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J Natl Cancer Inst. 2014 Apr;106(4):dju052. doi: 10.1093/jnci/dju052. Epub 2014 Mar 28.

Potentiation of colon cancer susceptibility in mice by colonic epithelial PPAR-δ/β overexpression.

Author information

1
Affiliations of authors: Department of Gastrointestinal Medical Oncology (XZ, MX, JY, IS), Department of Clinical Cancer Prevention (XZ, YW, IS), Department of Pathology (MJM, RRB), Department of Bioinformatics & Computational Biology (GCM, SL), Department of Veterinary Medicine and Surgery (MG), and Department of Biostatistics (JSM), University of Texas MD Anderson Cancer Center, Houston, TX.

Abstract

BACKGROUND:

The nuclear receptor peroxisome proliferator-activated receptor-δ/β (PPAR-d) is upregulated in human colorectal cancers, but its role in colonic tumorigenesis remains controversial.

METHODS:

We generated a novel mouse model of intestinally targeted PPAR-d overexpression to simulate PPAR-d upregulation in human colon carcinogenesis. Colon-specific PPAR-d overexpression was confirmed by real-time reverse transcription polymerase chain reaction, immunoblotting, and activity assays. Mice with and without targeted PPAR-d overexpression were tested for azoxymethane (AOM)-induced colonic tumorigenesis. Mouse whole-genome transcriptome microarray analyses were performed to identify PPAR-d target genes to promote tumorigenesis. We used linear models to test for PPAR-d overexpression trend effects on tumor multiplicity. All statistical tests were two-sided.

RESULTS:

Targeted PPAR-d overexpression markedly increased colonic tumor incidence (from 0 of 10 wild-type [WT] littermate mice to 9 of 10 mice [P < .001] in 2 FVB/N background mouse lines [villin-PPAR-d-1 and villin-PPAR-d-2] at a 5-mg/kg AOM dose) and multiplicity (number of tumors per mouse per mg/kg dose of AOM increased from 0.47 [95% confidence interval [CI] = 0.22 to 0.72] for the WT littermates to 2.15 [95% CI = 1.90 to 2.40] [P < .001] for the villin-PPAR-d-1 mice and from 0.44 [95% CI = 0.09 to 0.79] for the WT littermates to 1.91 [95% CI = 1.57 to 2.25] [P < .001] for the villin-PPAR-d-2 mice). PPAR-d overexpression reversed resistance to AOM-induced colonic tumorigenesis in C57BL/6 mice. PPAR-d overexpression modulated expression of several novel PPAR-d target genes in normal-appearing colonic epithelial cells of mice with PPAR-d overexpression in a pattern that matched the changes in colonic tumors.

CONCLUSIONS:

Our finding that PPAR-d upregulation profoundly enhances susceptibility to colonic tumorigenesis should impact the development of strategies of molecularly targeting PPAR-d in cancer and noncancerous diseases.

PMID:
24681603
PMCID:
PMC3982893
DOI:
10.1093/jnci/dju052
[Indexed for MEDLINE]
Free PMC Article
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