title: High expression of Claudin-2 in esophageal carcinoma and precancerous lesions is significantly associated with the bile salt receptors VDR and TGR5.
abstract: BACKGROUND
  Claudins are a family of integral membrane proteins and are components of tight junctions (TJs). Many TJ proteins are known to tighten the cell structure and maintain a barrier. Claudin-2 forms gated paracellular channels and allows sodium ions and other small positively charged ions to cross between adjacent cells. Recently, we found that vitamin D receptor (VDR) enhanced Claudin-2 expression in colon and that bile salt receptors VDR and Takeda G-protein coupled receptor5 (TGR5) were highly expressed in esophageal adenocarcinoma (EAC) and precancerous lesions. Here, we examined the expression of Claudin-2 in EAC and precancerous lesions and its association with VDR and TGR5 expression.
  
  
  METHODS
  Claudin-2 expression was examined by immunohistochemistry on tissue microarrays, containing EAC, high grade dysplasia (HGD), low grade dysplasia (LGD), Barrett's esophagus (BE), columnar cell metaplasia (CM), squamous cell carcinoma (SCC), and squamous epithelium (SE) cases. Intensity (0 to 3) and percentage were scored for each case. High expression was defined as 2-3 intensity in ≥ 10% of cells.
  
  
  RESULTS
  Claudin-2 was highly expressed in 77% EAC (86/111), 38% HGD (5/13), 61% LGD (17/28), 46% BE (18/39), 45% CM (29/65), 88% SCC (23/26), and 14% SE (11/76). It was significantly more highly-expressed in EAC, SCC and glandular lesions than in SE and more in EAC than in BE and CM. A significant association was found between Claudin-2 expression and VDR and TGR5 expression. No significant association was found between expression of Claudin-2 and age, gender, grade, stage, or patients' survival time in EAC and SCC.
  
  
  CONCLUSIONS
  We conclude that Claudin-2 expression is significantly associated with bile acid receptors VDR and TGR5 expression. Our studies identify a novel role of a tight junction protein in the development and progression of esophageal mucosal metaplasia, dysplasia and carcinoma.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester, Box 626, 601 Elmwood Ave, Rochester, NY, 14642, USA.
authors.forename: Sohaib
authors.initials: S
authors.lastname: Abu-Farsakh
authors.affiliation: Department of Biostatistics and Computational Biology, University of Rochester Medical Center, 265 Crittenden Boulevard CU 420630, Rochester, NY, 14642-0630, USA.
authors.forename: Tongtong
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Biostatistics and Computational Biology, University of Rochester Medical Center, 265 Crittenden Boulevard CU 420630, Rochester, NY, 14642-0630, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Lalonde
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois College of Medicine, 840 South Wood Street MC 716, Chicago, IL, 60612, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester, Box 626, 601 Elmwood Ave, Rochester, NY, 14642, USA. david_zhou@urmc.rochester.edu.
authors.forename: Zhongren
authors.identifier: http://orcid.org/0000-0002-6977-8414
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001471:Barrett Esophagus / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D062446:Claudin-2 / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology; D004947:Esophagus / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D011230:Precancerous Conditions / Q000378:metabolism* / Q000473:pathology; D018167:Receptors, Calcitriol / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
chemical_list: D062446:Claudin-2; C473772:GPBAR1 protein, human; D018167:Receptors, Calcitriol; D043562:Receptors, G-Protein-Coupled; C579457:VDR protein, human
keywords: Barrett’s esophagus; Claudin 2; Esophageal adenocarcinoma; TGR5; Tight junctions; VDR