Caspase-8 gene expression in neuroblastoma

Ida Casciano, Barbara Banelli, Michela Croce, Alessandro De Ambrosis, Angela Di Vinci, Ilaria Gelvi, Gabriella Pagnan, Chiara Brignole, Giorgio Allemanni, Silvano Ferrini, Mirco Ponzoni, Massimo Romani

Research output: Contribution to journalArticlepeer-review

Abstract

Neuroblastoma (NB) is a solid tumor of infancy that presents a high rate of spontaneous regression, a phenomenon that likely reflects the activation of an apoptotic/differentiation program. Indeed, the level of expression of molecules involved in the regulation of apoptosis, such as p73 or survivin, is a prognostic factor in NB patients. The caspase-8 gene (CASP8) encodes a key enzyme at the top of the apoptotic cascade. Although methylation of a putative regulatory region of the CASP8 gene reportedly inhibits its transcription in some MYCN-amplified NB, our results indicate that the transcriptional inactivation of caspase-8 occurs in a subset of primary NB independently of MYCN amplification or CpG methylation. In addition, the apoptotic agent fenretinide (4HPR) and interferon-γ (IFN-γ) induce caspase-8 expression without modifying the methylation status of this gene. Nevertheless, the methylation level of CASP8 intragenic and promoter regions is higher in MYCN-amplified tumors as compared to nonamplified samples. This phenomenon might reflect the existence of distinct DNA methylation errors in MYCN-amplified and MYCN-single copy tumors. To gain information on the mechanisms that regulate the expression of this crucial apoptotic gene, we searched for potential CASP8 regulatory regions and cloned a DNA element at the 5′ terminus of this gene that functionally acts as a promoter only in NB cell lines that express caspase-8. The retinoic acid analogue 4HPR, IFN-γ, and the demethylating agent 5-aza-cytidine activate this promoter in NB cells that lack endogenous caspase-8, indicating that this element may regulate both constitutive and inducible CASP8 expression. These results indicate also that demethylation of the cellular genome may upregulate CASP8 through the action of trans-acting factors. Our results provide new insights to the regulation of CASP8, a gene with an essential role in a variety of physiologic and pathologic conditions.

Original languageEnglish
Pages (from-to)157-167
Number of pages11
JournalAnnals of the New York Academy of Sciences
Volume1028
DOIs
Publication statusPublished - 2004

Keywords

  • Apoptosis
  • Caspase-8 gene (CASP8)
  • Expression
  • Methylation
  • Neuroblastoma (NB)
  • Regulation
  • Tumor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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