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Caspase‐8 Gene Expression in Neuroblastoma
Author(s) -
CASCIANO IDA,
BANELLI BARBARA,
CROCE MICHELA,
AMBROSIS ALESSANDRO,
VINCI ANGELA,
GELVI ILARIA,
PAGNAN GABRIELLA,
BRIGNOLE CHIARA,
ALLEMANNI GIORGIO,
FERRINI SILVANO,
PONZONI MIRCO,
ROMANI MASSIMO
Publication year - 2004
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1322.017
Subject(s) - dna methylation , biology , survivin , demethylating agent , gene , methylation , cancer research , cpg site , gene expression , neuroblastoma , microbiology and biotechnology , promoter , regulation of gene expression , retinoic acid , transcription factor , genetics , cell culture
A bstract : 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.