title: PAD2 overexpression in transgenic mice promotes spontaneous skin neoplasia.
abstract: Peptidylarginine deiminase 2 (PAD2/PADI2) has been implicated in various inflammatory diseases and, more recently, cancer. The goal of this study was to test the hypothesis that PAD2 promotes oncogenesis using a transgenic mouse model. We found that about 37% of transgenic mice overexpressing human FLAG-PAD2 downstream of the MMTV-LTR promoter develop spontaneous neoplastic skin lesions. Molecular and histopathologic analyses of the resulting lesions find that they contain increased levels of markers for invasion, inflammation, and epithelial-to-mesenchymal transition (EMT) and that a subset of the lesions progress to invasive squamous cell carcinoma (SCC). We then stably overexpressed FLAG-PAD2 in the human SCC cell line, A431, and found that the PAD2-overexpressing cells were more tumorigenic in vitro and also contained elevated levels of markers for inflammation and EMT. Collectively, these studies provide the first genetic evidence that PAD2 functions as an oncogene and suggest that PAD2 may promote tumor progression by enhancing inflammation within the tumor microenvironment.
authors.affiliation: Department of Nutritional Sciences, College of Human Ecology, Cornell University, Ithaca, New York.
authors.forename: John L
authors.initials: JL
authors.lastname: McElwee
authors.affiliation: Lilly Research Laboratories, Indianapolis, Indiana.
authors.forename: Sunish
authors.initials: S
authors.lastname: Mohanan
authors.affiliation: Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York.
authors.forename: Sachi
authors.initials: S
authors.lastname: Horibata
authors.affiliation: Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Sams
authors.affiliation: Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York.
authors.forename: Lynne J
authors.initials: LJ
authors.lastname: Anguish
authors.affiliation: Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York.
authors.forename: Dalton
authors.initials: D
authors.lastname: McLean
authors.affiliation: Faculty of Veterinary Medicine, University of Zagreb, Zagreb, Croatia.
authors.forename: Iva
authors.initials: I
authors.lastname: Cvitaš
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Wakshlag
authors.affiliation: Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York. sac269@cornell.edu.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Coonrod
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006867:Hydrolases / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D059016:Tumor Microenvironment
chemical_list: D006867:Hydrolases; C000620352:PADI2 protein, human; C000620353:Padi2 protein, mouse; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases