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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 | Eur. J. Biochem. 269 3732-3741 2002 FEBS 2002 doi 10.1046 j.1432-1033.2002.03066.x N-myc oncogene overexpression down-regulates leukemia inhibitory factor in neuroblastoma Elissavet Hatzi1. Carol Murnhv1 2. Andreas Zoenhel3 Horst Ahorn.3 Ulrike Tontsch3. Ana-Maria Bamberaer4 Keiko Yamauchi-Takihara5 Lothar Schweigerer6 and Theodore Fotsis1 1Laboratory of Biological Chemistry Medical School University of loannina Greece 2Biomedical Research Institute loannina Greece 3Boehringer Ingelheim Austria GmbH Vienna Austria 4Institute of Pathology Department of Gynecophathology University Hospital Hamburg Eppendorf Hamburg Germany 5Department of Molecular Medicine Osaka University Graduate School of Medicine Suita Japan 6Abt. Hamatologie Onkologie und Endokrinologie Universitats-Kinderklinik Essen Germany 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 phosphorylationdeficient 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 .