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

Niell, Núria; Larriba, María Jesús; Ferrer Mayorga, Gemma; Sánchez Pérez, Isabel; Cantero, Ramón; Real, Francisco X.; Peso, Luis Del; Muñoz, Alberto; González Sancho, José Manuel

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

Mostra el registre complet Registre parcial de l'ítem

dc.contributor.author Niell, Núriaca
dc.contributor.author Larriba, María Jesúsca
dc.contributor.author Ferrer Mayorga, Gemmaca
dc.contributor.author Sánchez Pérez, Isabelca
dc.contributor.author Cantero, Ramónca
dc.contributor.author Real, Francisco X.ca
dc.contributor.author Peso, Luis Delca
dc.contributor.author Muñoz, Albertoca
dc.contributor.author González Sancho, José Manuelca
dc.date.accessioned 2018-04-16T07:30:23Z
dc.date.available 2018-04-16T07:30:23Z
dc.date.issued 2018
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.
dc.description.sponsorship This work was supported by the Spanish Ministerio de Economía y Competitividad and the European Regional Development Fund (Fondos FEDER) (SAF2013-43468‐R, and SAF2014-53819‐R), the Agencia Estatal de Investigación‐Fondos FEDER (SAF2016-76377‐R, AEI/FEDER, UE), the Comunidad de Madrid (S2010/BMD‐2344 Colomics2), the Instituto de Salud Carlos III-Fondos FEDER (RD12/0036/0021, and CIBERONC‐CB16/12/00273) and the Nuclear Receptors Network (Nurcamein, SAF2015-71878‐REDT).
dc.format.mimetype application/pdf
dc.identifier.citation Niell N, Larriba MJ, Ferrer-Mayorga G, Sánchez-Pérez I, Cantero R, Real FX et al. The human PKP2/plakophilin-2 gene is induced by Wnt/beta-catenin in normal and colon cancer-associated fibroblasts. Int J Cancer. 2018 Feb 15;142(4):792-804. DOI: 10.1002/ijc.31104. Epub 2017 Oct 31
dc.identifier.doi http://dx.doi.org/10.1002/ijc.31104
dc.identifier.issn 0020-7136
dc.identifier.uri http://hdl.handle.net/10230/34358
dc.language.iso eng
dc.publisher Wileyca
dc.relation.ispartof International Journal of Cancer. 2018 Feb 15;142(4):792-804
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015-71878-REDT
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013-43468-R
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2014-53819-R
dc.rights © 2017 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.keyword PKP2/Plakophilin-2
dc.subject.keyword Wnt/β-catenin signalling
dc.subject.keyword Colon cancer
dc.subject.keyword Gene regulation
dc.subject.keyword Normal and cancer-associated fibroblasts
dc.title The human PKP2/plakophilin-2 gene is induced by Wnt/β-catenin in normal and colon cancer-associated fibroblastsca
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

Col·leccions

Articles (Departament de Medicina i Ciències de la Vida)