N-myc oncogene overexpression down-regulates leukemia inhibitory factor in neuroblastoma
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Hatzi, E.
Murphy, C.
Zoephel, A.
Ahorn, H.
Tontsch, U.
Bamberger, A. M.
Yamauchi-Takihara, K.
Schweigerer, L.
Fotsis, T.
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peer-reviewed
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Eur J Biochem
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Amplification of N-myc oncogene is a frequent event in advanced stages of human neuroblastoma and correlates with poor prognosis and enhanced neovascularization. Angiogenesis is an indispensable prerequisite for the progression and metastasis of solid malignancies, which is modulated by tumor suppressors and oncogenes. We have addressed the possibility that N-myc oncogene might regulate angiogenesis in neuroblastoma. Here, we report that experimental N-Myc overexpression results in down-regulation of leukemia inhibitory factor (LIF), a modulator of endothelial cell proliferation. Reporter assays using the LIF promoter and a series of N-Myc mutants clearly demonstrated that down-regulation of the LIF promoter was independent of Myc/Max interaction and required a contiguous N-terminal N-Myc domain. STAT3, a downstream signal transducer, was essential for LIF activity as infection with adenoviruses expressing a phosphorylation-deficient STAT3 mutant rendered endothelial cells insensitive to the antiproliferative action of LIF. LIF did not influence neuroblastoma cell proliferation suggesting that, at least in the context of neuroblastoma, LIF is involved in paracrine rather than autocrine interactions. Our data shed light on the mechanisms by which N-myc oncogene amplification enhances the malignant phenotype in neuroblastoma.
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Keywords
Cell Division/drug effects, Culture Media, Conditioned, DNA-Binding Proteins/genetics/metabolism, Down-Regulation, Endothelium/cytology/drug effects, Gene Expression Regulation, Neoplastic, Growth Inhibitors/genetics/*metabolism/pharmacology, Humans, *Interleukin-6, Leukemia Inhibitory Factor, Lymphokines/genetics/*metabolism/pharmacology, Mutation, Neuroblastoma/drug therapy/*genetics/pathology, Promoter Regions, Genetic, Proto-Oncogene Proteins c-myc/*genetics/metabolism, STAT3 Transcription Factor, Trans-Activators/genetics/metabolism, Transfection, Tumor Cells, Cultured
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http://www.ncbi.nlm.nih.gov/pubmed/12153570
http://onlinelibrary.wiley.com/store/10.1046/j.1432-1033.2002.03066.x/asset/j.1432-1033.2002.03066.x.pdf?v=1&t=h09a9iam&s=8d9d4eb089c353671b5a951da16c8d09f6eeafcd
http://onlinelibrary.wiley.com/store/10.1046/j.1432-1033.2002.03066.x/asset/j.1432-1033.2002.03066.x.pdf?v=1&t=h09a9iam&s=8d9d4eb089c353671b5a951da16c8d09f6eeafcd
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en
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Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής