Low expression of Wnt-5a gene is associated with high-risk neuroblastoma.
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.
Blanc
Etienne
E
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.
Roux
Gwenaëlle Le
GL
Bénard
Jean
J
Raguénez
Gilda
G
D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007527:Isoenzymes / Q000032:analysis / Q000235:genetics; D000071447:N-Myc Proto-Oncogene Protein; D009361:Neoplasm Invasiveness; D009432:Neural Crest / Q000187:drug effects / Q000502:physiology; D016501:Neurites / Q000502:physiology; D009447:Neuroblastoma / Q000235:genetics* / Q000276:immunology; D009474:Neurons / Q000166:cytology / Q000276:immunology / Q000502:physiology; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000032:analysis / Q000235:genetics; D011379:Prognosis; D011493:Protein Kinase C / Q000032:analysis / Q000235:genetics; D000074121:Protein Kinase C-theta; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation / Q000235:genetics; D051153:Wnt Proteins; D000071818:Wnt-5a Protein
D007527:Isoenzymes; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D014212:Tretinoin; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta