肝细胞癌中uPA和MMP-9的表达及其意义
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摘要
背景与目的:肝细胞癌(hepatocellular carcinoma,HCC,以下简称肝癌)为我国常见的恶性肿瘤,门静脉内生长和肝内转移是肝癌的生物学特征之一。肿瘤首先在肝内直接蔓延,也可在肝内沿门静脉分支转移,使肝内出现多处转移结节。肝外转移通过淋巴道,可转移至相关淋巴结。晚期亦可通过肝静脉转移至远处脏器,预后不佳。肿瘤的浸润转移是各种恶性肿瘤预后差的重要因素之一。肿瘤细胞的浸润和转移过程依赖于各种蛋白质水解系统的协同作用。其中,尿激酶型纤溶酶原激活物(urokinaseplasminogen activator,uPA)系统和金属蛋白酶(matrixmetalloproteirlases,MMPs)发挥了重要作用。uPA、金属蛋白酶-9(matrixmetalloproteinases-9,MMP-9)是降解细胞外基质(extracellufarmatrix,ECM)最重要的酶类之一,二者又与新生血管的形成,细胞间的黏附作用联系紧密。有研究表明,二者在肿瘤细胞的侵袭过程起着协同所用。但二者在肝癌中的联合表达情况,及它们与病理、临床相关指标的联系目前尚无报道。本课题通过研究uPA和MMP-9在肝癌中的表达情况,从而探讨uPA和MMP-9在肝癌发生、发展中的作用及其意义。
材料和方法:收集广西医科大学肝胆外科2004年12月—2006年4月45例肝癌病人的手术切除标本及对应的癌旁组织和相关临床资料,7例肝血管瘤的瘤旁肝组织作为对照组。用逆转录酶聚合酶链反应(reversetranscription polymerase chain reaction,RT-PCR)方法检测uPA和MMP-9在上述标本中的mRNA表达情况,并用凝胶扫描仪进行电泳条带强度分析;用免疫组织化学法(immunohistochemical method)检测uPA和MMP-9在上述标本中的蛋白表达情况,并由两名病理科医师采用双盲法阅片和评分。同时将实验结果与病理、临床资料(伴有静脉癌栓及肝内外转移形成、乙型肝炎病毒感染、病理分级、血清AFP水平、肿瘤直径)进行比较分析。
结果:
1,RT-PCR检测45例肝癌组织uPA mRNA阳性率为100%(45/45),相对应的癌旁组织阳性率为84.44%(38/45);对照组阳性率为28.57%(2/7)。三组比较均有显著性差异(P＜0.01,P＜0.05)。uPA mRNA在肝癌组织中的阳性表达率与静脉癌栓形成、肝内外转移明显有关(P＜0.01),而与乙型肝炎病毒(hepatitis B virus,HBV)感染、病理分级、血清AFP水平以及肿瘤直径无明显关系(P＞0.05)。
2,RT-PCR检测45例肝癌组织MMP-9 mRNA阳性率为100%(45/45),相对应的癌旁组织阳性率为86.67%(39/45);对照组阳性率分别为57.14%(4/7);三组比较均有显著性差异(P＜0.05,P＜0.01)。MMP-9 mRNA在肝癌组织中的阳性表达率与静脉癌栓形成、肝内外转移明显有关(P＜0.01),而与HBV感染、病理分级、血清AFP水平以及肿瘤直径无明显关系(P＞0.05)。
3,免疫组化检测uPA蛋白在肝癌中的阳性率为75.56%(34/45),明显高于癌旁(26.67%,12/45)及对照组(28.57%,2/7),三组比较有显著性差异(P＜0.01,P＜0.05)。并且uPA蛋白的表达与静脉癌栓形成、肝内外转移明显有关(P＜0.01),而与HBV感染、病理分级、血清AFP水平以及肿瘤直径无明显关系(P＞0.05)。
4,免疫组化检测MMP-9蛋白在肝癌中的阳性率为66.67%(30/45),明显高于癌旁(22.22%,10/45)及对照组(14.29%,1/7),三组比较有显著性差异(P＜0.01,P＜0.05)。并且MMP-9蛋白的表达与静脉癌栓形成、肝内外转移明显有关(P＜0.01),而与HBV感染、病理分级、血清AFP水平以及肿瘤直径无明显关系(P＞0.05)。
5,经Spearman等级相关分析,uPA和MMP-9的mRNA和蛋白表达水平之间呈正相关关系(分别为mRNA,r_s=0.749,P＜0.01;蛋白,r_s=0.475,P＜0.01)。
结论:研究结果显示,uPA和MMP-9在肝癌组织中呈高表达状态,这种高表达与肝癌的静脉癌栓形成和转移有关。对二者联合检测可能有助于提示早期发现肝癌的浸润和转移,在判断肝癌病人的预后和转归方面有一定作用。
Background ang Objective:Hepatocellular carcinoma(HCC)is one of the most common malignant tumors in China.The one of biologic features of HCC is the tumore cells growing in portal vein and metastasising in the liver.HCC first invades surrounding tissue or metastasizes within the liver.Then,HCC may also metastasize to lymph node through lymphatic pathway or to other organs through hematogenous pathway in advanced stage.Invasion and metastasis are the one of the reasons of poor prognosis of HCC,and this process is related to the protease system,Urokinase plasminogen activator(uPA) system and matrix metalloproteinases(MMPs)play a important role in the process.It was proven that uPA and matrix metalloproteinases-9 (MMP-9)are the most important erzymes in degrada extracellular matrix(ECM),they also association with angiogenesis and adhesion between ceils.But the combine expression of these two molecules in HCC,their relationship with pathology and clinic are unknown.In the present study,We would like to explore the expression of uPA and MMP-9 in HCC,and their effect and significance in the development of HCC.
