Recent studies suggest that
peroxisome proliferator-activated receptor gamma (PPARγ) agonists may have
cancer chemopreventive activity. Other studies have shown that loss of epidermal PPARγ results in enhanced chemical
carcinogenesis in mice via unknown mechanisms. However, ultraviolet B (UVB) exposure represents the primary etiological agent for
skin cancer formation and the role of PPARγ in photobiology and photocarcinogenesis is unknown. In previous studies, we demonstrated that UVB irradiation of cells results in the formation of oxidized glycerophosphocholines that exhibit PPARγ
ligand activity. We therefore hypothesized that PPARγ would prove to be a chemopreventive target in photocarcinogenesis. We first showed that UVB irradiation of mouse skin causes generation of PPARγ agonist species in vivo. We then generated SKH-1 hairless, albino mice deficient in epidermal Pparg (Pparg-/-(epi)) using a
cytokeratin 14 driven Cre-LoxP strategy. Using a chronic model of UVB photocarcinogenesis, we next showed that Pparg-/-(epi) mice exhibit an earlier onset of
tumor formation, increased
tumor burden and
tumor progression. Increased
tumor burden in Pparg-/-(epi) mice was accompanied by a significant increase in epidermal
hyperplasia and p53 positive epidermal cells in surrounding skin lacking
tumors. After acute UVB irradiation, Pparg-/-(epi) mice exhibited an augmentation of both UVB-induced
Caspase 3/7 activity and
inflammation. Increased apoptosis and
inflammation was also observed
after treatment with the PPARγ antagonist
GW9662. With chronic UVB irradiation, Pparg-/-(epi) mice exhibited a sustained increase in
erythema and transepidermal water loss relative to wildtype littermates. This suggests that PPARγ agonists could have possible chemopreventive activity in non-
melanoma skin cancer.