Interferon-gamma and retinoic acid down-regulate N-myc in neuroblastoma through complementary mechanisms of action

Cancer Lett. 1997 Dec 23;121(2):181-8. doi: 10.1016/s0304-3835(97)00351-0.


The N-myc oncogene plays a key role in the biology of neuroblastoma and the differentiation process. N-myc expression is associated with metastatic disease, as well as the undifferentiated state of normal neuroblasts migrating from the neural crest during embryogenesis. Its down-regulation is a pivotal event in the differentiation of neuroblastoma cells by retinoic acid (RA). Our previous work has shown that RA works synergistically with other agents, such as interferon-gamma (IFN-gamma), to down-regulate N-myc expression and induce differentiation. The present study demonstrates that IFN-gamma, like RA, decreases N-myc transcription. However, functional analysis of N-myc upstream regulatory sequences using 5' deletion mutants of a promoter-CAT construct containing germ line sequences from nucleotide position -887 to +151 showed that IFN-gamma and RA act through different sites on the N-myc promoter. In addition to its transcriptional effect, IFN-gamma was also found to shorten the half-life of N-myc mRNA. Taken together, these findings provide a mechanistic basis for the synergistic action of IFN-gamma and RA in inducing neuroblastoma differentiation and a rationale for the possible development of combination differentiation therapy for clinical use.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Cell Differentiation / drug effects
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Genes, myc*
  • Half-Life
  • Humans
  • Interferon-gamma / administration & dosage
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / metabolism
  • Promoter Regions, Genetic
  • RNA Processing, Post-Transcriptional
  • Transcription, Genetic
  • Tretinoin / administration & dosage
  • Tumor Cells, Cultured


  • Tretinoin
  • Interferon-gamma