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Identification of BIRC6 as a novel intervention target for neuroblastoma therapy

(2012) BMC CANCER. 12.
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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). 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
BIRC6, Neuroblastoma, DIABLO, Apoptosis, Cancer, CELL-DEATH, SURVIVIN SUPPRESSANT, ACTIVATING MUTATIONS, DOWN-REGULATION, ALK KINASE, APOPTOSIS, YM155, PROTEIN, TUMORS, GENE

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Chicago
Lamers, Fieke, Linda Schild, Jan Koster, Franki Speleman, Ingrid Øra, Ellen M Westerhout, Peter van Sluis, Rogier Versteeg, Huib N Caron, and Jan J Molenaar. 2012. “Identification of BIRC6 as a Novel Intervention Target for Neuroblastoma Therapy.” Bmc Cancer 12.
APA
Lamers, F., Schild, L., Koster, J., Speleman, F., Øra, I., Westerhout, E. M., van Sluis, P., et al. (2012). Identification of BIRC6 as a novel intervention target for neuroblastoma therapy. BMC CANCER, 12.
Vancouver
1.
Lamers F, Schild L, Koster J, Speleman F, Øra I, Westerhout EM, et al. Identification of BIRC6 as a novel intervention target for neuroblastoma therapy. BMC CANCER. 2012;12.
MLA
Lamers, Fieke et al. “Identification of BIRC6 as a Novel Intervention Target for Neuroblastoma Therapy.” BMC CANCER 12 (2012): n. pag. Print.
@article{3172215,
  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). 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.},
  articleno    = {285},
  author       = {Lamers, Fieke and Schild, Linda and Koster, Jan and Speleman, Franki and Øra, Ingrid and Westerhout, Ellen M and van Sluis, Peter and Versteeg, Rogier and Caron, Huib N and Molenaar, Jan J},
  issn         = {1471-2407},
  journal      = {BMC CANCER},
  keywords     = {BIRC6,Neuroblastoma,DIABLO,Apoptosis,Cancer,CELL-DEATH,SURVIVIN SUPPRESSANT,ACTIVATING MUTATIONS,DOWN-REGULATION,ALK KINASE,APOPTOSIS,YM155,PROTEIN,TUMORS,GENE},
  language     = {eng},
  pages        = {10},
  title        = {Identification of BIRC6 as a novel intervention target for neuroblastoma therapy},
  url          = {http://dx.doi.org/10.1186/1471-2407-12-285},
  volume       = {12},
  year         = {2012},
}

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