Role of hepatocyte growth factor/c-Met signaling in regulating urokinase plasminogen activator on invasiveness in human hepatocellular carcinoma: a potential therapeutic target

Clin Exp Metastasis. 2008;25(1):89-96. doi: 10.1007/s10585-007-9106-6. Epub 2007 Nov 9.


Hepatocyte growth factor (HGF), its transmembrane tyrosine kinase receptor (c-Met), and urokinase type plasminogen activator (uPA) is a key protein in the plasminogen activation system, which plays a proteolytically important role in the invasion and metastasis of various types of cancers. However, the mechanisms by which HGF/c-Met signaling mediates cancer progression and metastasis are unclear. This study was designed to investigate the roles of HGF/c-Met in tumor progression and metastasis in HepG2 and Hep3B hepatoma cell lines. Treatment with HGF increased c-Met phosphorylation in a dose-dependent manner. Activity of c-Met phosphorylation peaked 1-3 min after HGF treatment and then declined. HGF enhanced the protein level and the activity of uPA in HepG2 and Hep3B cells, and the uPAR protein level also increased in a HGF dose-dependent manner. HGF increased cell invasion through the Matrigel. A monoclonal antibody against human uPA receptor, mAb 3936, inhibited HGF-mediated tumor cell invasion in a dose-dependent manner. Down-regulation of uPA using uPA-shRNA induced a decrease in in vitro cell invasion. These results suggest that hepatoma cells express functional c-Met, which may provide a target for a therapeutic basis to interfere with metastases of cancer cells by inhibiting uPA system-mediated proteolysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Carcinoma, Hepatocellular / metabolism*
  • Cell Line, Tumor
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Hepatocyte Growth Factor / metabolism*
  • Humans
  • Immunoprecipitation
  • Liver Neoplasms / metabolism*
  • Neoplasm Invasiveness / physiopathology*
  • Oncogene Protein v-akt / metabolism
  • Proto-Oncogene Proteins c-met / metabolism*
  • Signal Transduction / physiology
  • Urokinase-Type Plasminogen Activator / metabolism*


  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met
  • Oncogene Protein v-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Urokinase-Type Plasminogen Activator