 25385C/T, 7635A/G, and 8055C/T were genotyped in 249 BE patients, 233 RE patients, and 201 controls matched for age and gender.ResultsPXR mRNA levels were significantly higher in adenocarcinoma tissue and columnar Barrett's epithelium, compared to squamous epithelium of these BE patients (P < 0.001), and RE patients (P = 0.003). Immunohistochemical staining of PXR showed predominantly cytoplasmic expression in BE tissue, whereas nuclear expression was found in adenocarcinoma tissue. In cell lines, stimulation with lithocholic acid did not increase PXR mRNA levels, but did induce nuclear translocation of PXR protein. Genotyping of the PXR 7635A/G polymorphism revealed that the G allele was significantly more prevalent in BE than in RE or controls (P = 0.037).ConclusionsPXR expresses in BE and adenocarcinoma tissue, and showed nuclear localization in adenocarcinoma tissue. Upon stimulation with lithocholic acid, PXR translocates to the nuclei of OE19 adenocarcinoma cells. Together with the observed association of a PXR polymorphism and BE, this data implies that PXR may have a function in prediction and treatment of esophageal disease.

Highlights

The continuous exposure of esophageal epithelium to refluxate may induce ectopic expression of bile-responsive genes and contribute to the development of Barrett’s esophagus (BE) and esophageal adenocarcinoma
PXR belongs to the nuclear receptor subfamily of ligand-activated transcription factors that play a key role in the regulation of biliary transport systems and enzymes that confer a protective role against toxic bile acids [12]
As these chronic inflammatory diseases are associated with aberrant bile acid metabolism, there may be a link between PXR and BE

Summary

Introduction

The continuous exposure of esophageal epithelium to refluxate may induce ectopic expression of bile-responsive genes and contribute to the development of Barrett’s esophagus (BE) and esophageal adenocarcinoma. PXR belongs to the nuclear receptor subfamily of ligand-activated transcription factors that play a key role in the regulation of biliary transport systems and enzymes that confer a protective role against toxic bile acids [12]. This group of nuclear receptors includes the constitutive androstrane receptor and the vitamin D receptor [17,18]. PXR is most abundantly found in the liver, the small intestine and the colon [13,15,16,19] It is activated by a structurally diverse array of xenobiotics and endogenous compounds, including bile acids and steroid hormones [13,17,18]. As these chronic inflammatory diseases are associated with aberrant bile acid metabolism, there may be a link between PXR and BE

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