Materials and Methods:All of the 45 surgical specimens of HCC and their adjacent liver tissues(from Dec.2004 to Apr.2006)were obtained from the department of liver and gall surgery of the first hospital affiliated to GuangXi Medical University,7 cases of adjacent liver tissues from hemangiomas of liver(as control group). Reverse transcription polymerase chain reaction(RT-PCR)and immunohistochemistry were used to detect the expression of uPA and MMP-9 in this specimens.The results were used to analyse the relationship between the expression of uPA and MMP-9 in HCC and the information of pathology and clinic(including the portal vein tumor thrombus, the presence of metastasis,hepatitis B virus,pathological stage, the level of serum alpha-fetoprotein(AFP)and the diameter of tumor).
Results:
1.RT-PCR was used to detect the expression of uPA in 45 cases.The positive rate of uPA mRNA in HCC was 100%(45/45),the rates of their adjacent liver tissues and the control group were 84.44%(38/45)and 28.57%(2/7)respectively(P＜0.01,P＜0.05).The positive rate of u-PA mRNA in HCC was significantly correlated with the portal vein tumor thrombus,the presence of metastasis(P＜0.01),but not correlated with the hepatitis B virus,pathological stage,the level of serum AFP and the diameter of tumor(P＞0.05)
2.RT-PCR was used to detect the expression of MMP-9 in 45 cases.The positive rate of MMP-9 mRNA in HCC was 100%(45/45),the rates of their adjacent liver tissues and the control group were 86.67%(39/45)and 57.14%(4/7)respectively(P＜0.05,P＜0.01).the positive rate of MMP-9 mRNA in HCC was significantly correlated with the portal vein tumor thrombus,the presence of metastasis(P＜0.01),but not correlated with the hepatitis B virus,pathological stage,the level of serum alpha-fetoprotein(AFP)and the diameter of tumor(P＞0.05)
3.Immunohistochemistry revealed that,among 45 cases,the positive rates of uPA protein were 75.56%(34/45)in HCC,26.67%(12/45) in their adjacent liver tissues,and 28.57%(2/7)in the control group, respectively(P＜0.05,P＜0.01).In addition,the positive rate of uPA protein in HCC was significantly correlated with the portal vein tumor thrombus,the.presence of metastasis(P＜0.01),but not correlated with the hepatitis B virus,pathological stage,the level of serum alpha-fetoprotein(AFP)and the diameter of tumor(P＞0.05).
