Arii S, Mise M, Harada T, Furutani M, Ishigami S, Niwano M, Mizumoto M, Fukumoto M, Imamura M
First Department of Surgery, Faculty of Medicine, Kyoto University, Japan.
Hepatology. 1996 Aug;24(2):316-22. doi: 10.1053/jhep.1996.v24.pm0008690399.
The prognosis for hepatocellular carcinoma (HCC) depends mainly on the clinicopathological characteristic regarding invasion and metastasis. In addition, another distinguishing feature of HCC is the high incidence of concomitant liver cirrhosis, in which the extracellular matrix proliferates markedly. Therefore, the present study was designed to investigate the molecules responsible for the invasion potential of HCC by focusing on matrix metalloproteinase (MMP) in particular, MMP-2 and MMP-9 and the corresponding tissue inhibitor of metalloproteinase (TIMP-2 and TIMP-1), because these enzymes participate in the degradation of the extracellular matrix including the basement membrane. Tumorous and adjacent nontumorous liver samples were obtained from 23 HCC patients who underwent a partial hepatectomy. In 16 of the 23 HCC samples, transcripts for MMP-9 were detected in the tumorous tissues, and 15 of 16 of these samples showed stronger expression in the tumorous tissues than in the nontumorous tissues. On the other hand, MMP-2 messenger RNA (mRNA) was detected in 18 of the 23 cases. Eight of these 18 cases showed more intense expression in the tumorous tissues than in the nontumorous tissues, whereas the expression levels were lower in the tumorous tissues than in the nontumorous tissues in 7 of 18 samples. With respect to the correlation between the clinicopathological features and mRNAs expression, it was found that the expression of MMP-9 mRNA in HCC with capsular infiltration was significantly higher than in HCC without capsular infiltration. HCC with capsular infiltration also tended to have a higher ratio of MMP-9 mRNA expression to TIMP-1 mRNA expression. In addition, the expression of MMP-2 mRNA in nontumorous cirrhotic tissues was significantly higher than in nontumorous tissues from patients with chronic hepatitis. Immunohistochemical examinations revealed that MMP-9 immunoreactivity was the most intense in the HCC cells, particularly in those cells in the marginal areas of the tumorous tissues. In conclusion, the present study shows that MMP-9 is closely participated in capsular infiltration in HCC.
肝细胞癌（HCC）的预后主要取决于与侵袭和转移相关的临床病理特征。此外，HCC的另一个显著特征是合并肝硬化的发生率高，其中细胞外基质明显增殖。因此，本研究旨在通过特别关注基质金属蛋白酶（MMP），尤其是MMP-2和MMP-9以及相应的金属蛋白酶组织抑制剂（TIMP-2和TIMP-1）来研究导致HCC侵袭潜能的分子，因为这些酶参与包括基底膜在内的细胞外基质的降解。从23例行部分肝切除术的HCC患者中获取肿瘤及相邻的非肿瘤肝组织样本。在23个HCC样本中的16个中，在肿瘤组织中检测到MMP-9的转录本，其中16个样本中的15个在肿瘤组织中的表达强于非肿瘤组织。另一方面，在23例中的18例检测到MMP-2信使核糖核酸（mRNA）。这18例中的8例在肿瘤组织中的表达比非肿瘤组织更强烈，而在18个样本中的7个中，肿瘤组织中的表达水平低于非肿瘤组织。关于临床病理特征与mRNA表达之间的相关性，发现有包膜浸润的HCC中MMP-9 mRNA的表达明显高于无包膜浸润的HCC。有包膜浸润的HCC也倾向于具有更高的MMP-9 mRNA表达与TIMP-1 mRNA表达的比率。此外，非肿瘤性肝硬化组织中MMP-2 mRNA的表达明显高于慢性肝炎患者的非肿瘤组织。免疫组织化学检查显示MMP-9免疫反应性在HCC细胞中最强，尤其是在肿瘤组织边缘区域的那些细胞中。总之，本研究表明MMP-9密切参与HCC的包膜浸润。
