Tumor necrosis factor alpha promotes invasiveness of cholangiocarcinoma cells via its receptor, TNFR2

Cancer Lett. 2005 Mar 10;219(2):205-13. doi: 10.1016/j.canlet.2004.07.027.


We studied the effect of TNF-alpha stimulation on a cholangiocarcinoma cell line, CCKS1. CCKS1 expressed only one type TNF receptor, TNFR2. Treatment of CCKS1 with TNF-alpha substantially activated NFkappaB, MAPK and Akt signalings which in turn activated matrix metalloproteinase-9 (MMP-9) secretion and in vitro invasiveness of CCKS1. Pretreatment of cells with anti-TNFR2 neutralizing antibody inhibited the TNF-alpha-dependent signaling and MMP-9 secretion and subsequently blocked invasion in vitro. Moreover, an inhibitor for matrix metalloproteinase, Galardin, suppressed the invasion in a dose-dependent manner. Similarly, pharmacological inhibition of signaling clearly suppressed the TNF-alpha dependent MMP-9 secretion. These results strongly suggest that TNF-alpha-TNFR2 signaling plays an important role to convert the cholangiocarcinoma cells to be more aggressive one.

MeSH terms

  • Cholangiocarcinoma / pathology*
  • Enzyme Activation
  • Humans
  • Matrix Metalloproteinase 9 / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / metabolism
  • Neoplasm Invasiveness / pathology
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Receptors, Tumor Necrosis Factor, Type II
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / pharmacology*


  • NF-kappa B
  • Proto-Oncogene Proteins
  • Receptors, Tumor Necrosis Factor, Type II
  • Tumor Necrosis Factor-alpha
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinase 9