Regulation of matrix metalloproteinase-2 (MMP-2) by hepatocyte growth factor/scatter factor (HGF/SF) in human glioma cells: HGF/SF enhances MMP-2 expression and activation accompanying up-regulation of membrane type-1 MMP

Int J Cancer. 1999 Jul 19;82(2):274-81. doi: 10.1002/(sici)1097-0215(19990719)82:2<274::aid-ijc19>3.0.co;2-2.

Abstract

Hepatocyte growth factor/scatter factor (HGF/SF) contributes to the malignant progression of human gliomas. We investigated the effect of HGF/SF on matrix metalloproteinase-2 (MMP-2), membrane type 1 matrix metalloproteinase (MT1-MMP) and tissue inhibitors of metalloproteinases (TIMPs), expressions of c-Met/HGF receptor-positive human glioblastoma cells. Treatment of U251 human glioblastoma cells with HGF/SF resulted in enhanced secretion of MMP-2 with an increased level of the active form. This was accompanied by enhanced expression (2.5-fold) of mRNA specific for MMP-2. The stimulatory effect of HGF/SF on MMP-2 expression did not occur in the presence of herbimycin A, a protein tyrosine kinase inhibitor. MT1 -MMP, a cell-surface activator of proMMP-2, was also up-regulated by HGF/SF in a dose-dependent manner. By contrast, the level of TIMP- 1 mRNAs was not altered significantly and that of TIMP-2 was reduced mildly by the HGF/SF treatment, suggesting that HGF/SF may eventually modulate a balance between MMP-2 and TIMPs in favor of the proteinase activity in the glioma cell microenvironment. HGF/SF also stimulated MMP-2 expression of other glioblastoma cell lines. Since glioblastomas frequently co-express HGF/SF and its receptor, our results suggest that HGF/SF might contribute to the invasiveness of glioblastoma cells through autocrine induction of MMP-2 expression and activation.

MeSH terms

  • Benzoquinones
  • Brain Neoplasms / enzymology
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology*
  • Disease Progression
  • Enzyme Induction / drug effects
  • Enzyme Inhibitors / pharmacology
  • Epidermal Growth Factor / pharmacology
  • Gelatinases / biosynthesis*
  • Gelatinases / genetics
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Glioblastoma / enzymology
  • Glioblastoma / genetics
  • Glioblastoma / pathology
  • Glioma / enzymology
  • Glioma / genetics
  • Glioma / pathology*
  • Hepatocyte Growth Factor / pharmacology*
  • Humans
  • Lactams, Macrocyclic
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases / biosynthesis*
  • Metalloendopeptidases / genetics
  • Neoplasm Invasiveness
  • Neoplasm Proteins / biosynthesis*
  • Neoplasm Proteins / genetics
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Quinones / pharmacology
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • RNA, Neoplasm / biosynthesis
  • RNA, Neoplasm / genetics
  • Recombinant Proteins / pharmacology
  • Rifabutin / analogs & derivatives
  • Signal Transduction / drug effects
  • Stimulation, Chemical
  • Tumor Cells, Cultured

Substances

  • Benzoquinones
  • Enzyme Inhibitors
  • Lactams, Macrocyclic
  • Neoplasm Proteins
  • Quinones
  • RNA, Messenger
  • RNA, Neoplasm
  • Recombinant Proteins
  • Rifabutin
  • Epidermal Growth Factor
  • Hepatocyte Growth Factor
  • herbimycin
  • Protein-Tyrosine Kinases
  • Gelatinases
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases
  • Matrix Metalloproteinase 2