Differential expression and origin of membrane-type 1 and 2 matrix metalloproteinases (MT-MMPs) in association with MMP2 activation in injured human livers.
Matrix metalloproteinase-2 (MMP2) activation is associated with basement membrane remodeling that occurs in injured tissues and during tumor invasion. The newly described membrane-type MMPs (MT-MMPs) form a family of potential MMP2 activators. We investigated the localization and steady-state levels of MT1-MMP and MT2-MMP mRNA, compared with those of MMP2 and tissue inhibitor of MMP-2 in 22 hepatocellular carcinomas, 12 liver metastases from colonic adenocarcinomas, 13 nontumoral samples from livers with metastases, 10 benign tumors, and 6 normal livers. MMP2 activation was analyzed by zymography in the same series. The expression of MT1-MMP mRNA and the activation of MMP-2 were increased in hepatocellular carcinomas, metastases, and cholestatic nontumoral samples. MT2-MMP mRNA was rather stable in the different groups. MT1-MMP mRNA levels, but not MT2-MMP mRNA, correlated with MMP-2 and tissue inhibitor of MMP-2 mRNA levels and with MMP2 activation. In situ hybridization showed that MT1-MMP mRNA was expressed in stromal cells, and MT2-MMP mRNA was principally located in both hepatocytes and biliary epithelial cells. Consistently, freshly isolated hepatocytes expressed only MT2-MMP mRNA, and culture-activated hepatic stellate cells showed high levels of MT1-MMP mRNA. These results indicate that in injured livers, MMP2 activation is related to a coordinated high expression of MMP2, tissue inhibitor of MMP-2, and MT1-MMP. Furthermore, the finding of a preferential expression of MT2-MMP in hepatocytes, together with our previous demonstration that the activation of stellate cell-derived MMP2 in co-culture requires interactions with hepatocytes (Am J Pathol 1997, 150:51-58), suggests that parenchymal cells might play a pivotal role in the MMP2 activation process.
Théret
N
N
Detoxication and Tissue Repair Unit, INSERM U456, Université de Rennes I, France.
Musso
O
O
L'Helgoualc'h
A
A
Campion
J P
JP
Clément
B
B
D000230:Adenocarcinoma / Q000201:enzymology / Q000556:secondary; D000328:Adult; D000368:Aged; D015152:Blotting, Northern; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology; D002779:Cholestasis / Q000201:enzymology / Q000473:pathology; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D018093:Gelatinases / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D008099:Liver / Q000033:anatomy & histology / Q000201:enzymology / Q000473:pathology; D008107:Liver Diseases / Q000201:enzymology* / Q000473:pathology; D008113:Liver Neoplasms / Q000201:enzymology / Q000556:secondary; D008297:Male; D053517:Matrix Metalloproteinase 15; D020778:Matrix Metalloproteinase 2; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
C507098:MMP15 protein, human; D012333:RNA, Messenger; D019716:Tissue Inhibitor of Metalloproteinase-2; D018093:Gelatinases; D053517:Matrix Metalloproteinase 15; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2