Midkine promotes neuroblastoma through Notch2 signaling

Cancer Res. 2013 Feb 15;73(4):1318-27. doi: 10.1158/0008-5472.CAN-12-3070. Epub 2012 Dec 14.


Midkine is a heparin-binding growth factor highly expressed in various cancers, including neuroblastoma, the most common extracranial pediatric solid tumor. Prognosis of patients with neuroblastoma in which MYCN is amplified remains particularly poor. In this study, we used a MYCN transgenic model for neuroblastoma in which midkine is highly expressed in precancerous lesions of sympathetic ganglia. Genetic ablation of midkine in this model delayed tumor formation and reduced tumor incidence. Furthermore, an RNA aptamer that specifically bound midkine suppressed the growth of neuroblastoma cells in vitro and in vivo in tumor xenografts. In precancerous lesions, midkine-deficient MYCN transgenic mice exhibited defects in activation of Notch2, a candidate midkine receptor, and expression of the Notch target gene HES1. Similarly, RNA aptamer-treated tumor xenografts also showed attenuation of Notch2-HES1 signaling. Our findings establish a critical role for the midkine-Notch2 signaling axis in neuroblastoma tumorigenesis, which implicates new strategies to treat neuroblastoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aptamers, Nucleotide / genetics
  • Aptamers, Nucleotide / metabolism
  • Aptamers, Nucleotide / pharmacology
  • Blotting, Western
  • Cell Line, Tumor
  • Cytokines / genetics*
  • Cytokines / metabolism
  • Ganglia, Sympathetic / metabolism
  • Ganglia, Sympathetic / pathology
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, 129 Strain
  • Mice, Knockout
  • Mice, Nude
  • Mice, Transgenic
  • Midkine
  • Neuroblastoma / genetics*
  • Neuroblastoma / pathology
  • Neuroblastoma / prevention & control
  • Protein Binding
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Receptor, Notch2 / genetics*
  • Receptor, Notch2 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction*
  • Xenograft Model Antitumor Assays


  • Aptamers, Nucleotide
  • Cytokines
  • Proto-Oncogene Proteins c-myc
  • Receptor, Notch2
  • Midkine