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

Authors

  • Alexandra Montagner,

    1. Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, Lausanne, Switzerland
    Current affiliation:
    1. INRA ToxAlim, Integrative Toxicology and Metabolism, UMR1331, Chemin de Tournefeuille, Toulouse Cedex, France
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  • Maria B Delgado,

    1. Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, Lausanne, Switzerland
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  • Corinne Tallichet-Blanc,

    1. Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, Lausanne, Switzerland
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  • Jeremy S K Chan,

    1. School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
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  • Ming K Sng,

    1. School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
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  • Hélène Mottaz,

    1. Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, Lausanne, Switzerland
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  • Gwendoline Degueurce,

    1. Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, Lausanne, Switzerland
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  • Yannick Lippi,

    1. GeT-TRiX Facility, INRA ToxAlim, UMR1331, Toulouse Cedex, France
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  • Catherine Moret,

    1. Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, Lausanne, Switzerland
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  • Michael Baruchet,

    1. Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, Lausanne, Switzerland
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  • Maria Antsiferova,

    1. Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
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  • Sabine Werner,

    1. Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
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  • Daniel Hohl,

    1. Department of Dermatology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland
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  • Talal Al Saati,

    1. INSERM/UPS, US006/CREFRE, Histopathology Facility, Place du Docteur Baylac, Toulouse Cedex, France
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  • Pierre J Farmer,

    1. Exploratory Biomarker Analysis, Biomarker Technologies, Bioinformatics, Non Clinical Development, Merck Serono International S.A. Switzerland, Geneva, Switzerland
    Current affiliation:
    1. Novartis Pharma AG Novartis Institutes for Biomedical Research Forum 1, Novartis Campus, Basel, Switzerland
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  • Nguan S Tan,

    1. School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
    2. Institute of Molecular and Cell Biology, Biopolis Drive, Singapore, Singapore
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  • Liliane Michalik,

    Corresponding author
    1. Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, Lausanne, Switzerland
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  • Walter Wahli

    Corresponding author
    1. Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, Lausanne, Switzerland
    2. Lee Kong Chian School of Medicine, Imperial College London, Nanyang Technological University, Singapore, Singapore
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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) β/δ and the oncogene Src, which promotes the development of ultraviolet (UV)-induced skin cancer in mice. UV-induced PPARβ/δ 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, PPARβ/δ-null mice developed fewer and smaller skin tumours, and a PPARβ/δ antagonist prevented UV-dependent Src stimulation. Furthermore, the expression of PPARβ/δ 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 PPARβ/δ and SRC and TGFβ1 transcriptional levels. Taken together, these observations motivate the future evaluation of PPARβ/δ modulators to attenuate the development of several epithelial cancers.

Synopsis

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PPARβ/δ regulates Src gene expression and activity in response to UV. In human skin cancer PPARβ/δ expression was also positively correlated with SRC expression with interaction between PPARβ/δ, SRC and TGFβ1 at the transcriptional level.

  • Expression of the oncogene Src is stimulated by PPARβ/δ through a direct transcriptional mechanism
  • Progression of UV-induced skin cancer is enhanced by PPARβ/δ - Src signaling
  • Markers of the epithelial-to-mesenchymal transition (EMT) are increased in keratinocytes by the PPARβ/δ - Src pathway
  • In human skin squamous cell carcinoma (SCCs), there is a positive correlation between the gene expression of PPARβ/δ, Src and EMT markers