Loss of caspase-8 mRNA expression is common in childhood primitive neuroectodermal brain tumour/medulloblastoma
T J Zuzak1, D F Steinhoff, L N Sutton
1Division of Oncology, University Children's Hospital of Zurich, Switzerland.
Abstract:
Upon binding of tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL), the agonistic TRAIL receptors DR4 and DR5 activate caspase-8 leading to apoptosis. In primitive neuroectodermal brain tumour (PNET) cell lines, TRAIL-induced apoptosis was recently shown to correlate with caspase-8 mRNA expression (Grotzer MA, Eggert A, Zuzak TJ, et al. Oncogene 2000, 19, 4604-4610). In this study, we analysed the expression of the TRAIL death pathway in 27 primary PNET/medulloblastoma. As shown by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR), all PNET/medulloblastoma evaluated expressed DR5, the adapter protein FADD and caspase-3, but only 48% expressed caspase-8. The mRNA expression of caspase-8 was significantly lower in primary PNET/medulloblastoma compared with normal brain samples. PCR revealed >75% methylation of the caspase-8 promoter region in three of seven PNET cell lines and in 55% of the primary PNET/medulloblastoma evaluated. In the PNET cell lines, the methylation status correlated with the caspase-8 mRNA expression. We conclude that loss of caspase-8 gene expression is common in PNET/medulloblastoma suggesting that suppression of death receptor induced apoptosis may play an important role in the pathogenesis of this common childhood brain tumour.
Insights
Loss of caspase-8 gene expression is common in primitive neuroectodermal brain tumours (PNETs), suggesting suppressed apoptosis contributes to their development. This impacts understanding of childhood brain tumour pathogenesis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) receptors DR4 and DR5 activate caspase-8, initiating apoptosis.
- Previous studies linked TRAIL-induced apoptosis in primitive neuroectodermal brain tumour (PNET) cell lines to caspase-8 mRNA expression.
Purpose of the Study:
- To analyze the expression of the TRAIL death pathway in primary PNET/medulloblastoma.
- To investigate the role of caspase-8 gene expression and promoter methylation in PNET pathogenesis.
Main Methods:
- Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) to assess mRNA expression of DR5, FADD, caspase-3, and caspase-8.
- Polymerase chain reaction (PCR) to determine the methylation status of the caspase-8 promoter region.
Main Results:
- All evaluated PNET/medulloblastomas expressed DR5, FADD, and caspase-3.
- Only 48% of primary PNET/medulloblastomas expressed caspase-8, with significantly lower mRNA levels compared to normal brain samples.
- Over 75% of PNET cell lines and 55% of primary PNET/medulloblastomas showed caspase-8 promoter methylation, correlating with reduced mRNA expression.
Conclusions:
- Loss of caspase-8 gene expression is frequent in PNET/medulloblastoma.
- Suppression of death receptor-induced apoptosis via caspase-8 downregulation may be crucial in the pathogenesis of these childhood brain tumours.
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