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

Ravi P. Sahu, Sonia C. Dasilva, Badri Rashid, Kellie Clay Martel, Danielle Jernigan, Shama R. Mehta, Deena R. Mohamed, Samin Rezania, Joshua R. Bradish, Andrew B. Armstrong, Simon Warren, Raymond Konger

Research output: Contribution to journalArticle

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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.

Original languageEnglish
JournalInternational Journal of Cancer
Volume131
Issue number7
DOIs
StatePublished - Oct 1 2012

Fingerprint

PPAR gamma
Apoptosis
Inflammation
Skin Neoplasms
Tumor Burden
Neoplasms
Photobiology
Keratin-14
Caspase 7
Hairless Mouse
Skin
Erythema
Caspase 3
Hyperplasia
Carcinogenesis
Ligands
Water

Keywords

  • apoptosis
  • differentiation
  • inflammation
  • nonmelanoma skin cancer
  • peroxisome proliferators activated receptor gamma
  • photocarcinogenesis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Mice lacking epidermal PPARγ exhibit a marked augmentation in photocarcinogenesis associated with increased UVB-induced apoptosis, inflammation and barrier dysfunction. / Sahu, Ravi P.; Dasilva, Sonia C.; Rashid, Badri; Martel, Kellie Clay; Jernigan, Danielle; Mehta, Shama R.; Mohamed, Deena R.; Rezania, Samin; Bradish, Joshua R.; Armstrong, Andrew B.; Warren, Simon; Konger, Raymond.

In: International Journal of Cancer, Vol. 131, No. 7, 01.10.2012.

Research output: Contribution to journalArticle

Sahu, Ravi P. ; Dasilva, Sonia C. ; Rashid, Badri ; Martel, Kellie Clay ; Jernigan, Danielle ; Mehta, Shama R. ; Mohamed, Deena R. ; Rezania, Samin ; Bradish, Joshua R. ; Armstrong, Andrew B. ; Warren, Simon ; Konger, Raymond. / Mice lacking epidermal PPARγ exhibit a marked augmentation in photocarcinogenesis associated with increased UVB-induced apoptosis, inflammation and barrier dysfunction. In: International Journal of Cancer. 2012 ; Vol. 131, No. 7.
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AU - Mehta, Shama R.

AU - Mohamed, Deena R.

AU - Rezania, Samin

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