Increased extracellular matrix remodeling is associated with tumor progression in human hepatocellular carcinomas.
Matrix metalloproteinase-2 (MMP2) is a key enzyme in the process of extracellular matrix remodeling involved in tumor invasion and metastasis. The activation of MMP2 involves interplay with the membrane type-matrix metalloproteinase-1 (MT1-MMP) and the tissue inhibitor of metalloproteinase-2 (TIMP2). In vitro, activated hepatic stellate cells are a main source of MMP2 and collagen I induces MMP2 activation. The steady-state mRNA levels of MMP2, MT1-MMP, TIMP2, collagen I, collagen IV, and laminin gamma1 were compared with MMP2 activity in 55 hepatocellular carcinomas, 47 matching nontumor biopsies and 19 histologically normal livers. In hepatocellular carcinomas, increased collagen I mRNA levels were strongly associated with those of MMP2 (Spearman R =.74, P <.001), MT1-MMP (R =.65, P <.001) and TIMP2 (R = 0.61, P <.001). MMP2 activity was correlated with the mRNA expression of collagen I (R =.45 P <.01), collagen IV (R =.40, P <.01) and laminin gamma1 (R =.33, P <.05). Unlike collagen IV and laminin gamma1 mRNAs, MMP2, MT1-MMP, TIMP2, collagen I mRNA levels were increased in nonencapsulated compared with encapsulated tumors (P <.05). In addition, MMP2 activity was fourfold higher (P <.01) in tumors arising in cirrhotic livers than in those arising in noncirrhotic livers. Moreover, tumor recurrence was associated with 4.6- and 2.8-fold (P <.05) higher collagen I and MMP2 mRNA levels, respectively, in hepatocellular carcinomas arising in cirrhotic livers. Thus, a high extracellular matrix remodeling favors tumor progression in hepatocellular carcinomas.
Théret
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N
Detoxication and Tissue Repair Unit, INSERM U-456, Université de Rennes I, Rennes, France. bdioui@rennes.inserm.fr
Musso
O
O
Turlin
B
B
Lotrian
D
D
Bioulac-Sage
P
P
Campion
J P
JP
Boudjéma
K
K
Clément
B
B
D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000201:enzymology / Q000473:pathology*; D003094:Collagen / Q000235:genetics / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D006801:Humans; D007797:Laminin / Q000235:genetics; D008113:Liver Neoplasms / Q000737:chemistry / Q000201:enzymology / Q000473:pathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D012333:RNA, Messenger / Q000032:analysis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics
D007797:Laminin; D012333:RNA, Messenger; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2