4.Immunohistochemistry revealed that,among 45 cases,the positive rates of MMP-9 protein were 66.67%(30/45)in HCC, 22.22%(10/45)in their adjacent liver tissues,and 14.29%(1/7)in the control group,respectively(P＜0.01,P＜0.05).In addition,the positive rate of MMP-9 protein in HCC was significantly correlated with the portal vein tumor thrombus,the presence of metastasis(P＜0.01),but not correlated with the hepatitis B virus,pathological stage,the level of serum alpha-fetoprotein(AFP)and the diameter of tumor(P＞0.05)
5.By Spearman correlation analysis,the expression of uPA and MMP-9 mRNA.is positively correlation(r_s=0.749,P＜0.01),the expression of uPA and MMP-9 protein is also positively correlation(r_s =0.475,P＜0.01)
Conclusions:The high level of expression of u-PA and MMP-9 in HCC might be related to the growth、invasion and metastasis of HCC,and they might be used as markers of prognosis of HCC in clinical practice.
材料和方法:收集广西医科大学肝胆外科2004年12月—2006年4月45例肝癌病人的手术切除标本及对应的癌旁组织和相关临床资料,7例肝血管瘤的瘤旁肝组织作为对照组。用逆转录酶聚合酶链反应(reversetranscription polymerase chain reaction,RT-PCR)方法检测uPA和MMP-9在上述标本中的mRNA表达情况,并用凝胶扫描仪进行电泳条带强度分析;用免疫组织化学法(immunohistochemical method)检测uPA和MMP-9在上述标本中的蛋白表达情况,并由两名病理科医师采用双盲法阅片和评分。同时将实验结果与病理、临床资料(伴有静脉癌栓及肝内外转移形成、乙型肝炎病毒感染、病理分级、血清AFP水平、肿瘤直径)进行比较分析。
结果:
1,RT-PCR检测45例肝癌组织uPA mRNA阳性率为100%(45/45),相对应的癌旁组织阳性率为84.44%(38/45);对照组阳性率为28.57%(2/7)。三组比较均有显著性差异(P＜0.01,P＜0.05)。uPA mRNA在肝癌组织中的阳性表达率与静脉癌栓形成、肝内外转移明显有关(P＜0.01),而与乙型肝炎病毒(hepatitis B virus,HBV)感染、病理分级、血清AFP水平以及肿瘤直径无明显关系(P＞0.05)。
2,RT-PCR检测45例肝癌组织MMP-9 mRNA阳性率为100%(45/45),相对应的癌旁组织阳性率为86.67%(39/45);对照组阳性率分别为57.14%(4/7);三组比较均有显著性差异(P＜0.05,P＜0.01)。MMP-9 mRNA在肝癌组织中的阳性表达率与静脉癌栓形成、肝内外转移明显有关(P＜0.01),而与HBV感染、病理分级、血清AFP水平以及肿瘤直径无明显关系(P＞0.05)。
3,免疫组化检测uPA蛋白在肝癌中的阳性率为75.56%(34/45),明显高于癌旁(26.67%,12/45)及对照组(28.57%,2/7),三组比较有显著性差异(P＜0.01,P＜0.05)。并且uPA蛋白的表达与静脉癌栓形成、肝内外转移明显有关(P＜0.01),而与HBV感染、病理分级、血清AFP水平以及肿瘤直径无明显关系(P＞0.05)。
4,免疫组化检测MMP-9蛋白在肝癌中的阳性率为66.67%(30/45),明显高于癌旁(22.22%,10/45)及对照组(14.29%,1/7),三组比较有显著性差异(P＜0.01,P＜0.05)。并且MMP-9蛋白的表达与静脉癌栓形成、肝内外转移明显有关(P＜0.01),而与HBV感染、病理分级、血清AFP水平以及肿瘤直径无明显关系(P＞0.05)。
5,经Spearman等级相关分析,uPA和MMP-9的mRNA和蛋白表达水平之间呈正相关关系(分别为mRNA,r_s=0.749,P＜0.01;蛋白,r_s=0.475,P＜0.01)。
结论:研究结果显示,uPA和MMP-9在肝癌组织中呈高表达状态,这种高表达与肝癌的静脉癌栓形成和转移有关。对二者联合检测可能有助于提示早期发现肝癌的浸润和转移,在判断肝癌病人的预后和转归方面有一定作用。
Background ang Objective:Hepatocellular carcinoma(HCC)is one of the most common malignant tumors in China.The one of biologic features of HCC is the tumore cells growing in portal vein and metastasising in the liver.HCC first invades surrounding tissue or metastasizes within the liver.Then,HCC may also metastasize to lymph node through lymphatic pathway or to other organs through hematogenous pathway in advanced stage.Invasion and metastasis are the one of the reasons of poor prognosis of HCC,and this process is related to the protease system,Urokinase plasminogen activator(uPA) system and