Src is activated by the nuclear receptor peroxisome proliferator-activated receptor ?/? 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) ?/? and the oncogene Src, which promotes the development of ultraviolet (UV)-induced skin cancer in mice. UV-induced PPAR?/? 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?/?-null mice developed fewer and smaller skin tumours, and a PPAR?/? antagonist prevented UV-dependent Src stimulation. Furthermore, the expression of PPAR?/? 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?/? and SRC and TGF?1 transcriptional levels. Taken together, these observations motivate the future evaluation of PPAR?/? modulators to attenuate the development of several epithelial cancers.

SUBMITTER: Montagner A 

PROVIDER: S-EPMC3936491 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature