Sequence-specific silencing of MT1-MMP expression suppresses tumor cell migration and invasion: importance of MT1-MMP as a therapeutic target for invasive tumors

Oncogene. 2003 Nov 27;22(54):8716-22. doi: 10.1038/sj.onc.1206962.


Membrane-type 1 matrix metalloproteinase (MT1-MMP/MMP-14) has been believed a key enzyme in tumor invasion, because it is expressed in a variety of malignant human tumors, and overexpression of the enzyme enhances the ability of cellular invasiveness. However, it has not necessarily been clarified whether the endogenously expressed MT1-MMP in human tumors plays a critical role in their invasiveness. We used RNA silencing technology to downregulate the endogenous MT1-MMP expression in human tumor cells (fibrosarcoma HT1080 and gastric carcinoma MKN-28 cell lines), and evaluated the effect on the invasion of a reconstituted basement membrane (Matrigel). Transfection of a double-stranded RNA targeted to the MT1-MMP gene decreased the level of the enzyme to less than 10-20% without affecting production of other MMPs. According to the degree of silencing, activation of proMMP-2 was inhibited. CD44 shedding was also inhibited, but only in part. Decreased MT1-MMP levels were also reflected in reduced cell motility on hyaluronan (HA) and invasion in Matrigel. Thus, specific downregulation of MT1-MMP expression was sufficient to cause significant inhibition of the migration and invasion of tumor cells, even though other MMPs continued to be expressed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Movement
  • Enzyme Activation
  • Enzyme Precursors / metabolism
  • Gelatinases / metabolism
  • Gene Silencing*
  • Humans
  • Hyaluronan Receptors / physiology
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases / antagonists & inhibitors*
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism
  • Metalloendopeptidases / physiology
  • Neoplasm Invasiveness
  • Neoplasms / therapy*
  • RNA, Double-Stranded / physiology
  • RNA, Messenger / analysis
  • Stomach Neoplasms / pathology


  • Enzyme Precursors
  • Hyaluronan Receptors
  • RNA, Double-Stranded
  • RNA, Messenger
  • Gelatinases
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases
  • progelatinase