matrix metalloproteinases(MMPs)play a important role in the process.It was proven that uPA and matrix metalloproteinases-9 (MMP-9)are the most important erzymes in degrada extracellular matrix(ECM),they also association with angiogenesis and adhesion between ceils.But the combine expression of these two molecules in HCC,their relationship with pathology and clinic are unknown.In the present study,We would like to explore the expression of uPA and MMP-9 in HCC,and their effect and significance in the development of HCC.
Materials and Methods:All of the 45 surgical specimens of HCC and their adjacent liver tissues(from Dec.2004 to Apr.2006)were obtained from the department of liver and gall surgery of the first hospital affiliated to GuangXi Medical University,7 cases of adjacent liver tissues from hemangiomas of liver(as control group). Reverse transcription polymerase chain reaction(RT-PCR)and immunohistochemistry were used to detect the expression of uPA and MMP-9 in this specimens.The results were used to analyse the relationship between the expression of uPA and MMP-9 in HCC and the information of pathology and clinic(including the portal vein tumor thrombus, the presence of metastasis,hepatitis B virus,pathological stage, the level of serum alpha-fetoprotein(AFP)and the diameter of tumor).
Results:
1.RT-PCR was used to detect the expression of uPA in 45 cases.The positive rate of uPA mRNA in HCC was 100%(45/45),the rates of their adjacent liver tissues and the control group were 84.44%(38/45)and 28.57%(2/7)respectively(P＜0.01,P＜0.05).The positive rate of u-PA mRNA in HCC was significantly correlated with the portal vein tumor thrombus,the presence of metastasis(P＜0.01),but not correlated with the hepatitis B virus,pathological stage,the level of serum AFP and the diameter of tumor(P＞0.05)
2.RT-PCR was used to detect the expression of MMP-9 in 45 cases.The positive rate of MMP-9 mRNA in HCC was 100%(45/45),the rates of their adjacent liver tissues and the control group were 86.67%(39/45)and 57.14%(4/7)respectively(P＜0.05,P＜0.01).the positive rate of MMP-9 mRNA in HCC was significantly correlated with the portal vein tumor thrombus,the presence of metastasis(P＜0.01),but not correlated with the hepatitis B virus,pathological stage,the level of serum alpha-fetoprotein(AFP)and the diameter of tumor(P＞0.05)
3.Immunohistochemistry revealed that,among 45 cases,the positive rates of uPA protein were 75.56%(34/45)in HCC,26.67%(12/45) in their adjacent liver tissues,and 28.57%(2/7)in the control group, respectively(P＜0.05,P＜0.01).In addition,the positive rate of uPA protein in HCC was significantly correlated with the portal vein tumor thrombus,the.presence of metastasis(P＜0.01),but not correlated with the hepatitis B virus,pathological stage,the level of serum alpha-fetoprotein(AFP)and the diameter of tumor(P＞0.05).
