4 research outputs found
Identification of a novel PPARÎČ/ÎŽ/miR-21-3p axis in UV-induced skin inflammation.
Although excessive exposure to UV is widely recognized as a major factor leading to skin perturbations and cancer, the complex mechanisms underlying inflammatory skin disorders resulting from UV exposure remain incompletely characterized. The nuclear hormone receptor PPARÎČ/ÎŽ is known to control mouse cutaneous repair and UV-induced skin cancer development. Here, we describe a novel PPARÎČ/ÎŽ-dependent molecular cascade involving TGFÎČ1 and miR-21-3p, which is activated in the epidermis in response to UV exposure. We establish that the passenger miRNA miR-21-3p, that we identify as a novel UV-induced miRNA in the epidermis, plays a pro-inflammatory function in keratinocytes and that its high level of expression in human skin is associated with psoriasis and squamous cell carcinomas. Finally, we provide evidence that inhibition of miR-21-3p reduces UV-induced cutaneous inflammation in ex vivo human skin biopsies, thereby underlining the clinical relevance of miRNA-based topical therapies for cutaneous disorders
Src is activated by the nuclear receptor peroxisome proliferator-activated receptor ÎČ/ÎŽ in ultraviolet radiation-induced skin cancer.
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) ÎČ/ÎŽ and the oncogene Src, which promotes the development of ultraviolet (UV)-induced skin cancer in mice. UV-induced PPARÎČ/ÎŽ 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, PPARÎČ/ÎŽ-null mice developed fewer and smaller skin tumours, and a PPARÎČ/ÎŽ antagonist prevented UV-dependent Src stimulation. Furthermore, the expression of PPARÎČ/ÎŽ 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 PPARÎČ/ÎŽ and SRC and TGFÎČ1 transcriptional levels. Taken together, these observations motivate the future evaluation of PPARÎČ/ÎŽ modulators to attenuate the development of several epithelial cancers