RESUMO
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) ß/δ and the oncogene Src, which promotes the development of ultraviolet (UV)-induced skin cancer in mice. UV-induced PPARß/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, PPARß/δ-null mice developed fewer and smaller skin tumours, and a PPARß/δ antagonist prevented UV-dependent Src stimulation. Furthermore, the expression of PPARß/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 PPARß/δ and SRC and TGFß1 transcriptional levels. Taken together, these observations motivate the future evaluation of PPARß/δ modulators to attenuate the development of several epithelial cancers.
Assuntos
Carcinoma de Células Escamosas/patologia , PPAR delta/metabolismo , PPAR beta/metabolismo , Neoplasias Cutâneas/patologia , Pele/efeitos da radiação , Raios Ultravioleta , Quinases da Família src/metabolismo , Animais , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/metabolismo , Ativação Enzimática , Transição Epitelial-Mesenquimal/efeitos da radiação , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Camundongos , Camundongos Pelados , Camundongos Knockout , PPAR delta/antagonistas & inibidores , PPAR delta/genética , PPAR beta/antagonistas & inibidores , PPAR beta/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos da radiação , Pele/metabolismo , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/metabolismo , Quinases da Família src/genéticaRESUMO
Platelet Activating Factor (PAF) is a very potent stimulant of various cell functions but little is known about the mechanisms responsible for its marked effect on endothelial permeability. An in vitro assay system was used to assess the direct effect of PAF on the permeability of a bovine aortic endothelial cell (BAEC) monolayer to albumin. PAF produced a small but not significant increase of the permeability of BAEC monolayer to albumin. However, pre-treatment of the monolayer with indomethacin (10 microM) resulted in a significant increase of BAEC permeability following PAF administration. This increase was concentration-dependent up to a maximal effect of 105% above basal value (for 0.1 microM PAF). Addition of the PAF antagonist SRI 63 441ZI (5 microM) abolished this effect. Exogenous administration of PGE2 (10(-7) M) inhibited the effect of PAF on the BAEC permeability suggesting that prostaglandins synthesized by the endothelium behave as a negative autoregulatory factor. Compound SRI 63 441ZI also partially inhibited bradykinin-induced permeability to albumin but did not significantly modify the activity of thrombin. These findings show that PAF can increase endothelial permeability to albumin when the synthesis of prostaglandins is inhibited. Our results also show that PAF might have an autocrine activity by mediating part of BK-induced permeability.