4.Immunohistochemistry revealed that,among 45 cases,the positive rates of MMP-9 protein were 66.67%(30/45)in HCC, 22.22%(10/45)in their adjacent liver tissues,and 14.29%(1/7)in the control group,respectively(P＜0.01,P＜0.05).In addition,the positive rate of MMP-9 protein in HCC was significantly correlated with the portal vein tumor thrombus,the presence of metastasis(P＜0.01),but not correlated with the hepatitis B virus,pathological stage,the level of serum alpha-fetoprotein(AFP)and the diameter of tumor(P＞0.05)
5.By Spearman correlation analysis,the expression of uPA and MMP-9 mRNA.is positively correlation(r_s=0.749,P＜0.01),the expression of uPA and MMP-9 protein is also positively correlation(r_s =0.475,P＜0.01)
Conclusions:The high level of expression of u-PA and MMP-9 in HCC might be related to the growth、invasion and metastasis of HCC,and they might be used as markers of prognosis of HCC in clinical practice.
引文
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[1]李玉林主编.病理学第六版[M]。北京:人民卫生出版社,2005:221
[2]Wojtukiewicz M,Sierko E,Zacharski L R,et al.Occurrence of components off fibrinolytic pathways in situ in laryngeal cancer[J].Semin Thromb Hemost,2003,29(3):317-320
[3]Rajput B et al.Science[J]1985;230-672
[4]Dano,K.et al.Plasminogen activators,tissuedegradation and cancer,idv[J].Cancer Res.1985,44,139-266
[5]Beh rendt N,Ploug M,Patthy L,et al.The ligand-binding domain of the cell surface receptor for urokinase-type plasminogen activator[J].JBio l Chem,1991,226:7842-7847
[6]Seetoo DQ,Crowe PJ,Russell PJ,et al.Quantitative expression of protein markers of p lasminogen activation system in prognosis of colorectal cancer[J].J SurgOncol.2003,82(3):184-193
[7]Tanaka N,Fukao H,Ueshima S,et al.Plasminogen activator inhibitor 1 in human carcinoma tissues[J].Int J Cancer.1991,48(4):481-484
[8]Sandstrom M,JohanssonM,Sandstrom J,et al.Expression of the proteolytic factors,tPA and uPA,PAI-1 and VEGF during malignant glioma progression[J].Int J Dev Neurosci,1999,17(5):473-481
[9]Subramanian R,Gondi CS,Lakka SS,et al.siRNA-mediated simultaneous downregulation of uPA and its receptor inhibits angiogenesis and invasiveness triggering apoptosis in breast cancer cells[J].Int J Oncol..2006 Apt;28(4):831-839
[10]Merchan JR,Tang J,Hu G,et al.Protease activity of urokinase and tumor progression in a syngeneic mammary cancer model[J].J Natl Cancer Inst.2006 Jun 7;98(11):756-64.
[11]Chapman HA,Wei Y,et al.Role of urokinase receptor andcaveolin in regulation of integrin signaling[J].Thromb Haemostasis,1999,82:291
[12]Ghosh S,Munshi HG,Sen R,et al.Loss of adhesion-regulated proteinase production is correlated with invasive activity in oral squamous cell carcinoma[J].Cancer.2002 Dec 15;95(12):2524-33.
[I3]Mitra SK,Lim ST,Chi A,et al.Intrinsic focal adhesion kinase activity controls orthotopic breast carcinoma metastasis via the regulation of urokinase plasminogen activator expression in a syngeneic tumor model[J].Oncogene.2006 Mar 20;Epub ahead of print.
[14]Zheng Q,Tang ZY,Xue Q,et al.Invasion and metastasis of hepatocellular carcinoma in relation to urokinase-type plasminogen activator,its receptor and inhibitor[J].J Cancer Res Clin Oncol.2000;126(11):641-645.
[15]Maatta M,Soini Y,Liakka A,et al.Differential expression of matrix metalloproteinase(MMP)-2,MMP-9,and membrane type 1-MMP in hepatocellular and pancreatic adenocarcinoma:implications for tumor progression and clinical prognosis[J].Clin Cancer Res.2000;6(7):2726-34.
[16]Itoh T,Hayashi Y,Kanamaru T,et al.Clinical significance of urokinase-type plasminogen activator activity in hepatocellular carcinoma[J].J Gastroenterol Hepatol 2000b 15:422-430.
