c-RET Molecule in Malignant Melanoma from Oncogenic RET-Carrying Transgenic Mice and Human Cell Lines 英文参考文献.docVIP

c-RETMoleculeinMalignantMelanomafromOncogenic RET-CarryingTransgenicMiceandHumanCellLines YuichiroOhshima1,2.,IchiroYajima1.,KozueTakeda1,MachikoIida1,MayukoKumasaka1 ,Yoshinari Matsumoto2,MasashiKato1* 1Units of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi, Japan, 2DepartmentofDermatology,AichiMedicalUniversitySchoolofMedicine,Nagakute-cho,Aichi-gun,Aichi,Japan Abstract Malignant melanoma is one of the most aggressive cancers and its incidence worldwide has been increasing at a greater rate than that of any other cancer. We previously reported that constitutively activated RFP-RET-carrying transgenic mice (RET-mice) spontaneously develop malignant melanoma. In this study, we showed that expression levels ofintrinsic c-Ret, glialcellline-derived neurotrophic factor (Gdnf)andGdnfreceptor alpha1(Gfra1) transcripts in malignant melanomas from RET-transgenic mice were significantly upregulated compared with those in benign melanocytic tumors. These results suggest that not only introduced oncogenic RET but also intrinsic c-Ret/Gdnf are involved inmurinemelanomagenesis inRET-mice. Wethenshowedthatc-RETandGDNFtranscript expression levelsin humanmalignant melanoma cell lines (HM3KO andMNT-1) werehigher thanthose inprimary cultured normal human epithelial melanocytes (NHEM), while GFRa1 transcript expression levels were comparable among NHEM, HM3KO and MNT-1. We next showed c-RET and GFRa1 protein expression in HM3KO cells and GDNF-mediated increased levels of their phosphorylated c-RET tyrosine kinase and signal transduction molecules (ERK and AKT) sited potentially downstream of c-RET. Taken together with the finding of augmented proliferation of HM3KO cells after GDNF stimulation, our results suggest that GDNF-mediated c-RET kinase activation is associated with the pathogenesis of malignant melanoma. Citation:OhshimaY,YajimaI,TakedaK,IidaM,KumasakaM,etal.(2010)c-RET