Tumor-associated trypsinogen-2 (trypsinogen-2) activates procollagenases (MMP-1, -8, -13) and stromelysin-1 (MMP-3) and degrades type I collagen.
A critical step in cancer growth and metastasis is the dissolution of the extracellular matrix surrounding the malignant tumor, which leads to tumor cell invasion and dissemination. Type I collagen degradation involves the initial action of collagenolytic matrix metalloproteinases (MMP-1, -8, and -13) activated by MMP-3 (stromelysin-1). The role of interactive matrix serine proteinases (MSPs), including tumor-associated trypsinogens, has been unclear in collagenolysis. Now, we provide evidence that the major isoenzyme of human tumor-associated trypsinogens, trypsin-2, can directly activate three collagenolytic proMMPs as well as proMMP-3. These proMMP activations are inhibited by tumor-associated trypsin inhibitor (TATI). Furthermore, we demonstrate that trypsin-2 efficiently degrades native soluble type I collagen, which can be inhibited by TATI. However, cell culture studies showed that trypsin-2 transfection into the HSC-3 cell line did not result in MMP-1, -3, -8, and -13 activation but affected MMP-3 and -8 production at the protein level. These findings indicate that human trypsin-2 can be regarded as a potent tumor-associated matrix serine protease capable of being the initial activator of the collagenolytic MMP activation network as well as directly attacking type I collagen.
Department of Diagnostics and Oral Medicine, Institute of Dentistry, University of Oulu, Oulu, Finland.
Merja
M
Moilanen
Timo
T
Sorsa
Mathias
M
Stenman
Pia
P
Nyberg
Otso
O
Lindy
Jaana
J
Vesterinen
Annukka
A
Paju
Yrjö T
YT
Konttinen
Ulf-Håkan
UH
Stenman
Tuula
T
Salo
D015153:Blotting, Western; D024042:Collagen Type I / Q000378:metabolism*; D017364:Collagenases / Q000378:metabolism*; D017931:DNA Primers / Q000737:chemistry; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D005109:Extracellular Matrix / Q000737:chemistry; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000494:pharmacology; D014357:Trypsin / Q000494:pharmacology; D014359:Trypsin Inhibitor, Kazal Pancreatic / Q000494:pharmacology; D014362:Trypsinogen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D024042:Collagen Type I; D017931:DNA Primers; D004792:Enzyme Precursors; C064831:PRSS2 protein, human; D014359:Trypsin Inhibitor, Kazal Pancreatic; D014362:Trypsinogen; D012697:Serine Endopeptidases; D014357:Trypsin; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3; D020784:Matrix Metalloproteinase 8; D020781:Matrix Metalloproteinase 1