TY - JOUR
T1 - Targeted genetic disruption of peroxisome proliferator-activated receptor-δ and colonic tumorigenesis
AU - Zuo, Xiangsheng
AU - Peng, Zhanglong
AU - Moussalli, Micheline J.
AU - Morris, Jeffrey S.
AU - Broaddus, Russell R.
AU - Fischer, Susan M.
AU - Shureiqi, Imad
N1 - Funding Information:
National Cancer Institute (grant no. R01-CA106577 and R01-CA104278 to I.S.), a Cancer Research Foundation of America grant (to X.Z.), and the Caroline Wiess Law Endowment for Cancer Prevention.
PY - 2009/5
Y1 - 2009/5
N2 - Peroxisome proliferator-activated receptor-delta (PPAR-δ) is overexpressed in human colon cancer, but its contribution to colonic tumorigenesis is controversial. We generated a mouse model in which PPAR-δ was genetically disrupted in colonic epithelial cells by targeted deletion of exon 4. Elimination of colon-specific PPAR-δ 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-δ genetic disruption (10-11 mice per group) were tested for incidence of azoxymethane-induced colon tumors. The effects of targeted PPAR-δ deletion on vascular endothelial growth factor expression were determined by real-time RT-PCR. Targeted PPAR-δ genetic disruption inhibited colonic carcinogenesis: Mice with PPAR-δ (-/-) colons developed 98.5% fewer tumors than wild-type mice (PPAR-δ (-/-) 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-δ expression. These findings indicate that PPAR-δ has a crucial role in promoting colonic tumorigenesis.
AB - Peroxisome proliferator-activated receptor-delta (PPAR-δ) is overexpressed in human colon cancer, but its contribution to colonic tumorigenesis is controversial. We generated a mouse model in which PPAR-δ was genetically disrupted in colonic epithelial cells by targeted deletion of exon 4. Elimination of colon-specific PPAR-δ 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-δ genetic disruption (10-11 mice per group) were tested for incidence of azoxymethane-induced colon tumors. The effects of targeted PPAR-δ deletion on vascular endothelial growth factor expression were determined by real-time RT-PCR. Targeted PPAR-δ genetic disruption inhibited colonic carcinogenesis: Mice with PPAR-δ (-/-) colons developed 98.5% fewer tumors than wild-type mice (PPAR-δ (-/-) 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-δ expression. These findings indicate that PPAR-δ has a crucial role in promoting colonic tumorigenesis.
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U2 - 10.1093/jnci/djp078
DO - 10.1093/jnci/djp078
M3 - Article
C2 - 19436036
AN - SCOPUS:66849099322
SN - 0027-8874
VL - 101
SP - 762
EP - 767
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 10
ER -