EP-007

In the advanced stages of human neuroblastomas, amplification of the N-MYC oncogene is a frequent event and correlates with poor prognosis and enhanced neovascularization. N-MYC amplification results in high N-MYC protein levels that can perturb the finely tuned interplay of N-MYC and MAX and could eventually induce abnormal expression patterns of target genes. However, to date few N-MYC target genes have been identified.Recently, Hatzi et al. questioned whether the N-MYC oncogene could stimulate tumor angiogenesis and thus enhance neuroblastoma progression [1xN-myc oncogene overexpression downregulates leukemia inhibitory factor in neuroblastoma. Hatzi, E. et al. Eur. J. Biochem. 2002; 269: 3732–3741Crossref | PubMed | Scopus (21)See all References[1]. Using a series of chromatographic steps, the authors isolated fractions from 47l of SH-EP007 supernatant that contained inhibitors of endothelial cell proliferation. One of the inhibitors identified was leukemia inhibitory factor (LIF). Its expression was dramatically downregulated in the presence of N-MYC overexpression, as determined using reporter assay experiments. This was significant because LIF has never before been reported to belong to a set of genes regulated by the MYC gene family members. The authors also found that downregulation of LIF was independent of N-MYC or MAX interaction and DNA binding because neither the HLH-Zip (helix-loop-helix zipper) nor the binding region deletion released the transcriptional repression. An intriguing observation is that the contiguous N-terminal N-MYC is required for repression because deletion of either the MbI (MYC box I) and MbII domains did not release the N-MYC mutants from the suppressive effect of the LIF promoter.In conclusion, N-MYC amplification could tilt the balance of angiomodulators in favor of the stimulators by downregulating LIF and thus participate in increasing neovascularization. Considering the functional similarities between C-MYC and N-MYC, data presented in this study correlate very well with results observed in mouse models. In these, the deregulated expression of C-MYC alone, in combination with suppressed apoptosis, is sufficient to give reversible angiogenic tumors, without the apparent need for a sudden ‘angiogenic switch’.