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Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN

Abstract

Caspase 8 is a cysteine protease regulated in both a death-receptor-dependent and -independent manner during apoptosis. Here, we report that the gene for caspase 8 is frequently inactivated in neuroblastoma, a childhood tumor of the peripheral nervous system. The gene is silenced through DNA methylation as well as through gene deletion. Complete inactivation of CASP8 occurred almost exclusively in neuroblastomas with amplification of the oncogene MYCN. Caspase 8-null neuroblastoma cells were resistant to death receptor- and doxorubicin-mediated apoptosis, deficits that were corrected by programmed expression of the enzyme. Thus, caspase 8 acts as a tumor suppressor in neuroblastomas with amplification of MYCN.

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Figure 1: Analysis of CASP8 structure and expression in human NB cell lines.
Figure 2: Methylation status of CASP8 and its effect on expression of caspase 8 in NB cell lines.
Figure 3: Analysis of NB patient material by methylation PCR.
Figure 4: Effects of retrovirus expression of caspase 8 in three different NB cell lines that are null for caspase 8.

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Acknowledgements

The authors thank S. Slabaugh, Y.Y. Ling and S. Rowe for technical assistance and J. Cleveland for comments and suggestions regarding the manuscript. We acknowledge the Hartwell Center for Bioinformatics and Biotechnology (St. Jude Children's Research Hospital) and C. Naeve for oligonucleotide synthesis and DNA sequence analysis. This research was supported by National Institutes of Health grants CA 67938, CA71907, a Cancer Center Core grant from the National Institutes of Health to St. Jude Children's Research Hospital (CA 21765), and by support from the American Lebanese Syrian Associated Charities.

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Correspondence to Vincent J. Kidd.

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Teitz, T., Wei, T., Valentine, M. et al. Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nat Med 6, 529–535 (2000). https://doi.org/10.1038/75007

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