Other
12 Authors
- Liang S,
- Moussalli MJ,
- Shureiqi I,
- Xu M,
- Manyam GC,
- Gagea M,
- Yu J,
- Wu Y,
- Zuo X,
- Broaddus RR,
- Morris JS,
- Lee SI
| First Author | Zuo X | Year | 2014 |
| Journal | J Natl Cancer Inst | Volume | 106 |
| Issue | 4 | Pages | dju052 |
| PubMed ID | 24681603 | Mgi Jnum | J:210812 |
| Mgi Id | MGI:5571939 | Doi | 10.1093/jnci/dju052 |
| Citation | Zuo X, et al. (2014) Potentiation of colon cancer susceptibility in mice by colonic epithelial PPAR-delta/beta overexpression. J Natl Cancer Inst 106(4):dju052 |
| abstractText | BACKGROUND: The nuclear receptor peroxisome proliferator-activated receptor-delta/beta (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. |
