Upregulation of macrophage migration inhibitory factor contributes to induced N-Myc expression by the activation of ERK signaling pathway and increased expression of interleukin-8 and VEGF in neuroblastoma

Oncogene. 2004 May 20;23(23):4146-54. doi: 10.1038/sj.onc.1207490.


Macrophage migration inhibitory factor (MIF) has been linked to fundamental processes such as control of cell proliferation, cell survival, angiogenesis, and tumor progression. The expression of MIF has been reported in several tumors. However, the precise role of MIF in tumor cells remains unclear. In the present study, we investigated the expression pattern and the function of MIF in neuroblastoma. Our results showed that intracellular MIF was upregulated in neuroblastoma tumor tissues and cell lines. MIF protein expression significantly correlated with the grade of tumor differentiation. In addition, we found that MIF induced a significant dose-dependent increase of vascular endothelial growth factor and interleukin-8 secretion. We also observed that an increased MIF expression level correlated with N-Myc protein (the N-myc oncogene product) expression in neuroblastoma tissues. MIF increased the expression of N-myc mRNA and N-Myc protein and induced N-Myc translocation from the cytoplasm to nucleus in neuroblastoma cell lines. MIF-induced N-Myc expression was found to be dependent on ERK signaling pathways. The inhibition of ERK activation reduced MIF-mediated N-Myc expression. These results suggest that MIF may contribute to the progression of neuroblastoma by (a) inducing N-Myc expression and (b) upregulating the expression of angiogenic factors.

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Down-Regulation
  • Female
  • Humans
  • Infant
  • Interleukin-8 / biosynthesis
  • Interleukin-8 / genetics*
  • Macrophage Migration-Inhibitory Factors / metabolism*
  • Male
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neuroblastoma / metabolism*
  • Neuroblastoma / pathology
  • Proto-Oncogene Proteins c-myc / biosynthesis
  • Proto-Oncogene Proteins c-myc / genetics*
  • Up-Regulation
  • Vascular Endothelial Growth Factor A / biosynthesis
  • Vascular Endothelial Growth Factor A / genetics*


  • Interleukin-8
  • Macrophage Migration-Inhibitory Factors
  • Proto-Oncogene Proteins c-myc
  • Vascular Endothelial Growth Factor A
  • Mitogen-Activated Protein Kinases