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Journal of the National Cancer Institute Advance Access originally published online on May 12, 2009
JNCI Journal of the National Cancer Institute 2009 101(10):762-767; doi:10.1093/jnci/djp078
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© The Author 2009. Published by Oxford University Press.

BRIEF COMMUNICATION

Targeted Genetic Disruption of Peroxisome Proliferator–Activated Receptor-{delta} and Colonic Tumorigenesis

Xiangsheng Zuo, Zhanglong Peng, Micheline J. Moussalli, Jeffrey S. Morris, Russell R. Broaddus, Susan M. Fischer, Imad Shureiqi

Affiliations of authors: Department of Clinical Cancer Prevention (XZ, ZP, IS), Department of Thoracic/Head and Neck Medical Oncology (MJM), Department of Biostatistics and Applied Mathematics (JSM), Department of Pathology (RRB), Department of Carcinogenesis (SMF), and Department of Gastrointestinal Medical Oncology (IS), The University of Texas M. D. Anderson Cancer Center, Houston, TX

Correspondence to: Imad Shureiqi, MD, Department of Clinical Cancer Prevention, Unit 1360, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009 (e-mail: ishureiqi{at}mdanderson.org).

Peroxisome proliferator–activated receptor-delta (PPAR-{delta}) is overexpressed in human colon cancer, but its contribution to colonic tumorigenesis is controversial. We generated a mouse model in which PPAR-{delta} was genetically disrupted in colonic epithelial cells by targeted deletion of exon 4. Elimination of colon-specific PPAR-{delta} expression was confirmed by real-time reverse transcription–polymerase chain reaction (real-time RT-PCR), immunoblotting, and activity assays. Mice with and without targeted PPAR-{delta} genetic disruption (10–11 mice per group) were tested for incidence of azoxymethane-induced colon tumors. The effects of targeted PPAR-{delta} deletion on vascular endothelial growth factor expression were determined by real-time RT-PCR. Targeted PPAR-{delta} genetic disruption inhibited colonic carcinogenesis: Mice with PPAR-{delta}(–/–) colons developed 98.5% fewer tumors than wild-type mice (PPAR-{delta}(–/–) vs wild-type, mean = 0.1 tumors per mouse vs 6.6 tumors per mouse, difference = 6.5 tumors per mouse, 95% confidence interval = 4.9 to 8.0 tumors per mouse, P < .001, two-sided test). Increased expression of vascular endothelial growth factor in colon tumors vs normal colon was suppressed by loss of PPAR-{delta} expression. These findings indicate that PPAR-{delta} has a crucial role in promoting colonic tumorigenesis.


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J Natl Cancer Inst 2009 101: 695. [Extract] [Full Text] [PDF]





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