Low expression of Wnt-5a gene is associated with high-risk neuroblastoma

Oncogene. 2005 Feb 10;24(7):1277-83. doi: 10.1038/sj.onc.1208255.


Disseminated forms of neuroblastoma (NB), a tumor derived from neuroectodermal tissue, pose a major therapeutic challenge for pediatric oncology. By performing a comparative cDNA array analysis of metastatic neuroblasts versus primary xenograft from the human IGR-N-91 NB model, we were able to identify a set of downregulated developmental genes in metastatic neuroblasts. One of these genes was Wnt-5a, a member of the Wnt signaling pathway, known to be involved in the development of neural crest cells. Since we also found a significant decrease in Wnt-5a mRNA in unfavorable versus favorable categories in 37 primary NB tumors (P<0.007), we wondered whether retinoic acid (RA), which has a role in neural crest induction and differentiation, might reverse the aberrant negative regulation of Wnt-5a in metastatic malignant neuroblasts. Following treatment with 10 muM RA for 6 days, the MYCN-amplified IGR-N-91 cell lines underwent neuronal differentiation as assessed by reduced MYCN gene expression and neuritic extension. In these conditions, data showed an upregulation of Wnt-5a and PKC-theta; isoform expressions. Our study highlights, for the first time, the involvement of Wnt-5a, which has a role in embryonic and morphogenetic processes, in the response of malignant neuroblasts to RA. In conclusion, we demonstrated that RA, which is used in the treatment of high-risk NB patients with recurrent/residual disease in the bone marrow, is able to upregulate Wnt-5a gene expression.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation / physiology
  • Cell Line, Tumor
  • Down-Regulation / drug effects
  • Down-Regulation / genetics*
  • Gene Expression / drug effects
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Isoenzymes / analysis
  • Isoenzymes / genetics
  • N-Myc Proto-Oncogene Protein
  • Neoplasm Invasiveness
  • Neural Crest / drug effects
  • Neural Crest / physiology
  • Neurites / physiology
  • Neuroblastoma / genetics*
  • Neuroblastoma / immunology
  • Neurons / cytology
  • Neurons / immunology
  • Neurons / physiology
  • Nuclear Proteins / analysis
  • Nuclear Proteins / genetics
  • Oligonucleotide Array Sequence Analysis
  • Oncogene Proteins / analysis
  • Oncogene Proteins / genetics
  • Prognosis
  • Protein Kinase C / analysis
  • Protein Kinase C / genetics
  • Protein Kinase C-theta
  • Proto-Oncogene Proteins / analysis
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / physiology
  • RNA, Messenger / analysis
  • RNA, Messenger / metabolism
  • Tretinoin / pharmacology
  • Up-Regulation / genetics
  • Wnt Proteins
  • Wnt-5a Protein


  • Isoenzymes
  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein
  • Nuclear Proteins
  • Oncogene Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • WNT5A protein, human
  • Wnt Proteins
  • Wnt-5a Protein
  • Tretinoin
  • PRKCQ protein, human
  • Protein Kinase C
  • Protein Kinase C-theta