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.
Highlights
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
UV radiation stimulates peroxisome proliferator-activated receptor beta/delta (PPARb/d) expression and activity, enhancing skin tumour formation and progression in vivo To test if PPARb/d is implicated in UV-dependent tumour development, we first investigated whether its expression responds to UV radiation
A 100% tumour incidence was reached in both genotypes after 22 weeks of UV exposure, which might have resulted from gene mutations arising from long-term UV exposure and associated modifications in gene expression in the Pparb/dÀ/À mice, which override the inhibitory effect of Pparb/d deficiency on tumourigenesis
Summary
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. UVinduced PPARb/d 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, PPARb/d-null mice developed fewer and smaller skin tumours, and a PPARb/d antagonist prevented UV-dependent Src stimulation. The expression of PPARb/d 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 PPARb/d and SRC and TGFb1 transcriptional levels. Taken together, these observations motivate the future evaluation of PPARb/d modulators to attenuate the development of several epithelial cancers
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