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Nuclear factor kappa B subunit p50 promotes melanoma angiogenesis by upregulating interleukin‐6 expression

Nuclear factor kappa B (NF‐κB) signaling is deregulated in many tumor types, resulting in aberrant expression and/or activation of NF‐κB transcriptional complexes. We have previously reported that nuclear expression of the NF‐κB 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‐κB p50. We found that NF‐κB 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‐κB p50 overexpression promotes angiogenesis, while silencing NF‐κB p50 inhibits blood vessel formation. Our results demonstrate for the first time that the NF‐κB p50 subunit mediates melanoma angiogenesis by specifically upregulating IL‐6, highlighting a novel and important role for the NF‐κB p50/IL‐6 signaling axis in melanoma progression. © 2008 Wiley‐Liss, Inc.