Claudin-1 up-regulates the repressor ZEB-1 to inhibit E-cadherin expression in colon cancer cells.
Claudin-1 up-regulates the repressor ZEB-1 to inhibit E-cadherin expression in colon cancer cells.
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Claudin-1上调阻遏物ZEB-1以抑制结肠癌细胞中的E-钙粘蛋白表达。
DOI：
10.1053/j.gastro.2011.08.038
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发表时间：
2011-12
期刊：
影响因子：
29.4
通讯作者：
Dhawan P
中科院分区：
文献类型：
--
作者：
Singh AB;Sharma A;Smith JJ;Krishnan M;Chen X;Eschrich S;Washington MK;Yeatman TJ;Beauchamp RD;Dhawan P
紧密连接蛋白claudin-1的表达在结肠肿瘤中失调，并与其进展有关。上调claudin-1可降低E-cadherin的表达。我们研究了claudin-1调控E-cadherin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锌指E-box结合同源盒-1 （ZEB-1）转录抑制因子与claudio -1的表达。我们分析了过表达claudin-1的SW480结肠癌细胞，或claudin-1表达被抑制的SW620细胞，以确定对ZEB-1和E-cadherin表达、侵袭活性和对anoikis的抗性的影响。我们研究了在Wnt或磷脂酰肌醇-3激酶信号通路中表达组成性活性或显性阴性形式因子的细胞，并使用这些通路的药理学抑制剂来研究它们在cludin -1依赖性的ZEB-1调节中的作用。我们使用微阵列分析检测了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的表达下调E-cadherin的表达。Claudin-1激活Wnt和磷脂酰肌醇-3激酶/Akt信号。ZEB-1介导claudin-1调控的细胞侵袭和凋亡的变化。claudin-1与ZEB-1在人结肠肿瘤中的表达相关。在从正常结肠上皮到结肠腺癌的过程中，E-cadherin水平下降，而claudin-1和ZEB-1水平升高。结肠肿瘤中E-cadherin下调和ZEB-1上调与生存时间缩短相关。Claudin-1上调抑制因子ZEB-1，降低结肠癌细胞中E-cadherin的表达，增加其侵袭活性，减少病变。该途径与结直肠癌的进展和患者生存有关。
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.
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