The human PKP2/plakophilin-2 gene is induced by Wnt/β-catenin in normal and colon cancer-associated fibroblasts

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Show simple item record Niell, Núria Larriba, María Jesús Ferrer-Mayorga, Gemma Sánchez-Pérez, Isabel Cantero, Ramón Real, Francisco X. del Peso, Luis Muñoz, Alberto González-Sancho, José Manuel
dc.contributor.other UAM. Departamento de Bioquímica es_ES
dc.contributor.other Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM) es_ES
dc.contributor.other Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ) es_ES 2018-03-21T12:04:50Z 2018-03-21T12:04:50Z 2018-02-15
dc.identifier.citation International Journal of Cancer 142.4 (2018): 792-804 en_US
dc.identifier.issn 0020-7136 es_ES
dc.description.abstract Colorectal cancer results from the malignant transformation of colonic epithelial cells. Stromal fibroblasts are the main component of the tumour microenvironment, and play an important role in the progression of this and other neoplasias. Wnt/β-catenin signalling is essential for colon homeostasis, but aberrant, constitutive activation of this pathway is a hallmark of colorectal cancer. Here we present the first transcriptomic study on the effect of a Wnt factor on human colonic myofibroblasts. Wnt3A regulates the expression of 1,136 genes, of which 662 are upregulated and 474 are downregulated in CCD-18Co cells. A set of genes encoding inhibitors of the Wnt/β-catenin pathway stand out among those induced by Wnt3A, which suggests that there is a feedback inhibitory mechanism. We also show that the PKP2 gene encoding the desmosomal protein Plakophilin-2 is a novel direct transcriptional target of Wnt/β-catenin in normal and colon cancer-associated fibroblasts. PKP2 is induced by β-catenin/TCF through three binding sites in the gene promoter and one additional binding site located in an enhancer 20 kb upstream from the transcription start site. Moreover, Plakophilin-2 antagonizes Wnt/β-catenin transcriptional activity in HEK-293T cells, which suggests that it may act as an intracellular inhibitor of the Wnt/β-catenin pathway. Our results demonstrate that stromal fibroblasts respond to canonical Wnt signalling and that Plakophilin-2 plays a role in the feedback control of this effect suggesting that the response to Wnt factors in the stroma may modulate Wnt activity in the tumour cells. en_US
dc.description.sponsorship Grant sponsor: Consejería de Educación, Juventud y Deporte, Comunidad de Madrid; Grant number: S2010/BMD-2344 Colomics2; Grant sponsor: Spanish Ministerio de Economía y Competitividad-Fondos FEDER; Grant numbers: Nurcamein SAF-2015-71878-REDT, SAF2013- 43468-R, SAF2014-53819-R; Grant sponsor: Instituto de la Salud Carlos III - Fondos FEDER; Grant number: CB16/12/00273 CIBERONC, RD12/0036/0021; Grant sponsor: Agencia Estatal de Investigación - Fondos FEDER; Grant number: SAF2016-76377-R en_US
dc.format.extent 13 pag. es_ES
dc.format.mimetype application/pdf en
dc.language.iso eng en
dc.publisher John Wiley & Sons Ltd on behalf of UICC en_US
dc.relation.ispartof International Journal of Cancer en_US
dc.rights © 2017 The Authors en_US
dc.subject.other Colon cancer en_US
dc.subject.other Gene regulation en_US
dc.subject.other Normal and cancer-associated fibroblasts en_US
dc.subject.other PKP2/Plakophilin-2 en_US
dc.subject.other Wnt/β-catenin signalling en_US
dc.title The human PKP2/plakophilin-2 gene is induced by Wnt/β-catenin in normal and colon cancer-associated fibroblasts en_US
dc.type article en
dc.subject.eciencia Medicina es_ES
dc.relation.publisherversion es_ES
dc.identifier.doi 10.1002/ijc.31104 es_ES
dc.identifier.publicationfirstpage 792 es_ES
dc.identifier.publicationissue 4 es_ES
dc.identifier.publicationlastpage 804 es_ES
dc.identifier.publicationvolume 142 es_ES
dc.relation.projectID Comunidad de Madrid. S2010/BMD-2344/Colomics 2 es_ES
dc.relation.projectID Gobierno de España. SAF-2015-71878-REDT es_ES
dc.relation.projectID Gobierno de España. SAF2013- 43468-R es_ES
dc.relation.projectID Gobierno de España. SAF2014-53819-R es_ES
dc.relation.projectID Gobierno de España. CB16/12/00273 CIBERONC es_ES
dc.relation.projectID Gobierno de España. RD12/0036/0021 es_ES
dc.relation.projectID Gobierno de España. SAF2016-76377-R es_ES
dc.type.version info:eu-repo/semantics/publishedVersion en Reconocimiento – NoComercial – SinObraDerivada es_ES
dc.rights.accessRights openAccess en
dc.authorUAM Niell Garolera, Nuria (278877)
dc.authorUAM Peso Ovalle, Luis (260044)

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