Aberrant nuclear factor-kappaB (NF-kappaB) activation has been implicated in the pathogenesis of several human malignancies. In this study, we determined whether NF-kappaB is constitutively activated in human prostate adenocarcinoma, and, if so, whether increased NF-kappaB activation and its binding to DNA influence tumor progression. Using tissue samples obtained during transurethral prostatic resection and paraffin-embedded sections of benign and cancer specimens, we determined the nuclear expression of NF-kappaB/p65 and NF-kappaB/p50, cytoplasmic expression of IkappaBalpha, its phosphorylation, and expression of NF-kappaB-regulated genes, specifically Bcl2, cyclin D1, matrix metalloproteinase-9 (MMP-9), and vascular endothelial growth factor (VEGF). A progressive increase in the expression of NF-kappaB/p65 (but not of p50) was observed in cancer specimens compared to benign tissue, which correlated with increasing levels of IkappaBalpha and its phosphorylation. NF-kappaB DNA-binding activity increased with increasing tumor grade and the binding complex mainly consisted of NF-kappaB/p65-p50 heterodimers. Immunohistochemical analysis showed enhanced nuclear staining for NF-kappaB/p65 in both high-grade (P <.0001) and low-grade (P <.003) cancer specimens, compared to benign tissue. The nuclear levels of NF-kappaB/p65 correlated with concurrent increase in cytosolic levels of IkappaBalpha along with NF-kappaB-dependent expression of Bcl2, cyclin D1, MMP-9, and VEGF. These results demonstrate that NF-kappaB/p65 is constitutively activated in human prostate adenocarcinoma and is related to tumor progression due to transcriptional regulation of NF-kappaB-responsive genes.
Copyright 2004 Neoplasia Press, Inc.