GATA6 activates Wnt signaling in pancreatic cancer by negatively regulating the Wnt antagonist Dickkopf-1

Zhong, Yi; Wang, Zheng; Fu, Baojin; Pan, Fan; Yachida, Shinichi; Dhara, Mousumi; Albesiano, Emilia; Li, Li; Naito, Yoshiki; Vilardell, Felip; Cummings, Christopher; Martinelli, Paola; Li, Ang; Yonescu, Raluca; Ma, Qingyong; Griffin, Constance A; Real, Francisco X.; Iacobuzio Donahue, Christine A

GATA6 activates Wnt signaling in pancreatic cancer by negatively regulating the Wnt antagonist Dickkopf-1

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dc.contributor.author Zhong, Yica
dc.contributor.author Wang, Zhengca
dc.contributor.author Fu, Baojinca
dc.contributor.author Pan, Fanca
dc.contributor.author Yachida, Shinichica
dc.contributor.author Dhara, Mousumica
dc.contributor.author Albesiano, Emiliaca
dc.contributor.author Li, Lica
dc.contributor.author Naito, Yoshikica
dc.contributor.author Vilardell, Felipca
dc.contributor.author Cummings, Christopherca
dc.contributor.author Martinelli, Paolaca
dc.contributor.author Li, Angca
dc.contributor.author Yonescu, Ralucaca
dc.contributor.author Ma, Qingyongca
dc.contributor.author Griffin, Constance Aca
dc.contributor.author Real, Francisco X.ca
dc.contributor.author Iacobuzio Donahue, Christine Aca
dc.date.accessioned 2015-05-04T07:42:50Z
dc.date.available 2015-05-04T07:42:50Z
dc.date.issued 2011ca
dc.description.abstract 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 carcinogenesis is by virtue of its activation of canonical Wnt signaling via regulation of DKK1.en
dc.description.sponsorship Supported by NIH grants CA106610, CA62924 and CA140599, The George Rubis Endowment for Pancreatic Cancer Research, The Michael Rolfe Pancreatic Cancer Foundation, Sigma Beta Sorority, The Joseph C. Monastra Foundation, The Alfredo Scatena Memorial, The Patty Boshell Pancreas Cancer Foundation, and Grants SAF2007-60860 and ONCOBIO Consolder from Ministerio de Ciencia e Innovación, Madrid, Spain (F.R.). The authors have no financial conflicts of interest related to this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscripten
dc.format.mimetype application/pdfca
dc.identifier.citation Zhong Y, Wang Z, Fu B, Pan F, Yachida S, Dhara M et al. GATA6 activates Wnt signaling in pancreatic cancer by negatively regulating the Wnt antagonist Dickkopf-1. PLoS ONE. 2011; 6(7): e22129. DOI 10.1371/journal.pone.0022129ca
dc.identifier.doi http://dx.doi.org/10.1371/journal.pone.0022129
dc.identifier.issn 1932-6203ca
dc.identifier.uri http://hdl.handle.net/10230/23508
dc.language.iso engca
dc.publisher Public Library of Science (PLoS)ca
dc.relation.ispartof PLoS ONE. 2011; 6(7): e22129
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PN/SAF2007-60860
dc.rights © 2011 Zhong et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
dc.rights.accessRights info:eu-repo/semantics/openAccessca
dc.subject.other Pàncrees -- Malaltiesca
dc.subject.other Fetge -- Càncerca
dc.subject.other Pèptidsca
dc.title GATA6 activates Wnt signaling in pancreatic cancer by negatively regulating the Wnt antagonist Dickkopf-1en
dc.type info:eu-repo/semantics/articleca
dc.type.version info:eu-repo/semantics/publishedVersionca

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