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Vitamin D receptor deficiency enhances Wnt/?-catenin signaling and tumor burden in colon cancer.

ABSTRACT: Aberrant activation of the Wnt/?-catenin pathway is critical for the initiation and progression of most colon cancers. This activation provokes the accumulation of nuclear ?-catenin and the induction of its target genes. Apc(min/+) 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 ?-catenin in the affected cells. Here we describe that vitamin D receptor (VDR) is a crucial modulator of nuclear ?-catenin levels in colon cancer in vivo. By appropriate breeding of Apc(min/+) 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 Apc(min/+)Vdr(-/-) mice had increased nuclear ?-catenin and the tumors reached a larger size than those of Apc(min/+)Vdr(+/+). Both ACF and carcinomas in Apc(min/+)Vdr(-/-) mice showed higher expression of ?-catenin/TCF target genes. In line with this, VDR knock-down in cultured human colon cancer cells enhanced ?-catenin nuclear content and target gene expression. Consistently, VDR depletion abrogated the capacity of 1,25(OH)(2)D(3) to promote the relocation of ?-catenin from the nucleus to the plasma membrane and to inhibit ?-catenin/TCF target genes. In conclusion, VDR controls the level of nuclear ?-catenin in colon cancer cells and can therefore attenuate the impact of oncogenic mutations that activate the Wnt/?-catenin pathway.

SUBMITTER: Larriba MJ

PROVIDER: S-EPMC3156234 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Vitamin D receptor deficiency enhances Wnt/β-catenin signaling and tumor burden in colon cancer.

Larriba María Jesús MJ Ordóñez-Morán Paloma P Chicote Irene I Martín-Fernández Génesis G Puig Isabel I Muñoz Alberto A Pálmer Héctor G HG

PloS one 20110815 8

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. Apc(min/+) 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 o ...[more]

PMID: 21858154

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Project description:BackgroundChemotherapeutic agents that modulate cell cycle checkpoints and/or tumor-specific pathways have shown immense promise in preclinical and clinical studies aimed at anti-cancer therapy. MASTL (Greatwall in Xenopus and Drosophila), a serine/threonine kinase controls the final G2/M checkpoint and prevents premature entry of cells into mitosis. Recent studies suggest that MASTL expression is highly upregulated in cancer and confers resistance against chemotherapy. However, the role and mechanism/s of MASTL mediated regulation of tumorigenesis remains poorly understood.MethodsWe utilized a large patient cohort and mouse models of colon cancer as well as colon cancer cells to determine the role of Mastl and associated mechanism in colon cancer.ResultsHere, we show that MASTL expression increases in colon cancer across all cancer stages compared with normal colon tissue (P < 0.001). Also, increased levels of MASTL associated with high-risk of the disease and poor prognosis. Further, the shRNA silencing of MASTL expression in colon cancer cells induced cell cycle arrest and apoptosis in vitro and inhibited xenograft-tumor growth in vivo. Mechanistic analysis revealed that MASTL expression facilitates colon cancer progression by promoting the β-catenin/Wnt signaling, the key signaling pathway implicated in colon carcinogenesis, and up-regulating anti-apoptotic proteins, Bcl-xL and Survivin. Further studies where colorectal cancer (CRC) cells were subjected to 5-fluorouracil (5FU) treatment revealed a sharp increase in MASTL expression upon chemotherapy, along with increases in Bcl-xL and Survivin expression. Most notably, inhibition of MASTL in these cells induced chemosensitivity to 5FU with downregulation of Survivin and Bcl-xL expression.ConclusionOverall, our data shed light on the heretofore-undescribed mechanistic role of MASTL in key oncogenic signaling pathway/s to regulate colon cancer progression and chemo-resistance that would tremendously help to overcome drug resistance in colon cancer treatment.

Dataset Information

Vitamin D receptor deficiency enhances Wnt/?-catenin signaling and tumor burden in colon cancer.

Publications

Vitamin D receptor deficiency enhances Wnt/β-catenin signaling and tumor burden in colon cancer.

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