MMP-2,MMP-9,TIMP-1和TIMP-2在肝癌中原位表达

目的 :探讨肝癌中基质金属蛋白酶MMP 2 ,MMP 9和组织金属蛋白酶抑制剂TIMP 1 ,TIMP 2的mRNA和蛋白质表达与临床病理特征和预后的关系。方法 :在 5 6例有完整随访资料的原发性肝癌标本中原位杂交检测MMP 2mRNA ,TIMP 2mRNA ;免疫组化检测MMP 2 ,MMP 9,TIMP 1 ,TIMP 2蛋白质的表达。结果 :MMP 2mRNA ,TIMP 2mRNA ,MMP 2 ,MMP 9,TIMP 1和TIMP 2蛋白质在肝癌中的阳性表达分别为 4 8(85 .7% )例 ,35 (6 2 .5 % )例 ,4 4 (78.6 % )例 ,4 1 (73.2 % )例 ,30 (5 3.6 % )例 ,38(6 8% )例。MMP 2mRNA ,MMP 2 ,MMP 9在肝癌中呈高表达 ,而TIMP 1蛋白呈低表达 (P <0 .0 1 ,P <0 .0 5 )。TIMP 2mRNA与TIMP 2蛋白 ;MMP 2mRNA与MMP 2蛋白在肝癌中的表达呈正相关 (分别为r=0 .31 6 ,P <0 .0 5 ;r=0 .35 6 ,P <0 .0 5 )。MMP 2mRNA的表达与肝癌肿瘤大小和临床分期呈正相关 (分别为r =0 .4 4 1 ,P <0 .0 1 ;r=0 .340 ,P <0 .0 5 ) ;MMP 9蛋白表达阳性的肝癌患者术后生存时间缩短 (P <0 .0 5 )。Kaplan Meier单因素分析发现MMP 2 ,MMP 9表达阳性患者的预后差 (P <0 .0 1 ,P <0 .0 5 )。多因素Cox回归分析显示MMP 2 ,MMP 9的蛋白表达可作为肝癌估测预后的指标。结论 :基质金属蛋白酶MMP 2 ,MMP 9的过表达以及其与TIMP 2 ,MMP

Expression of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in the hepatocellular carcinomas

Objective To explore the expression and clinical prognostic significance of matrix metalloproteinase 2 mRNA (MMP 2 mRNA),tissue inhibitor of matrix metalloproteinase 2 mRNA (TIMP 2 mRNA), matrix metalloproteinase 2 protein (MMP 2),matrix metalloproteinase 9 protein (MMP 9), tissue inhibitor of matrix metalloproteinase 1 protein (TIMP 1),and tissue inhibitor of matrix metalloproteinase 2 protein (TIMP 2) in the hepatocellular carcinomas (HCCs). Methods Fifty six specimens of HCCs from 56 patients, who were followed up , were investigated by in situ hybridization with specific probes for MMP 2,TIMP 2, and by immunohistochemistry with anti MMP 2, MMP 9 and anti TIMP 1, TIMP 2 monoclonal antibody. We analyzed the data with chi square test, spearman’s correlation analysis, monovariate Kaplan Meier plot and multivariate Cox regression analysis. Results ①The positive expression of MMP 2mRNA, TIMP 2mRNA, MMP 2 protein, MMP 9 protein, TIMP 1 protein and TIMP 2 protein in the 56 HCCs cases were 48 (85.7%), 35 (62.5%), 44 (78.6%), 41 (73.2%), 30(53.6%),and 38(68%), respectively. ②We found over expression of MMP 2 mRNA, MMP 2 protein, and MMP 9 protein,but low expression of TIMP 1 protein in the 56 cases of HCCs ( P<0.01,P <0.05).③There was a positive association between TIMP 2mRNA and TIMP 2 protein expression,and between MMP 2 mRNA and MMP 2 protein in HCCs , respectively (r=0.316, P <0.05; r= 0.356, P <0.05) . ④Over expression of MMP 2 mRNA was positively correlated to the tumor size and TNM classification (r=0.441, P <0.001; r= 0.340, P <0.05), and MMP 9 protein was related to shortened survival ( P <0.05). ⑤In both monovariate Kaplan Meir plot and multivariate Cox regression analysis, the expression of MMP 2 protein and MMP 9 protein were linked to unfavorable prognosis. These results were further confirmed by multivariate analysis in which MMP 2 protein and MMP 9 protein emerged as independent prognostic factors for poor survival regardless of the age, tumor size, tumor grades, TNM classification and expression of MMP 2mRNA,TIMP 2mRNA,TIMP 1 protein and TIMP 2 protein. The hazard ratios of expression of MMP 2 protein and MMP 9 protein were 3.875 and 4.528, respectively.Conclusion The over expression of MMP 2mRNA,MMP 2 protein and MMP 9 protein and the imbalance between MMP 2 and TIMP 2 play pivotal roles in the degradation of excellular matrix of HCCs.MMP 2 and MMP 9 immunoreactive protein have been closely related to a shortened survival independent of major prognostic indicators in the primary HCC and increase the risk of the patients after the operation.