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Src is activated by the nuclear receptor peroxisome proliferator-activated receptor beta/ in ultraviolet radiation-induced skin cancer

Montagner, A and Delgado, MB and Tallichet-Blanc, C and Chan, JSK and Sng, MK and Mottaz, H and Degueurce, G and Lippi, Y and Moret, C and Baruchet, M and Antsiferova, M and Werner, S and Hohl, D and Al, ST and Farmer, PJ and Tan, NS and Michalik, L and Wahli, W (2014) Src is activated by the nuclear receptor peroxisome proliferator-activated receptor beta/ in ultraviolet radiation-induced skin cancer. EMBO Molecular Medicine. pp. 80-98.

Abstract

Although non-melanoma skin cancer (NMSC) is the most common human cancer and its incidence continues to rise worldwide, the mechanisms underlying its development remain incompletely understood. Here, we unveil a cascade of events involving peroxisome proliferator-activated receptor (PPAR) beta/ and the oncogene Src, which promotes the development of ultraviolet (UV)-induced skin cancer in mice. UV-induced PPARbeta/ activity, which directly stimulated Src expression, increased Src kinase activity and enhanced the EGFR/Erk1/2 signalling pathway, resulting in increased epithelial-to-mesenchymal transition (EMT) marker expression. Consistent with these observations, PPARbeta/-null mice developed fewer and smaller skin tumours, and a PPARbeta/ antagonist prevented UV-dependent Src stimulation. Furthermore, the expression of PPARbeta/ positively correlated with the expression of SRC and EMT markers in human skin squamous cell carcinoma (SCC), and critically, linear models applied to several human epithelial cancers revealed an interaction between PPARbeta/ and SRC and TGFbeta1 transcriptional levels. Taken together, these observations motivate the future evaluation of PPARbeta/ modulators to attenuate the development of several epithelial cancers. 2013 The Authors

Item Type: Article
Additional Information: NIBR author: Farmer, PJ institute: NIBR- address only contributor address: (Montagner, Delgado, Tallichet-Blanc, Mottaz, Degueurce, Moret, Baruchet, Michalik, Wahli) Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, Le Genopode, Lausanne, Switzerland (Chan, Sng, Tan) School of Biological Sciences, Nanyang Technological University, Nanyang Drive, Singapore, Singapore (Lippi) GeT-TRiX Facility, INRA ToxAlim, UMR1331, Chemin de Tournefeuille, Toulouse Cedex, France (Antsiferova, Werner) Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Schafmattstrasse, Zurich, Switzerland (Hohl) Department of Dermatology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland (Al Saati) INSERM/UPS, US006/CREFRE, Histopathology Facility, Place du Docteur Baylac, CHU Purpan, Toulouse Cedex, France (Farmer) Exploratory Biomarker Analysis, Biomarker Technologies, Bioinformatics, Non Clinical Development, Merck Serono International S.A. Switzerland, Chemin des Mines, Geneva, Switzerland (Tan) Institute of Molecular and Cell Biology, Biopolis Drive, Proteos, Singapore, Singapore (Wahli) Lee Kong Chian School of Medicine, Imperial College London, Nanyang Technological University, Singapore, Singapore (Montagner) INRA ToxAlim, Integrative Toxicology and Metabolism, UMR1331, Chemin de Tournefeuille, Toulouse Cedex, France (Farmer) Novartis Pharma AG Novartis Institutes for Biomedical Research Forum 1, Novartis Campus, Basel, Switzerland
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/22652

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