title: Potentiation of colon cancer susceptibility in mice by colonic epithelial PPAR-δ/β overexpression.
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.
authors.affiliation: 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.
authors.forename: Xiangsheng
authors.initials: X
authors.lastname: Zuo
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.forename: Jiang
authors.initials: J
authors.lastname: Yu
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Wu
authors.forename: Micheline J
authors.initials: MJ
authors.lastname: Moussalli
authors.forename: Ganiraju C
authors.initials: GC
authors.lastname: Manyam
authors.forename: Sun Il
authors.initials: SI
authors.lastname: Lee
authors.forename: Shoudan
authors.initials: S
authors.lastname: Liang
authors.forename: Mihai
authors.initials: M
authors.lastname: Gagea
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Morris
authors.forename: Russell R
authors.initials: RR
authors.lastname: Broaddus
authors.forename: Imad
authors.initials: I
authors.lastname: Shureiqi
mesh_terms: D000818:Animals; D001397:Azoxymethane; D002273:Carcinogens; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D004198:Disease Susceptibility; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000378:metabolism; D048068:PPAR-beta / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D002273:Carcinogens; D048068:PPAR-beta; C091778:Ppard protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D001397:Azoxymethane