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.
Institute of Dentistry, University of Helsinki, Department of Oral and Maxillofacial Diseases, Helsinki University Hospital, Finland.
Suvi-Tuuli
ST
Vilen
Pia
P
Nyberg
Mika
M
Hukkanen
Meeri
M
Sutinen
Merja
M
Ylipalosaari
Anders
A
Bjartell
Annukka
A
Paju
Virpi
V
Haaparanta
Ulf-Håkan
UH
Stenman
Timo
T
Sorsa
Tuula
T
Salo
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