The human PKP2/plakophilin-2 gene is induced by Wnt/β-catenin in normal and colon cancer-associated fibroblasts
Entity
UAM. Departamento de Bioquímica; Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM); Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ)Publisher
John Wiley & Sons Ltd on behalf of UICCDate
2018-02-15Citation
10.1002/ijc.31104
International Journal of Cancer 142.4 (2018): 792-804
ISSN
0020-7136DOI
10.1002/ijc.31104Funded by
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-RProject
Comunidad de Madrid. S2010/BMD-2344/Colomics 2; Gobierno de España. SAF-2015-71878-REDT; Gobierno de España. SAF2013- 43468-R; Gobierno de España. SAF2014-53819-R; Gobierno de España. CB16/12/00273 CIBERONC; Gobierno de España. RD12/0036/0021; Gobierno de España. SAF2016-76377-REditor's Version
http://doi.org/10.1002/ijc.31104Subjects
Colon cancer; Gene regulation; Normal and cancer-associated fibroblasts; PKP2/Plakophilin-2; Wnt/β-catenin signalling; MedicinaRights
© 2017 The AuthorsEsta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
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.
Files in this item
Google Scholar:Niell, Núria
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Larriba, María Jesús
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Ferrer-Mayorga, Gemma
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Sánchez Pérez, María Isabel
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Cantero Cid, Ramón
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Real, Francisco X.
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del Peso, Luis
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Muñoz, Alberto
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González Sancho, José Manuel
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