Modulated expression levels of tyrosine kinases in spontaneously developed melanoma by single irradiation of non-thermal atmospheric pressure plasmas

Development of therapy for melanomas without BRAFV600E mutation, which account for about half of all melanomas, is an urgent issue because effective therapy is currently being developed for patients who have melanomas with BRAFV600E mutation. RET-transgenic mice (RET-mice) carrying the RFP-RET oncogene under the control of metallothionein-I promoter spontaneously developed skin melanomas without BrafV600E mutation from benign melanocytic tumors. We previously showed decreased expression levels of cell cycle regulators and matrix metalloproteinases in melanoma from RET-transgenic mice by single irradiation of non-equilibrium atmospheric pressure plasmas (NEAPPs). In this study, we focused on RFP-RET, c-Ret, Epidermal growth factor receptor (Egfr), Vascular endothelial growth factor receptor 2 (Vegfr2) and c-Src kinases, which are correlated with melanoma. We first confirmed significantly increased transcript expression levels of the 5 kinases in melanomas compared to those in benign tumors in RET-mice. We then found that transcript expression levels of c-Ret and Egfr, but not those of RFPRET, Vegfr2 and c-Src, were significantly decreased by single irradiation of NEAPP. Since EGFR-mediated promotion of melanoma has been reported, we further focused on the mechanism of NEAPP-mediated decrease in the level of Egfr. Transcript expression level of Y box protein 1 (Ybx1), but not those of p53, Early growth factor 1 (Egr1), GCrich sequence DNA binding factor 2 (Gcf2) and Kluppel-like factor 10 (Klf10), was significantly decreased by single irradiation of NEAPP. These results suggest that NEAPP decreased Egfr expression level through decrease of Ybx1 expression. Our results indicate that NEAPP irradiation to melanoma without BRAFV600E mutation is a possible novel therapy.