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Open Access Highly Accessed Research article

Identification of BIRC6 as a novel intervention target for neuroblastoma therapy

Fieke Lamers1, Linda Schild1, Jan Koster1, Frank Speleman2, Ingrid Øra3, Ellen M Westerhout1, Peter van Sluis1, Rogier Versteeg1, Huib N Caron4 and Jan J Molenaar15*

Author Affiliations

1 Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Meibergdreef 15, PO box 22700, Amsterdam, AZ 1105, The Netherlands

2 Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium

3 Department of Pediatric Oncology, Skåne University Hospital, Lund University, Lund, Sweden

4 Department of Pediatric Oncology, Emma Kinderziekenhuis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

5 Department of Oncogenomics, M1-132, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, AZ 1105, The Netherlands

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BMC Cancer 2012, 12:285  doi:10.1186/1471-2407-12-285

Published: 12 July 2012

Abstract

Background

Neuroblastoma are pediatric tumors of the sympathetic nervous system with a poor prognosis. Apoptosis is often deregulated in cancer cells, but only a few defects in apoptotic routes have been identified in neuroblastoma.

Methods

Here we investigated genomic aberrations affecting genes of the intrinsic apoptotic pathway in neuroblastoma. We analyzed DNA profiling data (CGH and SNP arrays) and mRNA expression data of 31 genes of the intrinsic apoptotic pathway in a dataset of 88 neuroblastoma tumors using the R2 bioinformatic platform ( http://r2.amc.nl webcite). BIRC6 was selected for further analysis as a tumor driving gene. Knockdown experiments were performed using BIRC6 lentiviral shRNA and phenotype responses were analyzed by Western blot and MTT-assays. In addition, DIABLO levels and interactions were investigated with immunofluorescence and co-immunoprecipitation.

Results

We observed frequent gain of the BIRC6 gene on chromosome 2, which resulted in increased mRNA expression. BIRC6 is an inhibitor of apoptosis protein (IAP), that can bind and degrade the cytoplasmic fraction of the pro-apoptotic protein DIABLO. DIABLO mRNA expression was exceptionally high in neuroblastoma but the protein was only detected in the mitochondria. Upon silencing of BIRC6 by shRNA, DIABLO protein levels increased and cells went into apoptosis. Co-immunoprecipitation confirmed direct interaction between DIABLO and BIRC6 in neuroblastoma cell lines.

Conclusion

Our findings indicate that BIRC6 may have a potential oncogenic role in neuroblastoma by inactivating cytoplasmic DIABLO. BIRC6 inhibition may therefore provide a means for therapeutic intervention in neuroblastoma.

Keywords:
Neuroblastoma; BIRC6; DIABLO; Apoptosis; Cancer