β-catenin/TCF4 complex induces the epithelial-to-mesenchymal transition (EMT)-activator ZEB1 to regulate tumor invasiveness
β-catenin/TCF4 complex induces the epithelial-to-mesenchymal transition (EMT)-activator ZEB1 to regulate tumor invasiveness
复制标题
DOI：
10.1073/pnas.1108977108
复制
发表时间：
2011-11-29
影响因子：
11.1
通讯作者：
Postigo, Antonio
中科院分区：
文献类型：
--
作者：
Sanchez-Tillo, Ester;de Barrios, Oriol;Postigo, Antonio
在大多数癌中，恶性细胞侵入周围组织涉及它们的分子重编程，作为上皮向间充质转化（EMT）的一部分。大多数结直肠癌（CRC）中APC基因的突变导致癌蛋白β-连环蛋白的核转位，其在与T细胞和淋巴增强子（TCF-LEF）因子结合后触发EMT和促浸润基因表达谱。EMT的关键诱导物是ZEB 1转录因子，其表达促进癌中的肿瘤发生和转移。作为上皮细胞表型的抑制剂，ZEB 1从不存在于正常结肠的上皮细胞或β-连环蛋白保持膜性的CRC的肿瘤中心。我们在这里表明，ZEB 1是由人类患者（家族性腺瘤性息肉病）和小鼠模型（APC（Min/+））与APC的种系突变，导致β-连环蛋白的核积累的肠肿瘤上皮细胞表达。然而，ZEB 1在携带野生型APC的遗传形式的CRC的上皮中不表达，并且其中β-连环蛋白被排除在细胞核之外（Lynch综合征）。我们发现β-catenin/TCF 4直接与ZEB 1启动子结合并激活其转录。APC突变的CRC细胞中β-连环蛋白和TCF 4的敲低抑制内源性ZEB 1，而APC野生型CRC细胞中β-连环蛋白强制易位至细胞核诱导ZEB 1的从头表达。β-连环蛋白/TCF 4上调MT 1-MMP和LAMC 2与CRC的侵袭性有关，我们在此表明，在APC突变的原发性结直肠肿瘤中，这两种蛋白质都被与其共表达的ZEB 1激活。这些结果将ZEB 1设定为EMT和肿瘤进展中β-连环蛋白/TCF 4信号传导的效应子。
In most carcinomas, invasion of malignant cells into surrounding tissues involves their molecular reprogramming as part of an epithelial-to-mesenchymal transition (EMT). Mutation of the APC gene in most colorectal carcinomas (CRCs) contributes to the nuclear translocation of the oncoprotein beta-catenin that upon binding to T-cell and lymphoid enhancer (TCF-LEF) factors triggers an EMT and a proinvasive gene expression profile. A key inducer of EMT is the ZEB1 transcription factor whose expression promotes tumorigenesis and metastasis in carcinomas. As inhibitor of the epithelial phenotype, ZEB1 is never present in the epithelium of normal colon or the tumor center of CRCs where beta-catenin remains membranous. We show here that ZEB1 is expressed by epithelial cells in intestinal tumors from human patients (familial adenomatous polyposis) and mouse models (APC(Min/+)) with germline mutations of APC that result in nuclear accumulation of beta-catenin. However, ZEB1 is not expressed in the epithelium of hereditary forms of CRCs that carry wild-type APC and where beta-catenin is excluded from the nucleus (Lynch syndrome). We found that beta-catenin/TCF4 binds directly to the ZEB1 promoter and activates its transcription. Knockdown of beta-catenin and TCF4 in APC-mutated CRC cells inhibited endogenous ZEB1, whereas forced translocation of beta-catenin to the nucleus in APC-wild-type CRC cells induced de novo expression of ZEB1. Upregulation of MT1-MMP and LAMC2 by beta-catenin/TCF4 has been linked to invasiveness in CRCs, and we show here that both proteins are activated by ZEB1 coexpressing with it in primary colorectal tumors with mutated APC. These results set ZEB1 as an effector of beta-catenin/TCF4 signaling in EMT and tumor progression.