Oncotarget

Research Papers:

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

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. Garcia-Pedrero, Anna M. Serafin, Xavier Cañas, Carmen Benito, Agustí Toll, Sònia-Vanina Forcales, Fred W. Perrino, Leopold Eckhart and Concepció Soler

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Oncotarget. 2015; 6:22375-22396. https://doi.org/10.18632/oncotarget.4296

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Abstract

Joan Manils1, Diana Gómez1, Mercè Salla-Martret1, Heinz Fischer2, Jason M. Fye3, Elena Marzo1, Laura Marruecos1, Inma Serrano1, Rocío Salgado4, Juan P. Rodrigo5, Juana M. Garcia-Pedrero5, Anna M. Serafin6, Xavier Cañas6, Carmen Benito7, Agustí Toll4, Sònia-Vanina Forcales8, Fred W. Perrino3, Leopold Eckhart2, Concepció Soler1

1Departament de Patologia i Terapèutica Experimental, Facultat de Medicina, Campus de Bellvitge, Universitat de Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain

2Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria

3Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA

4Dermatology Departament, Hospital del Mar, Barcelona, Spain

5Department of Otolaryngology, Hospital Universitario Central de Asturias, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain

6Plataforma de Recerca Aplicada en Animal de Laboratori, Parc Científic de Barcelona, Barcelona, Spain

7Protecció Radiològica, Universitat de Barcelona, Barcelona, Spain

8Institute 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.


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