title: Smad4 loss in mouse keratinocytes leads to increased susceptibility to UV carcinogenesis with reduced Ercc1-mediated DNA repair.
abstract: Smad4 loss occurs frequently in human skin squamous cell carcinoma (SCC), but it is unknown whether this loss increases UV-induced carcinogenesis, a major etiological factor in skin cancer. In the present study, mice with keratinocyte-specific Smad4 deletion (K14.Smad4(-/-)) and wild-type (WT) littermates were chronically UV-irradiated. Compared with WT, K14.Smad4(-/-) mice exhibited increased DNA damage and increased susceptibility to UV-induced skin cancer. Among genes involved in repairing UV-induced DNA damage, Excision repair cross-complementation group 1 (Ercc1) messenger RNA was significantly reduced in UV-treated K14.Smad4(-/-) skin compared with WT skin. Further analysis revealed that Smad4 loss confers reduced Snail binding to the Ercc1 regulatory elements, resulting in reduced Ercc1 transcription. Consistently, transient transfection of Snai1 into Smad4(-/-) keratinocytes led to increased repair of UV-induced DNA lesions. Transfection of Ercc1 into Smad4(-/-) keratinocytes restored repair of UV-induced DNA damage. Further, immunostaining revealed that the presence of Smad4 protein is associated with the presence of Snail and Ercc1 proteins in human skin SCC and precancerous actinic keratoses. Collectively, Smad4 loss-associated Snail reduction compromises Ercc1-mediated DNA repair, contributing to increased UV-induced skin carcinogenesis. Thus, we identified a role for Snail in UV-induced DNA repair.
authors: Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, USA.
authors: Doyel
authors: D
authors: Mitra
authors: Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, USA.
authors: Pamela
authors: P
authors: Fernandez
authors: Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, China.
authors: Li
authors: L
authors: Bian
authors: Department of Dermatopathology, Shanghai Skin Diseases Hospital, Shanghai, China.
authors: Ningjing
authors: N
authors: Song
authors: Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, USA; Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors: Fulun
authors: F
authors: Li
authors: Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, USA.
authors: Gangwen
authors: G
authors: Han
authors: Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, USA. Electronic address: xj.wang@ucdenver.edu.
authors: Xiao-Jing
authors: XJ
authors: Wang
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000503:physiopathology*; D002478:Cells, Cultured; D004260:DNA Repair / Q000502:physiology / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004720:Endonucleases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology / Q000528:radiation effects; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology* / Q000528:radiation effects; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics / Q000503:physiopathology*; D051901:Smad4 Protein / Q000235:genetics*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C000604407:SNAI1 protein, human; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D004720:Endonucleases; C499360:Ercc1 protein, mouse
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