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Open Access Highly Accessed Research article

Regulation of MYCN expression in human neuroblastoma cells

Joannes FM Jacobs124, Hans van Bokhoven3, Frank N van Leeuwen2, Christina A Hulsbergen-van de Kaa5, I Jolanda M de Vries12, Gosse J Adema1, Peter M Hoogerbrugge2 and Arjan PM de Brouwer3*

Author Affiliations

1 Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Nijmegen, the Netherlands

2 Department of Pediatric Hemato-Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands

3 Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Donders Institute for Brain, Cognition and Behaviour, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands

4 Department of Bloodtransfusion and Transplantation Immunology, University Nijmegen Medical Centre, Nijmegen, the Netherlands

5 Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands

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BMC Cancer 2009, 9:239  doi:10.1186/1471-2407-9-239

Published: 18 July 2009

Abstract

Background

Amplification of the MYCN gene in neuroblastoma (NB) is associated with a poor prognosis. However, MYCN-amplification does not automatically result in higher expression of MYCN in children with NB. We hypothesized that the discrepancy between MYCN gene expression and prognosis in these children might be explained by the expression of either MYCN-opposite strand (MYCNOS) or the shortened MYCN-isoform (ΔMYCN) that was recently identified in fetal tissues. Both MYCNOS and ΔMYCN are potential inhibitors of MYCN either at the mRNA or at the protein level.

Methods

Expression of MYCN, MYCNOS and ΔMYCN was measured in human NB tissues of different stages. Transcript levels were quantified using a real-time reverse transcriptase polymerase chain reaction assay (QPCR). In addition, relative expression of these three transcripts was compared to the number of MYCN copies, which was determined by genomic real-time PCR (gQPCR).

Results

Both ΔMYCN and MYCNOS are expressed in all NBs examined. In NBs with MYCN-amplification, these transcripts are significantly higher expressed. The ratio of MYCN:ΔMYCN expression was identical in all tested NBs. This indicates that ΔMYCN and MYCN are co-regulated, which suggests that ΔMYCN is not a regulator of MYCN in NB. However, the ratio of MYCNOS:MYCN expression is directly correlated with NB disease stage (p = 0.007). In the more advanced NB stages and NBs with MYCN-amplification, relatively more MYCNOS is present as compared to MYCN. Expression of the antisense gene MYCNOS might be relevant to the progression of NB, potentially by directly inhibiting MYCN transcription by transcriptional interference at the DNA level.

Conclusion

The MYCNOS:MYCN-ratio in NBs is significantly correlated with both MYCN-amplification and NB-stage. Our data indicate that in NB, MYCN expression levels might be influenced by MYCNOS but not by ΔMYCN.