Invasiveness of hepatocellular carcinoma cell lines: contribution of membrane-type 1 matrix metalloproteinase

Neoplasia. 1999 Nov;1(5):424-30. doi: 10.1038/sj.neo.7900046.


Intrahepatic metastasis is one of the malignant features of hepatocellular carcinoma (HCC). Matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator (u-PA)/plasmin, are known to be associated with the invasive properties of various types of tumor cells. In this study, we examined which proteinases play a role in the metastatic invasion of human HCC cell lines. JHH-5 and JHH-6 cells constitutively expressed mRNAs for both membrane-type 1 matrix metalloproteinase (MT1-MMP) and u-PA and invaded through reconstituted MATRIGEL in vitro, whereas JHH-7 cells expressed u-PA mRNA but not MT1-MMP and did not invade. However, hepatocyte growth factor (HGF) induced MT1-MMP expression on the surface of JHH-7 cells and markedly increased invasiveness of JHH-7 in a concentration-dependent manner. Moreover, cleavage activity for pro-MMP-2 was induced in HGF-treated JHH-7 cells. MMP inhibitor, rather than serine proteinase inhibitor, potently inhibited HCC cell invasion. Intrahepatic injection of HCC cell lines into athymic nude mice caused visible intrahepatic metastases in vivo. Moreover, JHH-7 tumors showed expression of MT1-MMP mRNA, while in vitro cultured JHH-7 cells did not. These findings suggest that MT1-MMP plays an important role in the invasive properties of HCC cells, and that HGF modifies the invasive properties of noninvasive HCC cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / pathology*
  • Collagen / metabolism
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Female
  • Hepatocyte Growth Factor / biosynthesis
  • Humans
  • Laminin / metabolism
  • Liver / pathology
  • Liver Neoplasms / pathology*
  • Matrix Metalloproteinase 14
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases / antagonists & inhibitors
  • Metalloendopeptidases / biosynthesis
  • Metalloendopeptidases / physiology*
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness*
  • Neoplasm Transplantation
  • Organ Size
  • Protease Inhibitors / pharmacology
  • Proteoglycans / metabolism
  • Recombinant Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Tumor Cells, Cultured
  • Urokinase-Type Plasminogen Activator / biosynthesis


  • Drug Combinations
  • Laminin
  • Mmp14 protein, mouse
  • Protease Inhibitors
  • Proteoglycans
  • Recombinant Proteins
  • matrigel
  • Hepatocyte Growth Factor
  • Collagen
  • Urokinase-Type Plasminogen Activator
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 14