PLoS ONE: Vitamin D Receptor Deficiency Enhances Wnt/β-Catenin Signaling and Tumor Burden in Colon Cancer

PLoS ONE: Vitamin D Receptor Deficiency Enhances Wnt/β-Catenin Signaling and Tumor Burden in Colon Cancer: "Vitamin D Receptor Deficiency Enhances Wnt/β-Catenin Signaling and Tumor Burden in Colon Cancer

Aberrant activation of the Wnt/β-catenin pathway is critical for the initiation and progression of most colon cancers. This activation provokes the accumulation of nuclear β-catenin and the induction of its target genes. Apcmin/+ mice are the most commonly used model for colon cancer. They harbor a mutated Apc allele and develop intestinal adenomas and carcinomas during the first months of life. This phenotype is caused by the mutation of the second Apc allele and the consequent accumulation of nuclear β-catenin in the affected cells. Here we describe that vitamin D receptor (VDR) is a crucial modulator of nuclear β-catenin levels in colon cancer in vivo. By appropriate breeding of Apcmin/+ mice and Vdr+/− mice we have generated animals expressing a mutated Apc allele and two, one, or none Vdr wild type alleles. Lack of Vdr increased the number of colonic Aberrant Crypt Foci (ACF) but not that of adenomas or carcinomas in either small intestine or colon. Importantly, colon ACF and tumors of Apcmin/+Vdr-/- mice had increased nuclear β-catenin and the tumors reached a larger size than those of Apcmin/+Vdr+/+. Both ACF and carcinomas in Apcmin/+Vdr-/- mice showed higher expression of β-catenin/TCF target genes. In line with this, VDR knock-down in cultured human colon cancer cells enhanced β-catenin nuclear content and target gene expression. Consistently, VDR depletion abrogated the capacity of 1,25(OH)2D3 to promote the relocation of β-catenin from the nucleus to the plasma membrane and to inhibit β-catenin/TCF target genes. In conclusion, VDR controls the level of nuclear β-catenin in colon cancer cells and can therefore attenuate the impact of oncogenic mutations that activate the Wnt/β-catenin pathway.

María Jesús Larriba1, Paloma Ordóñez-Morán1¤, Irene Chicote2, Génesis Martín-Fernández1, Isabel Puig2, Alberto Muñoz1, Héctor G. Pálmer2*

1 Instituto de Investigaciones Biomédicas 'Alberto Sols', Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain, 2 Vall d'Hebrón Institute of Oncology, Stem Cells and Cancer Laboratory, Barcelona, Spain


Abstract

Aberrant activation of the Wnt/β-catenin pathway is critical for the initiation and progression of most colon cancers. This activation provokes the accumulation of nuclear β-catenin and the induction of its target genes. Apcmin/+ mice are the most commonly used model for colon cancer. They harbor a mutated Apc allele and develop intestinal adenomas and carcinomas during the first months of life. This phenotype is caused by the mutation of the second Apc allele and the consequent accumulation of nuclear β-catenin in the affected cells. Here we describe that vitamin D receptor (VDR) is a crucial modulator of nuclear β-catenin levels in colon cancer in vivo. By appropriate breeding of Apcmin/+ mice and Vdr+/− mice we have generated animals expressing a mutated Apc allele and two, one, or none Vdr wild type alleles. Lack of Vdr increased the number of colonic Aberrant Crypt Foci (ACF) but not that of adenomas or carcinomas in either small intestine or colon. Importantly, colon ACF and tumors of Apcmin/+Vdr-/- mice had increased nuclear β-catenin and the tumors reached a larger size than those of Apcmin/+Vdr+/+. Both ACF and carcinomas in Apcmin/+Vdr-/- mice showed higher expression of β-catenin/TCF target genes. In line with this, VDR knock-down in cultured human colon cancer cells enhanced β-catenin nuclear content and target gene expression. Consistently, VDR depletion abrogated the capacity of 1,25(OH)2D3 to promote the relocation of β-catenin from the nucleus to the plasma membrane and to inhibit β-catenin/TCF target genes. In conclusion, VDR controls the level of nuclear β-catenin in colon cancer cells and can therefore attenuate the impact of oncogenic mutations that activate the Wnt/β-catenin pathway.

