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N-myc Regulation of Type I Insulin-like Growth Factor Receptor in a Human Neuroblastoma Cell Line¹

Institut National de la Santé et de la Recherche Médicale, INSERM Unité 515, Croissance, Différenciation et Processus Tumoraux, Hôpital Saint Antoine, 75571 Paris, France

Insulin-like growth factors I and II (IGF-I and IGF-II) stimulate proliferation and differentiation in many cell types, including cell lines derived from human neuroblastomas. Their effects are mediated via the IGF-I receptor (IGF-IR) that is essential for growth in these cells. Amplification of the N-myc oncogene is a marker for poor prognosis in neuroblastoma development, and it therefore seemed of interest to analyze the relationships that may exist between IGF-IR and N-myc. N-myc-deficient SK-N-SH neuroblastoma cells were used as an experimental model. After stable transfection with N-myc cDNA, Northern blotting revealed a marked increased in IGF-IR, IGF-II, IGF-binding protein (IGFBP)-2, and IGFBP-4 mRNA levels, whereas IGFBP-6 mRNA levels were clearly diminished. Western immunoblot analysis also demonstrated increased intact IGFBP-2 but decreased IGFBP-6 in the presence of N-myc oncogene. Parallel binding experiments using IGF-I missing the first 3 amino acids revealed a 47% increase in binding sites for IGF-I and an increase of at least 335% in DNA synthesis, as measured by labeled thymidine incorporation into DNA. s.c. injection of these cells into nude mice provoked xenograft development in 50–100% of cases (depending on the series of experiments). Control cells, in contrast, were not tumorigenic. In cells transfected with bp -420/+60 of the human IGF-IR promoter controlling expression of the luciferase reporter gene, promoter activity was stimulated by a factor of 3.8 ± 0.6 (n = 6) in the presence of N-myc oncogene. This suggests transcriptional regulation of IGF-IR expression by N-myc. IGF-IR activity and N-myc amplification are two events that to date have been identified as independently instrumental in the etiology of human neuroblastoma. Our results provide the first evidence of a direct link between them and demonstrate the effects of the oncogene on components of the IGF system in neuroblastoma cell growth in vitro and in vivo.

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