Montagner, Alexandra, Delgado, Maria, Tallichet, Corrine, Chan, Jeremy, Sng, Ming, Mottaz, Helene, Degeurce, Gwendoline, Moret, Catherine, Baruchet, Michael, Farmer, Pierre, Nguan, Tan, Michalik, Liliane and Wahli, Walter (2014) Src is activated by the nuclear receptor peroxisome proliferator-activated receptor b/d in ultraviolet radiation-induced skin cancer. EMBO molecular medicine, 6 (1). pp. 80-98. ISSN 17574676

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 proliferatoractivated
receptor (PPAR) b/d and the oncogene Src, which promotes
the development of ultraviolet (UV)-induced skin cancer in mice. 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.
Furthermore, 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.

Item Type:	Article
Keywords:	keratinocyte; PPAR beta/delta; Skin cancer; Src; UV
Date Deposited:	12 Oct 2016 00:45
Last Modified:	12 Oct 2016 00:45
URI:	https://oak.novartis.com/id/eprint/22898