β-catenin/TCF4 complex induces the epithelial-to-mesenchymal transition (EMT)-activator ZEB1 to regulate tumor invasiveness

Abstract

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 β-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 β-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∕þ ) with germline mutations of APC that result in nuclear accumulation of β-catenin. However, ZEB1 is not expressed in the epithelium of hereditary forms of CRCs that carry wild-type APC and where β-catenin is excluded from the nucleus (Lynch syndrome). We found that β-catenin/TCF4 binds directly to the ZEB1 promoter and activates its transcription. Knockdown of β-catenin and TCF4 in APC-mutated CRC cells inhibited endogenous ZEB1, whereas forced translocation of β-catenin to the nucleus in APC-wild-type CRC cells induced de novo expression of ZEB1. Upregulation of MT1-MMP and LAMC2 by β-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 β-catenin/TCF4 signaling in EMT and tumor progression.

The EMT activator ZEB1 promotes tumor growth and determines differential response to chemotherapy in mantle cell lymphoma

“…3,5,6,8 In carcinomas, ZEB1 coexpresses with b-catenin in undifferentiated tumor cells at their leading front, promoting invasiveness and metastasis. [27][28][29][30][31] We therefore decided to examine ZEB1 expression in a tissue microarray (TMA) of MCLs. ZEB1 was expressed in 50.0% of the cases for about 43.4% that were positive for b-catenin (Figure 1), (Supplementary Figures S1A and S1B).…”

“…20,26 In solid tumors, b-catenin colocalizes with the transcription factor ZEB1 in the nuclei of undifferentiated cancer cells at the invasive front. [27][28][29][30][31] Depending on the target gene, ZEB1 could function as either a transcriptional repressor or an activator through the recruitment of different cofactors. 29,[32][33][34][35] In malignant epithelial cells, ZEB1 triggers an epithelial-tomesenchymal transition (EMT), a process by which cancer cells acquire a pro-invasive phenotype.…”

LAMC2 enhances the metastatic potential of lung adenocarcinoma

“…15 There is growing evidence that LAMC2 expression increases in the carcinoma cells undergoing EMT, [16][17][18] and that level of LAMC2 expression is regulated directly by the EMT master regulator ZEB1 and activated β-catenin in invasive colorectal carcinoma cells. 19,20 Combining results of gene expression microarrays with a metastasis selection model in mice, we found a robust association between metastatic derivatives of A549 lung ADC cells and increased expression of LAMC2. Here we demonstrate that LAMC2 promotes migration, invasion and metastasis in human lung ADC cells via induction of EMT.…”

DKK3 blocked translocation of β‐catenin/EMT induced by hypoxia and improved gemcitabine therapeutic effect in pancreatic cancer Bxpc‐3 cell

“…One of the signals initiating EMT is Wnt pathway whose stimulation triggers nuclear translocation of β‐catenin, which in turn forms a complex with T cell factor(TCF) transcription factors to transcribe target genes, resulting in activation of c‐myc and cyclinD1 6. Furthermore, a strong correlation between EMT and drug resistance has been established 7.…”