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A noncanonical Frizzled2 pathway regulates epithelial-mesenchymal transition and metastasis.

ABSTRACT: Wnt signaling plays a critical role in embryonic development, and genetic aberrations in this network have been broadly implicated in colorectal cancer. We find that the Wnt receptor Frizzled2 (Fzd2) and its ligands Wnt5a/b are elevated in metastatic liver, lung, colon, and breast cancer cell lines and in high-grade tumors and that their expression correlates with markers of epithelial-mesenchymal transition (EMT). Pharmacologic and genetic perturbations reveal that Fzd2 drives EMT and cell migration through a previously unrecognized, noncanonical pathway that includes Fyn and Stat3. A gene signature regulated by this pathway predicts metastasis and overall survival in patients. We have developed an antibody to Fzd2 that reduces cell migration and invasion and inhibits tumor growth and metastasis in xenografts. We propose that targeting this pathway could provide benefit for patients with tumors expressing high levels of Fzd2 and Wnt5a/b.

SUBMITTER: Gujral TS

PROVIDER: S-EPMC4243058 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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A noncanonical Frizzled2 pathway regulates epithelial-mesenchymal transition and metastasis.

Gujral Taranjit S TS Chan Marina M Peshkin Leonid L Sorger Peter K PK Kirschner Marc W MW MacBeath Gavin G

Cell 20141101 4

Wnt signaling plays a critical role in embryonic development, and genetic aberrations in this network have been broadly implicated in colorectal cancer. We find that the Wnt receptor Frizzled2 (Fzd2) and its ligands Wnt5a/b are elevated in metastatic liver, lung, colon, and breast cancer cell lines and in high-grade tumors and that their expression correlates with markers of epithelial-mesenchymal transition (EMT). Pharmacologic and genetic perturbations reveal that Fzd2 drives EMT and cell migr ...[more]

PMID: 25417160

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Project description:GATA6 acts as an oncogene or tumour suppressor in different cancers. Previously, we found that aberrant expression of GATA6 promoted metastasis in cholangiocarcinoma (CCA). However, the mechanism by which GATA6 promotes metastasis in CCA is unclear. In the present study, we aimed to investigate the role of GATA6 in CCA cell epithelial-mesenchymal transition (EMT). Our results showed that GATA6 expression was positively associated with N-cadherin and vimentin expression but negatively associated with E-cadherin expression in 91 CCA samples. GATA6 promoted EMT and metastasis in CCA cells in vitro and in vivo based on knockdown and overexpression analyses. ChIP-sequencing data revealed that MUC1 is a novel downstream target of GATA6. GATA6 upregulated MUC1 expression through binding to both the 1584 and 1456 GATA-motifs in the promoter region and enhancing its transcription by luciferase reporter assays and point-mutant assays. MUC1 expression was positively associated with N-cadherin and vimentin expression but negatively associated with E-cadherin expression in 91 CCA samples. In addition, MUC1 promoted EMT in CCA cells based on knockdown and overexpression analyses. Moreover, MUC1 knockdown significantly abrogated the GATA6-induced EMT in CCA cells, indicating that MUC1 promoted EMT through upregulating MUC1 in CCA cells. β-Catenin is a putative transcriptional coactivator that regulates EMT in cancers. Our data showed that MUC1 expression was positively associated with nuclear β-catenin expression in 91 CCA samples. MUC1 upregulated nuclear β-catenin expression in CCA cells. Moreover, MUC1 bound to β-catenin in CCA cells based on protein immunoprecipitation analyses. MUC1 knockdown significantly decreased the binding of MUC1 to β-catenin, and thereby decreased nuclear β-catenin protein levels in CCA cells, indicating that MUC1 bound to β-catenin and increased its nuclear expression in CCA cells. Together, our results show that GATA6 promotes EMT through MUC1/β-catenin pathway in CCA, indicating potential implications for anti-metastatic therapy.

Dataset Information

A noncanonical Frizzled2 pathway regulates epithelial-mesenchymal transition and metastasis.

Publications

A noncanonical Frizzled2 pathway regulates epithelial-mesenchymal transition and metastasis.

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