title: Combined deletion of p38γ and p38δ reduces skin inflammation and protects from carcinogenesis.
abstract: The contribution of chronic skin inflammation to the development of squamous cell carcinoma (SCC) is poorly understood. While the mitogen-activated protein kinase p38α regulates inflammatory responses and tumour development, little is known about the role of p38γ and p38δ in these processes. Here we show that combined p38γ and p38δ (p38γ/δ) deletion blocked skin tumour development in a chemically induced carcinogenesis model. p38γ/δ deletion reduced TPA-induced epidermal hyperproliferation and inflammation; it inhibited expression of proinflammatory cytokines and chemokines in keratinocytes in vitro and in whole skin in vivo, resulting in decreased neutrophil recruitment to skin. Our data indicate that p38γ/δ in keratinocytes promote carcinogenesis by enabling formation of a proinflammatory microenvironment that fosters epidermal hyperproliferation and tumourigenesis. These findings provide genetic evidence that p38γ and p38δ have essential roles in skin tumour development, and suggest that targeting inflammation through p38γ/δ offers a therapeutic strategy for SCC treatment and prevention.
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Rafal
authors.initials: R
authors.lastname: Zur
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Garcia-Ibanez
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Nunez-Buiza
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Aparicio
authors.affiliation: Molecular Biology Centre Severo Ochoa/CSIC-UAM, Madrid, Spain.
authors.forename: Georgios
authors.initials: G
authors.lastname: Liappas
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Escós
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Risco
authors.affiliation: Molecular Oncology Unit, CIEMAT and I+12 Biomedical Research Institute, University Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Angustias
authors.initials: A
authors.lastname: Page
authors.affiliation: Molecular Oncology Unit, CIEMAT and I+12 Biomedical Research Institute, University Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Saiz-Ladera
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Dayanira
authors.initials: D
authors.lastname: Alsina-Beauchamp
authors.affiliation: Centro Anatomopatológico, Camino de Vinateros, Madrid, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Montans
authors.affiliation: Molecular Oncology Unit, CIEMAT and I+12 Biomedical Research Institute, University Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Paramio
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Cuenda
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000201:enzymology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003872:Dermatitis / Q000201:enzymology*; D005260:Female; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D018345:Mice, Knockout; D008819:Mice, Nude; D048291:Mitogen-Activated Protein Kinase 12 / Q000172:deficiency* / Q000235:genetics; D048292:Mitogen-Activated Protein Kinase 13 / Q000172:deficiency* / Q000235:genetics; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology
chemical_list: D048291:Mitogen-Activated Protein Kinase 12; D048292:Mitogen-Activated Protein Kinase 13
keywords: inflammation-associated cancer; knockout mice; p38γ; p38δ; skin