Combined deletion of p38γ and p38δ reduces skin inflammation and protects from carcinogenesis

// Rafal Zur 1 , Laura Garcia-Ibanez 1 , Angel Nunez-Buiza 1 , Noelia Aparicio 1 , Georgios Liappas 2 , Alejandra Escós 1 , Ana Risco 1 , Angustias Page 3 , Cristina Saiz-Ladera 3 , Dayanira Alsina-Beauchamp 1 , José Montans 4 , Jesús M. Paramio 3 and Ana Cuenda 1 1 Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain 2 Molecular Biology Centre Severo Ochoa/CSIC-UAM, Madrid, Spain 3 Molecular Oncology Unit, CIEMAT and I+12 Biomedical Research Institute, University Hospital 12 de Octubre, Madrid, Spain 4 Centro Anatomopatológico, Camino de Vinateros, Madrid, Spain Correspondence to: Ana Cuenda, email: // Keywords : p38γ, p38δ, skin, inflammation-associated cancer, knockout mice Received : April 13, 2015 Accepted : May 25, 2015 Published : May 28, 2015 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.