Expression of the tumor necrosis factor receptor-associated factors 1 and 2 and regulation of the nuclear factor-kappaB antiapoptotic activity in human gliomas

Abstract

Tumor necrosis factor receptor (TNFR)-associated factors (TRAFs) are a recently established group of proteins involved in the intracellular signaling of the TNFR superfamily members. The TRAFs have been implicated in promoting cell survival through the activation of transcription factor nuclear factor (NF)-kappaB. The authors investigated the expression of NF-kappaB, caspase 3, TRAF1, TRAF2, and TRAF-associated NF-kappaB activator/TRAF-interacting protein (TANK/I-TRAF), a regulator of TRAF activity, in human gliomas. METHODS: Tumor samples were obtained in 27 adult patients harboring seven low-grade gliomas, nine anaplastic astrocytomas, and 11 glioblastomas multiforme. The NF-kappaB activation was analyzed using the electrophoresis mobility shift assay; TRAF1, TRAF2, TANK/I-TRAF, and caspase 3 expression were studied using Western blot analysis. Upregulated NF-kappaB DNA-binding activity, compared with that in normal brain tissue, was detected in all tumor samples (p = 0.002). The level of NF-kappaB activity showed some correlation with World Health Organization tumor grades (p = 0.01), even though variable activity levels were demonstrated in relation to tissue heterogeneity, which resulted in a substantial number of outliers in the quantitative analysis. Increased levels of TRAF1, TRAF2, and TANK/ I-TRAF were expressed in astrocytomas compared with levels in normal brain tissue (p = 0.02, 0.006, and 0.01, respectively). CONCLUSIONS: Data in this study confirm the upregulation of NF-kappaB in gliomas and reveal a correlation between levels of this transcription factor and tumor grade. A constitutive expression of TRAF1, TRAF2, and TANK/I-TRAF in human gliomas was documented. These proteins are involved in the intracellular signal transduction of the TNFR superfamily and in the control of NF-kappaB expression and its antiapoptotic activity.