cadherin-17在腸道的屏障功能以及腸道致癌中所扮演的角色

Abstract

有許多微生物以及各種的營養物質每天和我們的腸胃道進行接觸。而腸道屏障是一個具有功能的構造，它保護我們免受病原體的入侵、調節營養物質的吸收並且維護腸道免疫黏膜系統的平衡。因此維持一個健康的腸道屏障是非常重要的。腸道上皮細胞接合物複合體包含連接複合體（AJ）以及緊密複合體（TJ）。當接合物複合體失調時，會造成腸道上皮細胞調節腸道通透性的功能喪失，這在許多疾病中扮演著重要的角色。鈣黏著蛋白(Cadherin)是一種跨膜醣蛋白(transmembrane glycoprotein)，會去調節由鈣作為傳導物質的連接，並且是連接複合體（AJ）著主要組成之一。鈣黏著蛋白17(Cadherin-17)是一種腸道專一性表現的鈣黏著蛋白。我們利用類轉錄激活因子活化物核酸酶技術(TALEN)來生產鈣黏著蛋白17的基因剔除小鼠。我們發現在鈣黏著蛋白17的基因剔除小鼠中，在絨毛的長度以及增值比率上並沒有變化。且透過電子顯微鏡觀察，鈣黏著蛋白17的基因剔除小鼠和正常小鼠在腸道上皮細胞之間的細胞複合體並沒有不同。然而對於鈣黏著蛋白17的基因剔除小鼠，不論是在體內還是體外的腸道通透性實驗，相較於正常小鼠，通透性都有顯著的增加。而且鈣黏著蛋白17的基因剔除小鼠相較於正常小鼠，牠對於由葡聚糖硫酸钠(DSS)所誘導的結腸炎(colitis)也更為敏感。更為重要的是我們可以在鈣黏著蛋白17的基因剔除小鼠腸道中發現自發性生長的腺瘤(adenoma)。在AOM/DSS小鼠腸道致癌的實驗中，我們也發現鈣黏著蛋白17的基因剔除小鼠有較多，較大，和較惡性的腸道腫瘤。

A wide variety of microorganisms and nutrient compounds contact with the gastrointestinal tract every day. The gut barrier is the functional unit required for protection from pathogen, regulation of nutrient absorption, and maintenance of the balance of gut mucosal immune system. The maintenance of a healthy intestinal barrier is very important. The intestinal epithelial cell junctional complexes include adherens junctions (AJs) and tight junctions(TJs). The epithelial permeability dysfunction caused by derangement in the junctional complex plays importance roles in many diseases. Cadherins are transmembrane glycoproteins that mediate Ca2+-dependent adhesion between adjacent cells and are the major components of AJ.Cadherin-17is an intestine-specific cadherin. We generated a knockout mice model of cadherin-17 using the TALEN technique. We found that the length of villus of the cdh17-/-mice was no changed. The proliferation rate was also not changed in cdh17-/- mice. Electomicroscopy showed the cell junction between intestinal epithelial cells did not different between the cdh17-/-mice and wild type mice. Cdh17-/- mice showed increased permeability of small intestinal wall in vitro and in vivo permeability assays. Cdh17-/-mice were also more susceptible to DSS-induced colitis. Spontaneous adenoma formation was found in cdh17-/- mice. In AOM/DSS colitis-induced intestinal carcinogenesis model, cdh17-/- mice had more number, larger, and more malignant tumor than the wild type mice