Increased extracellular matrix remodeling is associated with tumor progression in human hepatocellular carcinomas
Increased extracellular matrix remodeling is associated with tumor progression in human hepatocellular carcinomas
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DOI：
10.1053/jhep.2001.25758
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发表时间：
2001-07-01
期刊：
影响因子：
13.5
通讯作者：
Clément, B
中科院分区：
文献类型：
--
作者：
Théret, N;Musso, O;Clément, B
基质金属蛋白酶-2（MMP-2）是细胞外基质重塑过程中的关键酶，参与肿瘤的侵袭和转移。MMP 2的活化涉及与膜型基质金属蛋白酶-1（MT 1-MMP）和金属蛋白酶组织抑制剂-2（TIMP 2）的相互作用。在体外，活化的肝星状细胞是MMP 2的主要来源，胶原I诱导MMP 2活化。在55例肝细胞癌、47例匹配的非肿瘤活检组织和19例组织学正常肝脏中，将MMP 2、MT 1-MMP、TIMP 2、胶原I、胶原IV和层粘连蛋白yl的稳态mRNA水平与MMP 2活性进行比较。在肝细胞癌中，I型胶原mRNA水平的增加与MMP 2（斯皮尔曼R = 0.74，P <0.001）、MTI-MMP（R = 0.65，P <0.001）和TIMP 2（R = 0.61，P <0.001）的增加密切相关。MMP 2活性与I型胶原（R =.45，P < .01）、IV型胶原（R = .40，P < .01）和层粘连蛋白γ 1（R = .33，P < .05）的mRNA表达相关。与IV型胶原和层粘连蛋白γ 1 mRNA不同，MMP 2、MT 1-MMP、TIMP 2、I型胶原mRNA水平在无包膜肿瘤中比有包膜肿瘤中升高（P <0.05）。此外，MMP 2活性在发生于肝硬化的肿瘤中比发生于非肝硬化的肿瘤高4倍（P <0.01）。此外，在发生于肝硬化的肝细胞癌中，肿瘤复发与I型胶原和MMP 2 mRNA水平分别升高4.6倍和2.8倍（P <0.05）相关。因此，高细胞外基质重塑有利于肝细胞癌的肿瘤进展。
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-l (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 yl 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), MTI-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.