c-RET molecule in malignant melanoma from oncogenic RET-carrying transgenic mice and human cell lines.
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 of intrinsic c-Ret, glial cell line-derived neurotrophic factor (Gdnf) and Gdnf receptor alpha 1 (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 in murine melanomagenesis in RET-mice. We then showed that c-RET and GDNF transcript expression levels in human malignant melanoma cell lines (HM3KO and MNT-1) were higher than those in primary 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.
Ohshima
Yuichiro
Y
Units of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi, Japan.
Yajima
Ichiro
I
Takeda
Kozue
K
Iida
Machiko
M
Kumasaka
Mayuko
M
Matsumoto
Yoshinari
Y
Kato
Masashi
M
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics*; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000737:chemistry / Q000209:etiology* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis
C495039:GDNF protein, human; C494987:GFRA1 protein, human; C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D012333:RNA, Messenger; D051096:Proto-Oncogene Proteins c-ret