Mice lacking epidermal PPARγ exhibit a marked augmentation in photocarcinogenesis associated with increased UVB-induced apoptosis, inflammation and barrier dysfunction
| Autor: | Badri Rashid, Deena R. Mohamed, Sonia C. DaSilva, Shama R. Mehta, Simon Warren, Samin Rezania, Raymond L. Konger, Joshua R. Bradish, Danielle Jernigan, Kellie Clay Martel, Ravi P. Sahu, Andrew B. Armstrong |
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| Rok vydání: | 2012 |
| Předmět: |
Keratinocytes
Cancer Research Skin Neoplasms Ultraviolet Rays Peroxisome proliferator-activated receptor Apoptosis Inflammation Caspase 3 Biology Ligands medicine.disease_cause Article Mice medicine Animals Caspase 7 Mice Knockout chemistry.chemical_classification Mice Hairless Hyperplasia integumentary system medicine.disease Tumor Burden Hairless PPAR gamma Cell Transformation Neoplastic Oncology UVB-induced apoptosis chemistry Erythema Tumor progression Immunology Cancer research Female Epidermis Tumor Suppressor Protein p53 medicine.symptom Skin cancer Carcinogenesis |
| Zdroj: | International Journal of Cancer. 131:E1055-E1066 |
| ISSN: | 0020-7136 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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