title: Mice lacking epidermal PPARγ 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 (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.
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Sahu
authors.forename: Sonia C
authors.initials: SC
authors.lastname: DaSilva
authors.forename: Badri
authors.initials: B
authors.lastname: Rashid
authors.forename: Kellie Clay
authors.initials: KC
authors.lastname: Martel
authors.forename: Danielle
authors.initials: D
authors.lastname: Jernigan
authors.forename: Shama R
authors.initials: SR
authors.lastname: Mehta
authors.forename: Deena R
authors.initials: DR
authors.lastname: Mohamed
authors.forename: Samin
authors.initials: S
authors.lastname: Rezania
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Bradish
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Armstrong
authors.forename: Simon
authors.initials: S
authors.lastname: Warren
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Konger
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects*; D004890:Erythema / Q000378:metabolism / Q000473:pathology; D005260:Female; D006965:Hyperplasia; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D051379:Mice; D008812:Mice, Hairless; D018345:Mice, Knockout; D047495:PPAR gamma / Q000172:deficiency / Q000235:genetics*; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D008024:Ligands; D047495:PPAR gamma; D016159:Tumor Suppressor Protein p53; D053148:Caspase 3; D053179:Caspase 7