N-myc oncogene overexpression down-regulates leukemia inhibitory factor in neuroblastoma

E. Hatzi, C. Murphy, A. Zoephel, H. Ahorn, U. Tontsch, A. M. Bamberger, K. Yamauchi-Takihara, L. Schweigerer, T. Fotsis

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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.
Original languageEnglish
Pages (from-to)3732-41.
JournalJ Cell Biochem
Publication statusPublished - 2002

Bibliographical note

M1 - 15


  • 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 Human Lymphokines/genetics/*metabolism/pharmacology Mutation Neuroblastoma/drug therapy/*genetics/pathology Promoter Regions (Genetics) Proto-Oncogene Proteins c-myc/*genetics/metabolism Support, Non-U.S. Gov't Trans-Activators/genetics/metabolism Transfection Tumor Cells, Cultured


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