Abu-Farsakh Sohaib, Wu Tongtong, Lalonde Amy, Sun Jun, Zhou Zhongren
Department of Pathology and Laboratory Medicine, University of Rochester, Box 626, 601 Elmwood Ave, Rochester, NY, 14642, USA.
Department of Biostatistics and Computational Biology, University of Rochester Medical Center, 265 Crittenden Boulevard CU 420630, Rochester, NY, 14642-0630, USA.
BMC Gastroenterol. 2017 Feb 17;17(1):33. doi: 10.1186/s12876-017-0590-0.
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.
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.
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.
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.
闭合蛋白是一类整合膜蛋白，是紧密连接（TJ）的组成成分。已知许多TJ蛋白可强化细胞结构并维持屏障功能。闭合蛋白-2形成门控性细胞旁通道，允许钠离子和其他带正电荷的小离子在相邻细胞间穿过。最近，我们发现维生素D受体（VDR）可增强结肠中闭合蛋白-2的表达，且胆汁酸受体VDR和武田G蛋白偶联受体5（TGR5）在食管腺癌（EAC）及癌前病变中高表达。在此，我们检测了EAC及癌前病变中闭合蛋白-2的表达及其与VDR和TGR5表达的相关性。
采用免疫组织化学方法检测组织芯片中闭合蛋白-2的表达，该组织芯片包含EAC、高级别异型增生（HGD）、低级别异型增生（LGD）、巴雷特食管（BE）、柱状细胞化生（CM）、鳞状细胞癌（SCC）及鳞状上皮（SE）病例。对每个病例的强度（0至3）和百分比进行评分。高表达定义为≥10%的细胞中强度为2 - 3。
闭合蛋白-2在77%的EAC（86/111）、38%的HGD（5/13）、61%的LGD（17/28）、46%的BE（18/39）、45%的CM（29/65）、88%的SCC（23/26）及14%的SE（11/76）中高表达。其在EAC、SCC及腺性病变中的表达显著高于SE，在EAC中的表达高于BE和CM。闭合蛋白-2表达与VDR和TGR5表达之间存在显著相关性。在EAC和SCC中，闭合蛋白-2的表达与年龄、性别、分级、分期或患者生存时间之间未发现显著相关性。
我们得出结论，闭合蛋白-2的表达与胆汁酸受体VDR和TGR5的表达显著相关。我们的研究确定了一种紧密连接蛋白在食管黏膜化生、异型增生及癌发生发展过程中的新作用。
