Intracellular co-localization of trypsin-2 and matrix metalloprotease-9: possible proteolytic cascade of trypsin-2, MMP-9 and enterokinase in carcinoma.
Tumor-associated trypsin-2 and matrix metalloprotease-9 (MMP-9) are associated with cancer, particularly with invasive squamous cell carcinomas. They require activation for catalytical competence via proteolytic cascades. One cascade is formed by enterokinase, trypsin-2 and MMP-9; enterokinase activates trypsinogen-2 to trypsin-2, which is an efficient proMMP-9 activator. We describe here that oral squamous cell carcinomas express all members of this cascade: MMP-9, trypsin-2 and enterokinase. The expression of enterokinase in a carcinoma cell line not derived from the duodenum was shown here for the first time. Enterokinase directly cleaved proMMP-9 at the Lys65-Ser66 site, but failed to activate it in vitro. We demonstrated by confocal microscopy that MMP-9 and trypsin-2 co-localized in intracellular vesicles of the carcinoma cells. This co-localization of trypsin-2 and MMP-9 resulted in intracellular proMMP-9 processing that represented fully or partially activated MMP-9. However, although both proteases were present also in various bone tumor tissues, MMP-9 and trypsin-2 never co-localized at the cellular level in these tissues. This suggests that the intracellular vesicular co-localization, storage and possible activation of these proteases may be a unique feature for aggressive epithelial tumors, such as squamous cell carcinomas, but not for tumors of mesenchymal origin.
Vilen
Suvi-Tuuli
ST
Institute of Dentistry, University of Helsinki, Department of Oral and Maxillofacial Diseases, Helsinki University Hospital, Finland.
Nyberg
Pia
P
Hukkanen
Mika
M
Sutinen
Meeri
M
Ylipalosaari
Merja
M
Bjartell
Anders
A
Paju
Annukka
A
Haaparanta
Virpi
V
Stenman
Ulf-Håkan
UH
Sorsa
Timo
T
Salo
Tuula
T
D001859:Bone Neoplasms / Q000201:enzymology; D002277:Carcinoma / Q000201:enzymology; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D004765:Enteropeptidase / Q000378:metabolism*; D004792:Enzyme Precursors / Q000378:metabolism; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000201:enzymology* / Q000235:genetics; D014357:Trypsin / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D014362:Trypsinogen / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
D004792:Enzyme Precursors; C064831:PRSS2 protein, human; D014362:Trypsinogen; D014357:Trypsin; D004765:Enteropeptidase; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9