Targeted genetic disruption of peroxisome proliferator-activated receptor-delta and colonic tumorigenesis.
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.
Department of Clinical Cancer Prevention, Unit 1360, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
Xiangsheng
X
Zuo
Zhanglong
Z
Peng
Micheline J
MJ
Moussalli
Jeffrey S
JS
Morris
Russell R
RR
Broaddus
Susan M
SM
Fischer
Imad
I
Shureiqi
D000818:Animals; D001397:Azoxymethane; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000628:therapy*; D004195:Disease Models, Animal; D005091:Exons; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D047494:PPAR delta / Q000235:genetics* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D047494:PPAR delta; D042461:Vascular Endothelial Growth Factor A; D001397:Azoxymethane