N-myc oncogene overexpression down-regulates leukemia inhibitory factor in neuroblastoma.
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.
Hatzi
Elissavet
E
Laboratory of Biological Chemistry, Medical School, University of Ioannina, Greece.
Murphy
Carol
C
Zoephel
Andreas
A
Ahorn
Horst
H
Tontsch
Ulrike
U
Bamberger
Ana-Maria
AM
Yamauchi-Takihara
Keiko
K
Schweigerer
Lothar
L
Fotsis
Theodore
T
D002455:Cell Division / Q000187:drug effects; D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004727:Endothelium / Q000166:cytology / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006131:Growth Inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D009154:Mutation; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D016271:Proto-Oncogene Proteins c-myc; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators