Mice lacking epidermal PPAR? exhibit a marked augmentation in photocarcinogenesis associated with increased UVB-induced apoptosis, inflammation and barrier dysfunction.

ABSTRACT: Recent studies suggest that peroxisome proliferator-activated receptor gamma (PPAR?) agonists may have cancer chemopreventive activity. Other studies have shown that loss of epidermal PPAR? 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 PPAR? 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 PPAR? ligand activity. We therefore hypothesized that PPAR? would prove to be a chemopreventive target in photocarcinogenesis. We first showed that UVB irradiation of mouse skin causes generation of PPAR? 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 PPAR? 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 PPAR? agonists could have possible chemopreventive activity in non-melanoma skin cancer.

SUBMITTER: Sahu RP 

PROVIDER: S-EPMC4280796 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature