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

Oncogene volume 24, pages 1277–1283 (2005)Cite this article

Abstract

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 μ M 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-θ 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.

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Acknowledgements

We thank SFCE, Dr O Hartmann, Dr Dominique Valteau-Couanet (Service de Pédiatrie), Dr Serge Koscielny (Département de Santé Publique), and Dr Marie-José Terrier-Lacombe (Service d'anatomo-pathologie). We are also grateful to Michel Barrois for his invaluable assistance in designing the gene probes, Sabrina Cantais and Nadine Béron-Gaillard for their technical assistance (all from Institut Gustave Roussy). We also thank Dr Ashani T Weeraratna and Dr Yuan Jiang from the National Human Genome Research Institute/USA for donating the PcDNA3-Wnt-5a. Edited by Englishbooster S.A. This work was supported by the Ligue contre le Cancer, Comité de Montbéliard.

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  1. Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8126, Université Paris-Sud, Institut Fédératif de Recherche 54, Institut Gustave-Roussy (IGR), 39, rue Camille Desmoulins, 94805, Villejuif Cedex, France

    Etienne Blanc, Gwenaëlle Le Roux, Jean Bénard & Gilda Raguénez

  2. Département de Biologie, Service de Génétique, Institut Gustave-Roussy, Villejuif, France

    Jean Bénard

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  1. Etienne Blanc
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Correspondence to Gilda Raguénez.

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Blanc, E., Roux, G., Bénard, J. et al. Low expression of Wnt-5a gene is associated with high-risk neuroblastoma. Oncogene 24, 1277–1283 (2005). https://doi.org/10.1038/sj.onc.1208255

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