Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Gastroenterology. 2011 Dec;141(6):2140-53. doi: 10.1053/j.gastro.2011.08.038. Epub 2011 Aug 28.
BACKGROUND & AIMS: Expression of the tight junction protein claudin-1 is dysregulated in colon tumors and associates with their progression. Up-regulation of claudin-1 reduces expression of E-cadherin. We investigated the mechanisms by which claudin-1 regulates E-cadherin expression and its effects in colon cancer cells.
We used gene expression analysis, immunoblotting, and reverse transcription polymerase chain reaction to associate expression of the repressor of transcription Zinc Finger E-box binding homeobox-box1 (ZEB-1) with claudin-1. We analyzed SW480 colon cancer cells that overexpressed claudin-1, or SW620 cells in which claudin-1 expression was repressed, to determine the effects on ZEB-1 and E-cadherin expression, invasive activity, and resistance to anoikis. We studied cells that expressed constitutively active or dominant negative forms of factors in the Wnt or phosphotidylinositol-3-kinase signaling pathways and used pharmacologic inhibitors of these pathways to study their role in claudin-1-dependent regulation of ZEB-1. We used microarray analysis to examine gene expression patterns in 260 colorectal tumor and normal colon samples.
Claudin-1 down-regulates E-cadherin expression by up-regulating expression of ZEB-1. Claudin-1 activates Wnt and phosphotidylinositol-3-kinase/Akt signaling. ZEB-1 mediates claudin-1-regulated changes in cell invasion and anoikis. Expression of claudin-1 correlated with that of ZEB-1 in human colon tumor samples. In the progression from normal colonic epithelium to colon adenocarcinoma, levels of E-cadherin decreased, whereas levels of claudin-1 and ZEB-1 increased. Down-regulation of E-cadherin and up-regulation of ZEB-1 in colon tumors were associated with shorter survival times.
Claudin-1 up-regulates the repressor ZEB-1 to reduce expression of E-cadherin in colon cancer cells, increasing their invasive activity and reducing anoikis. This pathway is associated with colorectal cancer progression and patient survival.
紧密连接蛋白 Claudin-1 的表达在结肠肿瘤中失调，并与肿瘤的进展相关。Claudin-1 的上调会降低 E-钙黏蛋白的表达。我们研究了 Claudin-1 调节 E-钙黏蛋白表达的机制及其在结肠癌细胞中的作用。
我们使用基因表达分析、免疫印迹和逆转录聚合酶链反应来关联转录抑制因子锌指 E 盒结合同源盒 1（ZEB-1）与 Claudin-1 的表达。我们分析了过表达 Claudin-1 的 SW480 结肠癌细胞或 Claudin-1 表达受抑制的 SW620 细胞，以确定其对 ZEB-1 和 E-钙黏蛋白表达、侵袭活性和抗失巢凋亡的影响。我们研究了表达 Wnt 或磷酸肌醇 3-激酶信号通路中组成性激活或显性负形式因子的细胞，并使用这些通路的药理学抑制剂研究它们在 Claudin-1 依赖性调节 ZEB-1 中的作用。我们使用微阵列分析研究了 260 个结直肠肿瘤和正常结肠样本的基因表达模式。
Claudin-1 通过上调 ZEB-1 表达下调 E-钙黏蛋白表达。Claudin-1 激活 Wnt 和磷酸肌醇 3-激酶/Akt 信号通路。ZEB-1 介导 Claudin-1 调节的细胞侵袭和失巢凋亡变化。Claudin-1 在人结肠肿瘤样本中的表达与 ZEB-1 的表达相关。在从正常结肠上皮到结肠腺癌的进展过程中，E-钙黏蛋白的水平降低，而 Claudin-1 和 ZEB-1 的水平升高。结肠肿瘤中 E-钙黏蛋白的下调和 ZEB-1 的上调与较短的生存时间相关。
Claudin-1 上调转录抑制因子 ZEB-1，降低结肠癌细胞中 E-钙黏蛋白的表达，增加其侵袭活性并减少失巢凋亡。该通路与结直肠癌的进展和患者的生存时间相关。
