title: Expression, localization and polymorphisms of the nuclear receptor PXR in Barrett's esophagus and esophageal adenocarcinoma.
abstract: BACKGROUND
  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. 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.
  
  
  METHODS
  PXR 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.
  
  
  RESULTS
  PXR 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).
  
  
  CONCLUSIONS
  PXR 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.
authors: Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands. A.vandewinkel@erasmusmc.nl
authors: Anouk
authors: A
authors: van de Winkel
authors: Vivianda
authors: V
authors: Menke
authors: Astrid
authors: A
authors: Capello
authors: Leon M G
authors: LM
authors: Moons
authors: Raymond G J
authors: RG
authors: Pot
authors: Herman
authors: H
authors: van Dekken
authors: Peter D
authors: PD
authors: Siersema
authors: Johannes G
authors: JG
authors: Kusters
authors: Luc J W
authors: LJ
authors: van der Laan
authors: Ernst J
authors: EJ
authors: Kuipers
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D001471:Barrett Esophagus / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D004942:Esophagitis, Peptic / Q000235:genetics / Q000473:pathology; D004947:Esophagus / Q000473:pathology; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011987:Receptors, Steroid / Q000235:genetics*; D014178:Translocation, Genetic; D055815:Young Adult
chemical_list: D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid