Nuclear factor-kappaB activation and differential expression of survivin and Bcl-2 in human grade 2-4 astrocytomas
Filippo F Angileri1, M'Hammed Aguennouz, Alfredo Conti
1Department of Neuroscience, University of Messina School of Medicine, Messina, Italy.
Background:
Antiapoptotis resulting from hyperactivation of the transcription factor NF-kappaB has been described in several cancer types. It is triggered by the interaction of the tumor necrosis factor (TNF) with its receptors and recruitment of the intermediate factor TNF-receptor associated factor (TRAF) 2. The NF-kappaB transcriptional activity could amplify the expression of antiapoptotic genes. The authors investigated the activity of NF-kappaB, and the mRNA expression of TNFalpha, TNFalpha receptor, TRAF1, TRAF2, and TRAF-associated NF-kappaB activator (TANK), and the antiapoptotic genes Bcl-2, c-IAP 1 and 2, and Survivin in human astrocytic tumors.
Methods:
Eight low-grade astrocytomas (LGA), 10 anaplastic astrocytomas (AAs), 10 glioblastoma multiforme (GBM) samples were used; 4 samples of normal brain tissue were used as controls. The NF-kappaB activation was analyzed by electrophoretic mobility shift assay; TRAF1, TRAF2, TANK/I-TRAF, Bcl-2, c-IAP 1 and 2, and Survivin mRNA expressions were studied using real-time quantitative reverse-transcriptase polymerase chain reaction.
Results:
NF-kappaB hyperactivity was detected in tumor samples. mRNA of antiapoptotic genes, particularly BCL-2 and Survivin, was hyperexpressed in gliomas. Interestingly, BCL-2 was hyperexpressed in LGAs, whereas a very high level of Survivin featured high-grade gliomas. The differential expression of antiapoptotic genes yielded a tight clustering of all LGA and nearly all GBM samples in cluster analysis.
Conclusions:
NF-kappaB and factors involved in its intracellular activation were up-regulated in gliomas. NF-kappaB-activated antiapoptotic genes were hyperexpressed in tumor samples, but showed a differential expression with higher levels of Bcl-2 in LGAs and higher levels of Survivin in GBMs.
Insights
NF-kappaB hyperactivity drives antiapoptotic gene expression in astrocytic tumors. Bcl-2 and Survivin show differential expression, with Bcl-2 higher in low-grade astrocytomas and Survivin in glioblastomas.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Genetics
Background:
- Hyperactivation of NF-kappaB transcription factor promotes antiapoptosis in cancers.
- NF-kappaB activation is triggered by TNF receptor signaling and TRAF2 recruitment.
- NF-kappaB can amplify the expression of genes that inhibit apoptosis.
Purpose of the Study:
- To investigate NF-kappaB activity in human astrocytic tumors.
- To analyze the mRNA expression of key factors in the NF-kappaB pathway and antiapoptotic genes.
- To correlate gene expression patterns with tumor grade.
Main Methods:
- Analysis of NF-kappaB activation using electrophoretic mobility shift assay.
- Quantification of mRNA expression for TNFalpha, TNFalpha receptor, TRAF1, TRAF2, TANK, Bcl-2, c-IAP 1/2, and Survivin via real-time RT-PCR.
- Inclusion of low-grade astrocytomas, anaplastic astrocytomas, glioblastoma multiforme, and normal brain tissue samples.
Main Results:
- NF-kappaB hyperactivity was observed in astrocytic tumor samples.
- mRNA expression of antiapoptotic genes, notably Bcl-2 and Survivin, was upregulated in gliomas.
- BCL-2 was overexpressed in low-grade astrocytomas, while Survivin was highly expressed in high-grade gliomas.
Conclusions:
- NF-kappaB and its associated intracellular activation factors are upregulated in gliomas.
- NF-kappaB-activated antiapoptotic genes are overexpressed in tumor samples.
- Differential expression patterns of Bcl-2 and Survivin correlate with glioma grade.
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