Citation: Larriba MJ, Ordóñez-Morán P, Chicote I, Martín-Fernández G, Puig I, et al. (2011) Vitamin D Receptor Deficiency Enhances Wnt/β-Catenin Signaling and Tumor Burden in Colon Cancer. PLoS ONE 6(8): e23524. doi:10.1371/journal.pone.0023524

Editor: Moray Campbell, Roswell Park Cancer Institute, United States of America

Received: March 23, 2011; Accepted: July 19, 2011; Published: August 15, 2011

Copyright: © 2011 Larriba 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.

Funding: This work was supported by Fondo de Investigación Sanitaria-Instituto de Salud Carlos III (ISCIII, PI081356), Vall d'Hebrón Institute of Oncology, Olga Torres Foundation, Fundación de la Asociación Española de Lucha Contra el Cáncer (AECC), Ministerio de Ciencia e Innovación (SAF2010-18302) and Red Temática de Investigación Cooperativa en Cáncer (ISCIII, RD06/0020/0009). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

* E-mail: hgpalmer@vhio.net

¤ Current address: École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

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Actualidad Ultimas noticias - JANOes y agencias - El receptor de la vitamina D frena la progresion del cancer de colon - JANO.es - ELSEVIER: "ONCOLOGÍA
El receptor de la vitamina D frena la progresión del cáncer de colon

JANO.es y agencias · 17 Agosto 2011 11:18


Frena la acción de la beta-catenina acumulada en el núcleo celular y evita que la célula intestinal se convierta en tumoral maligna.

El receptor de la vitamina D (VDR) es esencial para frenar el avance del cáncer de colon y limitar su agresividad, lo que avala el desarrollo de fármacos antitumorales basados en la estructura de esta vitamina, según una investigación del Vall d’Hebron Institut d’Oncologia (VHIO) y del Instituto de Investigaciones Biomédicas Alberto Sols-CSIC-UAB, publicado en PLoS One.

El trabajo ha confirmado que la estimulación del VDR es fundamental para proteger contra el avance del cáncer de colon, puesto que frena la acción de la proteína beta-catenina acumulada en el núcleo celular y evita que la célula intestinal se convierta en tumoral maligna.

“El VDR controla la señal anómala que desata el crecimiento y la multiplicación incontrolada de las células de colon que acaba provocando la aparición del tumor”, ha explicado en un comunicado el coordinador del estudio y responsable del laboratorio de Células Madre y Cáncer del VHIO, Héctor Palmer.

El receptor VDR no protege frente a la aparición del tumor, pero interviene en su fase de crecimiento y frena su agresividad, tal y como demuestra este estudio realizado en ratones que replican las fases iniciales de la enfermedad y en cultivos de células de cáncer de colon humanas.

Además, este factor escasea en dos tercios de los tumores de colon avanzados, lo que indica que su pérdida contribuye a acelerar el crecimiento del tumor.

Los resultados sugieren que la deficiencia crónica de vitamina D supone un factor de riesgo para desarrollar tumores de colon más agresivos, y que los pacientes en las etapas iniciales de la enfermedad, que aún tienen una cantidad sustancial de VDR en las células, podrían beneficiarse de la administración de la vitamina D3.

También abren las puertas al desarrollo de fármacos antitumorales basados en la estructura de la vitamina D, aunque faltan años de investigación antes de aplicarlos en pacientes.



PLoS ONE 2011;10.1371/journal.pone.0023524
PLoS ONE: Vitamin D Receptor Deficiency Enhances Wnt/β-Catenin Signaling and Tumor Burden in Colon Cancer: "- Enviado mediante la barra Google"

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