Nuclear factor kappa B subunit p50 promotes melanoma angiogenesis by upregulating interieukin-6 expression

Nuclear factor kappa B (NF-kappa B) signaling is deregulated in many tumor types, resulting in aberrant expression and/or activation of NF-kappa B transcriptional complexes. We have previously reported that nuclear expression of the NF-kappa B subunit p50 is strongly correlated with melanoma progression and poor 5-year patient survival. In this study, we used cDNA microarray to analyze the gene expression profiles of melanoma cells overexpressing NF-kappa B p50. We found that NF-kappa B p50 expression strongly induced interleukin-6 (IL-6) upregulation in melanoma cells at both the transcriptional and translational levels and that IL-6 production by melanoma cells enhanced the growth of endothelial cells in vitro. Expression of activating transcription factor 3 (ATF3), a negative regulator of IL-6 gene transcription, inhibited p50-mediated IL-6 upregulation. Knockdown of p50 expression using lentiviral-based shRNA abrogated IL-6 induction in melanoma cells and inhibited its effects on endothelial cell growth. Finally, we used an in vivo matrigel plug assay to show that NF-kappa B p50 overexpression promotes angiogenesis, while silencing NF-kappa B p50 inhibits blood vessel formation. Our results demonstrate for the first time that the NF-kappa B p50 subunit mediates melanoma angiogenesis by specifically upregulating IL-6, highlighting a novel and important role for the NF-kappa B p50/IL-6 signaling axis in melanoma progression. (c) 2008 Wiley-Liss, Inc.