Although it is known that nuclear receptor peroxisome proliferator-activated receptor-δ/β (PPAR-d) is upregulated in colorectal cancer, the role of PPAR-d in tumorigenesis remains uncertain. In a study reported in Journal of the National Cancer Institute, Zuo and colleagues developed a mouse model of intestinally targeted PPAR-d overexpression to simulate PPAR-d upregulation in human colon cancer. Mice with and without targeted PPAR-d overexpression were tested for azoxymethane-induced colonic tumorigenesis.
It was found that targeted PPAR-d overexpression increased colon tumor incidence from 0 of 10 wild-type littermate mice to 9 of 10 mice in PPAR-d-1 and PPAR-d-2 mouse lines and tumor number from 0.47 in wild-type littermates to 2.15 in PPAR-d-1 mice and from 0.44 in wild-type littermates to 1.91 in PPAR-d-2 mice.
PPAR-d overexpression reversed resistance to azoxymethane-induced colon tumorigenesis in C57BL/6 mice. Further, PPAR-d overexpression modulated the expression of a number of novel PPAR-d target genes in normal-appearing mouse colon epithelial cells in a pattern that matched changes in colon tumors.
The investigators concluded, “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.” ■