Deregulated Wnt/beta-catenin program in high-risk neuroblastomas without MYCN amplification

Oncogene. 2008 Feb 28;27(10):1478-88. doi: 10.1038/sj.onc.1210769. Epub 2007 Aug 27.


Neuroblastoma (NB) is a frequently lethal tumor of childhood. MYCN amplification accounts for the aggressive phenotype in a subset while the majority have no consistently identified molecular aberration but frequently express MYC at high levels. We hypothesized that activated Wnt/beta-catenin (CTNNB1) signaling might account for this as MYC is a beta-catenin transcriptional target and multiple embryonal and neural crest malignancies have oncogenic alterations in this pathway. NB cell lines without MYCN amplification express higher levels of MYC and beta-catenin (with aberrant nuclear localization) than MYCN-amplified cell lines. Evidence for aberrant beta-catenin-TCF transcriptional activity was demonstrated using expression profiles from 73 primary NBs. Findings included increased WNT ligands (WNT1, WNT6, WNT7A, WNT10B), DVL1 and TCF7 expression in high-risk NBs without MYCN amplification, consistent with canonical beta-catenin signaling. More directly, Patterns of Gene Expression and Gene Set Enrichment Analyses demonstrated beta-catenin target genes (for example, MYC, PPARD, NRCAM, CD44, TCF7) as coordinately upregulated in high-risk NBs without MYCN amplification in comparison to high-risk MYCN-amplified or intermediate-risk NBs, supporting pathway activation in this subset. Thus, high-risk NBs without MYCN amplification may deregulate MYC and other oncogenic genes via altered beta-catenin signaling providing a potential candidate pathway for therapeutic inhibition.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Gene Amplification*
  • Humans
  • Infant
  • N-Myc Proto-Oncogene Protein
  • Neuroblastoma / metabolism*
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Oncogene Proteins / genetics*
  • Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Risk Factors
  • Signal Transduction / genetics
  • Tumor Cells, Cultured
  • Wnt Proteins / physiology*
  • beta Catenin / antagonists & inhibitors
  • beta Catenin / physiology*


  • CTNNB1 protein, human
  • MYC protein, human
  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein
  • Nuclear Proteins
  • Oncogene Proteins
  • Proto-Oncogene Proteins c-myc
  • Wnt Proteins
  • beta Catenin