c-RET Molecule in Malignant Melanoma from Oncogenic RET-Carrying Transgenic Mice and Human Cell Lines

Units of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi, Japan.
PLoS ONE (Impact Factor: 3.23). 04/2010; 5(4):e10279. DOI: 10.1371/journal.pone.0010279
Source: PubMed


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.

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Available from: Ichiro Yajima, Mar 14, 2014
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    • "MT/ret+/− transgenic mice (RET mice) expressing the rfp-ret oncogene develop a spontaneous melanoma that constitutively enhances cRET protein expression in the development of melanoma in RET mice (Kato et al. 1998; Ohshima et al. 2010). To study the anti-carcinogenic activity of HB-19, 10-day-old RET mice were treated with 50 μg HB-19, 5 i.p. injections for the first week, 100 μg for the second week, and 200 μg for the rest of the experiment, and control mice received PBS only. "
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    • "The entire process of melanoma development via tumor-free, benign, premalignant, and malignant stages in RET mice corresponds to the multistep melanomagenesis in humans [32]. Recently, we identified ZFP 28, CD109, and c-RET as melanoma-related molecules through analysis of tumors in RET mice [4, 33, 34]. "
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