Integrin-linked kinase regulates melanoma angiogenesis by activating NF-κB/interleukin-6 signaling pathway

Oncogene. 2011 Jun 16;30(24):2778-88. doi: 10.1038/onc.2010.644. Epub 2011 Jan 31.


Integrin-linked kinase (ILK) is a highly conserved serine-threonine protein kinase involved in cell-extracellular matrix interactions, cytoskeletal organization and cell signaling. Overexpression of ILK in epithelial cells leads to anchorage-independent growth with increased cell cycle progression. Previously, we have shown that ILK upregulation strongly correlates with melanoma progression, invasion and inversely correlates with 5-year survival of melanoma patients. However, the molecular mechanism by which ILK enhances melanoma progression is currently unknown. In the present study, we found that proangiogenic molecule interleukin-6 (IL-6) is the downstream target of ILK in melanoma cells. ILK overexpression increased IL-6, whereas silencing of ILK suppressed IL-6 expression at both messenger RNA and protein levels. ILK also altered the activity and subcellular localization of nuclear factor-kappaB (NF-κB) subunit p65. We further found that ILK enhanced the IL-6 gene transcription by promoting the binding of NF-κB p65 to IL-6 promoter. Moreover, ILK overexpression in melanoma cells enhanced the tube-forming ability of endothelial cells in vitro and microvessel formation in vivo. ILK-induced tube and blood vessel formation of endothelial cells was significantly reduced upon IL-6 inhibition in ILK-overexpressing melanoma cells. To delineate the mechanism by which ILK-induced IL-6 production can enhance angiogenesis, further analysis of the downstream targets of IL-6 signaling showed an increased activity of the signal transducer and activator of transcription 3 (STAT3) in ILK-overexpressing cells. As STAT3 binds to vascular endothelial growth factor (VEGF) promoter, we found that VEGF levels were elevated in ILK-overexpressing cells and declined upon transfection of IL-6 small interfering RNA, suggesting that ILK may regulate VEGF expression through IL-6 pathway by activating STAT3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Cell Line, Tumor
  • Gene Expression Regulation
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-6 / physiology*
  • Melanoma / blood supply*
  • Melanoma / pathology
  • Neovascularization, Pathologic / etiology*
  • Neovascularization, Physiologic
  • Promoter Regions, Genetic
  • Protein-Serine-Threonine Kinases / physiology*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / physiology*
  • Transcription Factor RelA / physiology*
  • Vascular Endothelial Growth Factor A / genetics


  • Interleukin-6
  • RELA protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Transcription Factor RelA
  • Vascular Endothelial Growth Factor A
  • integrin-linked kinase
  • Protein-Serine-Threonine Kinases