Portal de Periódicos da CAPES

Multifaceted role of TREX2 in the skin defense against UV-induced skin carcinogenesis

2015; Impact Journals LLC; Volume: 6; Issue: 26 Linguagem: Inglês

10.18632/oncotarget.4296

1949-2553

Joan Manils, Diana Gómez, Mercè Salla‐Martret, Heinz Fischer, Jason M. Fye, Elena Marzo, Laura Marruecos, Inma Serrano, Rocío Salgado, Juan P. Rodrigo, Juana M. García‐Pedrero, Anna Serafín, Xavier Cañas, Carmen Benito, Agustí Toll, Sonia Vanina Forcales, Fred W. Perrino, Leopold Eckhart, Concepció Soler,

Immune Response and Inflammation

// Joan Manils 1 , Diana Gómez 1 , Mercè Salla-Martret 1 , Heinz Fischer 2 , Jason M. Fye 3 , Elena Marzo 1 , Laura Marruecos 1 , Inma Serrano 1 , Rocío Salgado 4 , Juan P. Rodrigo 5 , Juana M. Garcia-Pedrero 5 , Anna M. Serafin 6 , Xavier Cañas 6 , Carmen Benito 7 , Agustí Toll 4 , Sònia-Vanina Forcales 8 , Fred W. Perrino 3 , Leopold Eckhart 2 , Concepció Soler 1 1 Departament de Patologia i Terapèutica Experimental, Facultat de Medicina, Campus de Bellvitge, Universitat de Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain 2 Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria 3 Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA 4 Dermatology Departament, Hospital del Mar, Barcelona, Spain 5 Department of Otolaryngology, Hospital Universitario Central de Asturias, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain 6 Plataforma de Recerca Aplicada en Animal de Laboratori, Parc Científic de Barcelona, Barcelona, Spain 7 Protecció Radiològica, Universitat de Barcelona, Barcelona, Spain 8 Institute of Predictive and Personalized Medicine of Cancer, Badalona, Barcelona, Spain Correspondence to: Concepció Soler, e-mail: concepciosoler@ub.edu Keywords: TREX2, skin carcinogenesis, UV radiation, DNA damage, inflammation Received: April 23, 2015 Accepted: June 02, 2015 Published: June 15, 2015 ABSTRACT TREX2 is a 3′-DNA exonuclease specifically expressed in keratinocytes. Here, we investigated the relevance and mechanisms of TREX2 in ultraviolet (UV)-induced skin carcinogenesis. TREX2 expression was up-regulated by chronic UV exposure whereas it was de-regulated or lost in human squamous cell carcinomas (SCCs). Moreover, we identified SNPs in the TREX2 gene that were more frequent in patients with head and neck SCCs than in healthy individuals. In mice, TREX2 deficiency led to enhanced susceptibility to UVB-induced skin carcinogenesis which was preceded by aberrant DNA damage removal and degradation as well as reduced inflammation. Specifically, TREX2 loss diminished the up-regulation of IL12 and IFNγ, key cytokines related to DNA repair and antitumor immunity. In UV-treated keratinocytes, TREX2 promoted DNA repair and passage to late apoptotic stages. Notably, TREX2 was recruited to low-density nuclear chromatin and micronuclei, where it interacted with phosphorylated H2AX histone, which is a critical player in both DNA repair and cell death. Altogether, our data provide new insights in the molecular mechanisms of TREX2 activity and establish cell autonomous and non-cell autonomous functions of TREX2 in the UVB-induced skin response.