MMP-9 activation by tumor trypsin-2 enhances in vivo invasion of human tongue carcinoma cells.
Various human cancer cells express tumor-associated trypsinogen-2 (TAT-2), which can efficiently activate matrix metalloproteinases (MMPs) in vitro. MMP-2 and MMP-9 are particularly associated with the invasive malignant potential of several tumors. To investigate the role of TAT-2 in tumor invasion, we overexpressed TAT-2 in two malignant human squamous cell carcinoma cell lines of tongue and in non-malignant human papilloma virus transformed gingival keratinocytes. The TAT-2 overexpression significantly increased the levels of active MMP-9 in the most malignant cell line. TAT-2-transfected cells intravasated (invaded blood vessels) up to 60% more efficiently than did the control cells in an in vivo chick embryo chorioallantoic membrane invasion model. This increased intravasation was almost completely abolished by a specific tumor-associated trypsin inhibitor (TATI). These results indicate that TAT-2 has a role in the invasive growth of tumors, either alone or in cascade with gelatinases, especially by generating active MMP-9.
Nyberg
P
P
Department of Diagnostics, Institute of Dentistry, University of Oulu, PO Box 5281, FIN-90014, Oulu, Finland.
Moilanen
M
M
Paju
A
A
Sarin
A
A
Stenman
U-H
UH
Sorsa
T
T
Salo
T
T
D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000502:physiology*; D000818:Animals; D001681:Biological Assay; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000201:enzymology*; D002461:Cell Line, Transformed; D002642:Chick Embryo; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000096:biosynthesis; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D061965:Matrix Metalloproteinase Inhibitors; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000502:physiology*; D009360:Neoplastic Cells, Circulating / Q000187:drug effects; D014062:Tongue Neoplasms / Q000737:chemistry / Q000201:enzymology*; D014162:Transfection; D014359:Trypsin Inhibitor, Kazal Pancreatic / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D004792:Enzyme Precursors; D061965:Matrix Metalloproteinase Inhibitors; D009363:Neoplasm Proteins; C071692:TAP2 protein, human; D014359:Trypsin Inhibitor, Kazal Pancreatic; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9