Open AccessSrc is activated by the nuclear receptor peroxisome proliferator‐activated receptor β/δ in ultraviolet radiation‐induced skin cancer
Author(s) -
Montagner Alexandra,
Delgado Maria B,
TallichetBlanc Corinne,
Chan Jeremy S K,
Sng Ming K,
Mottaz Hélène,
Degueurce Gwendoline,
Lippi Yannick,
Moret Catherine,
Baruchet Michael,
Antsiferova Maria,
Werner Sabine,
Hohl Daniel,
Al Saati Talal,
Farmer Pierre J,
Tan Nguan S,
Michalik Liliane,
Wahli Walter
Publication year - 2014
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201302666
Subject(s) - peroxisome proliferator activated receptor , proto oncogene tyrosine protein kinase src , cancer research , nuclear receptor , oncogene , cancer , receptor , biology , epithelial–mesenchymal transition , skin cancer , signal transduction , microbiology and biotechnology , medicine , transcription factor , metastasis , cell cycle , gene , biochemistry
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 PPAR β/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, PPAR β/δ‐null mice developed fewer and smaller skin tumours, and a PPAR β/δ antagonist prevented UV ‐dependent Src stimulation. Furthermore, the expression of PPAR β / 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 PPAR β/δ and SRC and TGF β1 transcriptional levels. Taken together, these observations motivate the future evaluation of PPAR β/δ modulators to attenuate the development of several epithelial cancers.