Deletion of cadherin-17 enhances intestinal permeability andsusceptibility to intestinal tumour formation
Deletion of cadherin-17 enhances intestinal permeability andsusceptibility to intestinal tumour formation
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DOI：
10.1002/path.5138
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发表时间：
2018-11-01
影响因子：
7.3
通讯作者：
Jeng, Yung-Ming
中科院分区：
文献类型：
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作者：
Chang, Ya-Yun;Yu, Linda Chia-Hui;Jeng, Yung-Ming
钙粘蛋白-17是一种在肠上皮细胞中特异性表达的粘附分子。它在人类结直肠癌中经常表达不足。钙粘蛋白-17的生理功能及其在肿瘤发生中的作用尚未确定。我们使用转录激活因子样效应物核酸酶技术来产生Cdh 17敲除（KO）小鼠模型。对肠组织进行组织学、免疫组织化学和超微结构分析。通过口服葡聚糖硫酸钠（DSS）诱导结肠炎，并研究对肠道肿瘤发生的影响，小鼠给予氧化偶氮甲烷（AOM）和DSS诱导结肠炎相关癌症。Cdh 17 KO小鼠存活且可生育。它们的小肠和大肠的组织学与野生型小鼠相似。肠上皮的连接结构得以保留。钙粘蛋白-17的丢失导致对DSS诱导的结肠炎的渗透性和易感性增加。AOM/DSS模型表明Cdh 17 KO增强了肠道中的肿瘤形成和进展。在Cdh 17基因敲除小鼠的肿瘤中，发现了Yap 1核转位增加，但β-连环蛋白核转位未增加。总之，钙粘蛋白-17通过限制肠上皮细胞的通透性在肠内稳态中起着至关重要的作用。钙粘蛋白-17也是肠上皮细胞的肿瘤抑制因子。版权所有（c）2018大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
Cadherin-17 is an adhesion molecule expressed specifically in intestinal epithelial cells. It is frequently underexpressed in human colorectal cancer. The physiological function of cadherin-17 and its role in tumourigenesis have not yet been determined. We used the transcription activator-like effector nuclease technique to generate a Cdh17 knockout (KO) mouse model. Intestinal tissues were analysed with histological, immunohistochemical and ultrastructural methods. Colitis was induced by oral administration of dextran sulphate sodium (DSS), and, to study effects on intestinal tumourigenesis, mice were given azoxymethane (AOM) and DSS to induce colitis-associated cancer. Cdh17 KO mice were viable and fertile. The histology of their small and large intestines was similar to that of wild-type mice. The junctional architecture of the intestinal epithelium was preserved. The loss of cadherin-17 resulted in increased permeability and susceptibility to DSS-induced colitis. The AOM/DSS model demonstrated that Cdh17 KO enhanced tumour formation and progression in the intestine. Increased nuclear translocation of Yap1, but not of -catenin, was identified in the tumours of Cdh17 KO mice. In conclusion, cadherin-17 plays a crucial role in intestinal homeostasis by limiting the permeability of the intestinal epithelium. Cadherin-17 is also a tumour suppressor for intestinal epithelia. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.