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

Int J Cancer. 2009 Jan 15;124(2):494-501. doi: 10.1002/ijc.23973.


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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 3 / biosynthesis
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Collagen / chemistry
  • Drug Combinations
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Interleukin-6 / biosynthesis*
  • Laminin / chemistry
  • Male
  • Mice
  • Mice, Nude
  • NF-kappa B p50 Subunit / metabolism
  • NF-kappa B p50 Subunit / physiology*
  • Neoplasm Transplantation
  • Neovascularization, Pathologic*
  • Proteoglycans / chemistry
  • Up-Regulation


  • ATF3 protein, human
  • Activating Transcription Factor 3
  • Drug Combinations
  • Interleukin-6
  • Laminin
  • NF-kappa B p50 Subunit
  • Proteoglycans
  • matrigel
  • Collagen