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Published on: September 25, 2012
Identification of BIRC6 as a novel intervention target for neuroblastoma therapy
Fieke Lamers1, Linda Schild, Jan Koster
1Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Meibergdreef 15, PO box 22700, Amsterdam, AZ 1105, The Netherlands.
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). 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.
Insights
Neuroblastoma tumors show increased BIRC6 gene copy number, leading to higher BIRC6 protein. This inhibits DIABLO, a pro-apoptotic protein. Silencing BIRC6 triggers apoptosis, suggesting BIRC6 as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Neuroblastoma, a pediatric cancer, has a poor prognosis.
- Apoptosis defects are implicated in cancer, but poorly understood in neuroblastoma.
Purpose of the Study:
- Investigate genomic aberrations in the intrinsic apoptotic pathway in neuroblastoma.
- Identify potential therapeutic targets for neuroblastoma.
Main Methods:
- Analyzed DNA and mRNA expression data from 88 neuroblastoma tumors.
- Performed BIRC6 gene knockdown experiments.
- Investigated DIABLO protein levels and interactions.
Main Results:
- Frequent gain of the BIRC6 gene correlated with increased mRNA expression.
- BIRC6, an inhibitor of apoptosis protein, binds and degrades cytoplasmic DIABLO.
- Silencing BIRC6 increased DIABLO levels and induced apoptosis.
Conclusions:
- BIRC6 may promote neuroblastoma oncogenesis by inactivating cytoplasmic DIABLO.
- Inhibiting BIRC6 could be a therapeutic strategy for neuroblastoma.
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