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Int J Cancer. 2008 Jul 15;123(2):389-394. doi: 10.1002/ijc.23533.

Assessment of NORE1A as a putative tumor suppressor in human neuroblastoma.

Author information

1
Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital-Solna, SE-171 76 Stockholm, Sweden.
2
Department of Woman and Child Health, Karolinska Institutet, Karolinska University Hospital-Solna, SE-171 76 Stockholm, Sweden.
3
Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
4
Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital-Solna, SE-171 76 Stockholm, Sweden.
5
JG Brown Cancer Center, University of Louisville, Louisville, KY 40202.
6
Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital-Solna, SE-171 76 Stockholm, Sweden.

Abstract

The putative tumor suppressor NORE1A (RASSF5) is a member of the Ras association domain family and is commonly inactivated in human cancer. The closely related gene family member and functional collaborator RASSF1A is a bona fide tumor suppressor and is frequently involved in neuroblastoma. In the present study, we sought to investigate the role of NORE1A in human neuroblastoma. A panel of tumors (36 neuroblastomas and 4 ganglioneuromas) and neuroblastoma cell lines was assessed for NORE1A gene expression by Taqman quantitative RT-PCR. Promoter methylation was quantitatively determined by methylation sensitive pyrosequencing. The antitumourigenic role was functionally investigated in Nore1a transfected SK-N-BE (2) cells by fluorescent inhibition of caspase activity and BrdU incorporation assays. Neuroblastoma cells showed very low or absent NORE1A mRNA expression, which could not be reversed by trichostatin A or 5-aza-cytidine treatments. Neuroblastoma tumors showed suppressed NORE1A gene expression that was particularly pronounced in cases without MYCN amplification or 1p loss. Methylation of the NORE1A promoter was not observed in primary tumors and only one out of seven neuroblastoma cell lines displayed weak partial methylation. Transient expression of Nore1a resulted in enhanced apoptosis and delayed cell cycle progression. In conclusion NORE1A appears to be strongly suppressed in neuroblastic tumors and reconstitution of its expression diminishes the tumorigenic phenotype. Promotor methylation is not a common mechanism responsible for NORE1A transcriptional suppression in this tumor type.

PMID:
18452173
DOI:
10.1002/ijc.23533
[Indexed for MEDLINE]
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