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Increased extracellular matrix remodeling is associated with tumor progression in human hepatocellular carcinomas
1Detoxication and Tissue Repair Unit, INSERM U-456, Université de Rennes I, Rennes, France. bdioui@rennes.inserm.fr
Abstract:
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.
Insights
Matrix metalloproteinase-2 (MMP2) and collagen I mRNA levels are elevated in hepatocellular carcinoma, particularly in cirrhotic livers, correlating with tumor invasion and recurrence. High extracellular matrix remodeling drives tumor progression.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Matrix metalloproteinase-2 (MMP2) is crucial for extracellular matrix remodeling, impacting tumor invasion and metastasis.
- MMP2 activation involves membrane type-matrix metalloproteinase-1 (MT1-MMP) and tissue inhibitor of metalloproteinase-2 (TIMP2).
- Activated hepatic stellate cells and collagen I are key sources and inducers of MMP2 activity.
Purpose of the Study:
- To investigate the correlation between MMP2, its regulators, extracellular matrix components, and hepatocellular carcinoma (HCC) progression.
- To compare mRNA levels and MMP2 activity in HCC tissues versus non-tumor and normal liver samples.
- To determine the association of these factors with tumor encapsulation, liver cirrhosis, and tumor recurrence in HCC.
Main Methods:
- Quantitative analysis of steady-state mRNA levels for MMP2, MT1-MMP, TIMP2, collagen I, collagen IV, and laminin gamma1.
- Measurement of MMP2 enzymatic activity in tumor tissues.
- Statistical analysis (Spearman correlation, t-tests) to assess relationships between gene expression, MMP2 activity, and clinical parameters in 55 HCCs, 47 matched non-tumor biopsies, and 19 normal livers.
Main Results:
- Strong positive correlations were found between collagen I mRNA and MMP2, MT1-MMP, and TIMP2 mRNA in HCCs.
- MMP2 activity correlated significantly with mRNA levels of collagen I, collagen IV, and laminin gamma1.
- Elevated MMP2, MT1-MMP, TIMP2, and collagen I mRNA were observed in non-encapsulated tumors. MMP2 activity was significantly higher in cirrhotic livers. Collagen I and MMP2 mRNA levels were associated with tumor recurrence in cirrhotic HCCs.
Conclusions:
- Increased extracellular matrix remodeling, particularly involving collagen I and MMP2, is strongly associated with hepatocellular carcinoma progression.
- These molecular changes, especially in the context of liver cirrhosis, may serve as indicators of tumor aggressiveness and recurrence risk.
- Targeting MMP2 and associated matrix remodeling pathways could offer therapeutic strategies for HCC.