High expression of Claudin-2 in esophageal carcinoma and precancerous lesions is significantly associated with the bile salt receptors VDR and TGR5

Sohaib Abu-Farsakh,Jun Sun,Tongtong Wu,Amy Lalonde,Zhongren Zhou

doi:10.1186/s12876-017-0590-0

Abstract

BackgroundClaudins 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.MethodsClaudin-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.ResultsClaudin-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.ConclusionsWe 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.

Highlights

Claudins are a family of integral membrane proteins and are components of tight junctions (TJs)
Our study has demonstrated that bile salt receptors vitamin D receptor (VDR) and Takeda G-protein coupled receptor5 (TGR5) were highly expressed in esophageal adenocarcinoma (EAC) and precancerous lesions [29, 30]
High expression of Claudin-2 in precancerous lesions, EAC, and esophageal squamous cell carcinoma (ESCC) Claudin-2 immunostaining is located at cytoplasm and membrane, but predominantly at the cell and the basal membrane of the glands and squamous mucosa

Summary

Introduction

Claudins are a family of integral membrane proteins and are components of tight junctions (TJs). We found that vitamin D receptor (VDR) enhanced Claudin-2 expression in colon and that bile salt receptors VDR and Takeda G-protein coupled receptor (TGR5) were highly expressed in esophageal adenocarcinoma (EAC) and precancerous lesions. Abu-Farsakh et al BMC Gastroenterology (2017) 17:33 and Vitamin D receptor (VDR) [4, 8, 9] They alter gene expression by acting as ligands for nuclear receptors or by activating kinase signaling pathways [10, 11]. Bile acid receptors, including FXR, the Takeda G-proteincouples receptor 5 (TGR5) and VDR, have recently been identified in EAC and esophageal squamous cell carcinoma (ESCC) [4, 12,13,14,15]. We showed that bile salts at pH of 5 destroyed intercellular junctions in squamous mucosa [16]

Methods

Results

Conclusion