Caspase-8 levels correlate with the expression of signal transducer and activator of transcription 1 in high-grade but not lower grade neuroblastoma

Cancer. 2006 Aug 15;107(4):824-31. doi: 10.1002/cncr.22052.

Abstract

Background: Previous studies in advanced-stage neuroblastoma (NB) have shown a link between the silencing of caspase-8 and methylation of a regulatory region at the boundary between caspase-8 exon 3 and intron 3. However, a number of recent studies from NB cell lines have shown that the transcriptional regulation of caspase-8 may reside with interferon gamma-sensitive promoters through the action of transcription factors, such as signal transducer and activator of transcription 1 (STAT-1). In this study, the authors tested the hypothesis that there is a correlation between caspase-8 and STAT-1 protein expression levels that may be linked to methylation of the regulatory elements of either of these genes.

Methods: Thirty clinical tumor samples of all stages, including 13 samples from patients with Stage 4 disease, were analyzed by quantitative immunoblotting for caspase-8 and STAT-1. The DNA methylation status of putative caspase-8 and STAT-1 regulatory elements were determined by bisulfite-modified sequencing analysis.

Results: A significant correlation was observed between caspase-8 and STAT-1 protein levels in Stage 4 NB samples but not in lower stage NB samples. Caspase-8 and STAT-1 protein levels varied widely across all stages of NB and did not correlate with methylation of these genes.

Conclusions: A strong correlation was observed between STAT-1 levels and caspase-8 levels in clinical Stage 4 NB. This suggests that STAT-1 or similar transcription factors, and not methylation, may play a role in controlling caspase-8 levels in this illness. No evidence of such a correlation between caspase-8 and STAT-1 levels was observed in lower clinical stages, suggesting that mechanisms controlling caspase-8 expression in NB vary with clinical stage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caspase 8
  • Caspases / metabolism*
  • Cell Line, Tumor
  • Child
  • Child, Preschool
  • DNA Methylation
  • DNA, Neoplasm / genetics
  • Female
  • Humans
  • Immunoblotting
  • Infant
  • Infant, Newborn
  • Male
  • Neoplasm Staging
  • Neuroblastoma / metabolism*
  • Neuroblastoma / pathology
  • Promoter Regions, Genetic
  • STAT1 Transcription Factor / metabolism*

Substances

  • DNA, Neoplasm
  • STAT1 Transcription Factor
  • CASP8 protein, human
  • Caspase 8
  • Caspases