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Rationale for targeting the Wnt signalling modulator Dickkopf-1 for oncology.

ABSTRACT: Wnt signalling is a fundamental pathway involved in embryonic development and adult tissue homeostasis. Mutations in the pathway frequently lead to developmental defects and cancer. As such, therapeutic intervention of this pathway has generated tremendous interest. Dickkopf-1 (DKK1) is a secreted inhibitor of β-catenin-dependent Wnt signalling and was originally characterized as a tumour suppressor based on the prevailing view that Wnt signalling promotes cancer pathogenesis. However, DKK1 appears to increase tumour growth and metastasis in preclinical models and its elevated expression correlates with a poor prognosis in a range of cancers, indicating that DKK1 has more complex cellular and biological functions than originally appreciated. Here, we review current evidence for the cancer-promoting activity of DKK1 and recent insights into the effects of DKK1 on signalling pathways in both cancer and immune cells. We discuss the rationale and promise of targeting DKK1 for oncology.

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This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc.

SUBMITTER: Kagey MH

PROVIDER: S-EPMC5727329 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Rationale for targeting the Wnt signalling modulator Dickkopf-1 for oncology.

Kagey Michael H MH He Xi X

British journal of pharmacology 20170707 24

Wnt signalling is a fundamental pathway involved in embryonic development and adult tissue homeostasis. Mutations in the pathway frequently lead to developmental defects and cancer. As such, therapeutic intervention of this pathway has generated tremendous interest. Dickkopf-1 (DKK1) is a secreted inhibitor of β-catenin-dependent Wnt signalling and was originally characterized as a tumour suppressor based on the prevailing view that Wnt signalling promotes cancer pathogenesis. However, DKK1 appe ...[more]

PMID: 28574171

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease characterized by late diagnosis and treatment resistance. Recurrent genetic alterations in defined genes in association with perturbations of developmental cell signaling pathways have been associated with PDAC development and progression. Here, we show that GATA6 contributes to pancreatic carcinogenesis during the temporal progression of pancreatic intraepithelial neoplasia by virtue of Wnt pathway activation. GATA6 is recurrently amplified by both quantitative-PCR and fluorescent in-situ hybridization in human pancreatic intraepithelial neoplasia and in PDAC tissues, and GATA6 copy number is significantly correlated with overall patient survival. Forced overexpression of GATA6 in cancer cell lines enhanced cell proliferation and colony formation in soft agar in vitro and growth in vivo, as well as increased Wnt signaling. By contrast siRNA mediated knockdown of GATA6 led to corresponding decreases in these same parameters. The effects of GATA6 were found to be due to its ability to bind DNA, as forced overexpression of a DNA-binding mutant of GATA6 had no effects on cell growth in vitro or in vivo, nor did they affect Wnt signaling levels in these same cells. A microarray analysis revealed the Wnt antagonist Dickopf-1 (DKK1) as a dysregulated gene in association with GATA6 knockdown, and direct binding of GATA6 to the DKK1 promoter was confirmed by chromatin immunoprecipitation and electrophoretic mobility shift assays. Transient transfection of GATA6, but not mutant GATA6, into cancer cell lines led to decreased DKK1 mRNA expression and secretion of DKK1 protein into culture media. Forced overexpression of DKK1 antagonized the effects of GATA6 on Wnt signaling in pancreatic cancer cells. These findings illustrate that one mechanism by which GATA6 promotes pancreatic intraepithelial neoplasia is by virtue of its activation of canonical Wnt signaling via regulation of DKK1. AsPC1 and A13A cells were stably transfected with a lentivirus expressing mock shRNA or shRNA to GATA6. Each control/shRNA pair (total 4 samples) was analyzed by two-color microarray and the genes commonly dysregulated in both cell lines identified.

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Rationale for targeting the Wnt signalling modulator Dickkopf-1 for oncology.

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Rationale for targeting the Wnt signalling modulator Dickkopf-1 for oncology.

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