title: Src is activated by the nuclear receptor peroxisome proliferator-activated receptor β/δ in ultraviolet radiation-induced skin cancer.
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.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Montagner
authors.forename: Maria B
authors.initials: MB
authors.lastname: Delgado
authors.forename: Corinne
authors.initials: C
authors.lastname: Tallichet-Blanc
authors.forename: Jeremy S K
authors.initials: JS
authors.lastname: Chan
authors.forename: Ming K
authors.initials: MK
authors.lastname: Sng
authors.forename: Hélén
authors.initials: H
authors.lastname: Mottaz
authors.forename: Gwendoline
authors.initials: G
authors.lastname: Degueurce
authors.forename: Yannick
authors.initials: Y
authors.lastname: Lippi
authors.forename: Catherine
authors.initials: C
authors.lastname: Moret
authors.forename: Michael
authors.initials: M
authors.lastname: Baruchet
authors.forename: Maria
authors.initials: M
authors.lastname: Antsiferova
authors.forename: Sabine
authors.initials: S
authors.lastname: Werner
authors.forename: Daniel
authors.initials: D
authors.lastname: Hohl
authors.forename: Talal Al
authors.initials: TA
authors.lastname: Saati
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Farmer
authors.forename: Nguan S
authors.initials: NS
authors.lastname: Tan
authors.forename: Liliane
authors.initials: L
authors.lastname: Michalik
authors.forename: Walter
authors.initials: W
authors.lastname: Wahli
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D004789:Enzyme Activation; D058750:Epithelial-Mesenchymal Transition / Q000528:radiation effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D051379:Mice; D008812:Mice, Hairless; D018345:Mice, Knockout; D047494:PPAR delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048068:PPAR-beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000528:radiation effects; D012867:Skin / Q000378:metabolism / Q000528:radiation effects*; D012878:Skin Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D014466:Ultraviolet Rays; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D047494:PPAR delta; D048068:PPAR-beta; D012333:RNA, Messenger; D019061:src-Family Kinases