[17]Zhou L,Hayashi Y,Itoh T,et al.Expression of urokinase-type plasminogen activator,urokinase-type plasminogen activator receptor,and plasminogen activator inhibitor-1 and -2 in hepatocellular carcinoma[J].Pathol Int.2000;50(5):392-397.
[18]Nieto-Rodriguez A,Hernandez-Pando R,Kershenobich D,et al.Expression of urokinase-type plasminogen activator in an experimental model of hepatocarcinoma[J].Toxicology:2001 Mar 21;161(1-2):13-23.
[19]Zheng Q,Tang ZY,Xue Q,et al.Invasion and metastasis of hepatocellular carcinoma in relation to urokinase-type plasminogen activator,its receptor and inhibitor[J].J Cancer Res Clin Oncol.2000 Nov;126(11):641-6.
[20]Jouce ER.Mat fix M etalloproteinases.Angiogenesis,and Cancer Clinical[J].Cancer Research,2003;9:551
[21]Nagase H,Woessner J F,J r.Matrix metalloproteinases[J].J BiolChem,1999,274(31):21491-21494
[22]Massova I,Kotra L P,Fridman R,et al.Matrix metalloproteinases:structure,evolution and diversification[J].FASEB,1998,12:1075-1095
[23]Morgunova E,Tuuttila i,Bergmann U,et al.Structure of human pro-matrix metalloproteinase-2:activation mechanism revealed [J].Science,1999,284:1667-1670
[24]Woessner JF.Matrix metalloproteinases and their inhibitors in connective tissue remodeling[J].FA SEB,1991;5:2145
[25]Kleiner D,Stetler2Stevenson W.Matrix metalloproteinase and metastasis[J].Cancer Chemother Phamacol,1999,43:42.
[26]Goregory J M,YongLiang C,Smith RM,et al.A role for matrix metalloDroteinases and tumor host interaction in hepatocellular carcinomas[J]. AmJ Sury , 2002 ,183 :588-594.
[27]Powell WC , Knox JD , Navre M, et al. Expression of the metallopro-teinases matrilysis in Dn - 145 cells increases their invasive poteontial insevere combined immunodeficient mice [J]. Cancer Res , 1993 , 53 :417 - 4221
[28]Puli S, Lai JC, Bhushan A, Inhibition of matrix degrading enzymes and invasion in human glioblastoma (U87MG) Cells by isoflavones [J]. J Neurooncol. 2006 Apr 6; Epub ahead of print
[29]van Hinsbergh VW, Engelse MA, Quax PH. Pericellular proteases in angiogenesis and vasculogenesis[J]. Arterioscler Thromb Vasc Biol. 2006 Apr; 26(4):716-28.
[30]Birchmeier W, Behrens J. Cadherin expression in carcinomas: role in the formation of cell junctions and the p revention of invasiveness[J]. Biochim BiophysActa, 1994, 1198(1): 11-26.
[31]Zhang JF , Zhang YP, Hao FY, et al. DNA ploidy analysis and expression of MMP-9, TIMP-2, and E-cadherin in gastric carcinoma[J]. World J Gastroenterol, 2005, 11 (36) :5592 —5600
[32]Gao ZH, Tretiakova MS, Liu WH, et al. Association of E-cadherin, matrix metalloproteinases, and tissue inhibitors of metalloproteinases with the progression and metastasis of hepatocellular carcinoma [J]. Mod Pathol. 2006 Apr; 19(4) : 533-40.
[33] Ishii Y, Nakasato Y, Kobayashi S, et al. A study on angiogenesis-related matrix metalloproteinase networks in primary hepatocellular carcinoma [J]. J Exp Clin Cancer Res. 2003 Sep; 22 (3): 461-70.
[34]Arii S , Mise M, Harada T , et al . Overexpression of matrix metalloproteinase-9 gene in hepatocellular carcinoma with invasion potential[J].Hepatology,1996,24:316-322.
[35]Xia D,Yan LN,Xie JG,et al.Overexpression of TIMP-1 mediated by recombinant adenovirus in hepatocellular carcinoma cells inhibits proliferation and invasion in vitro[J].Hepatobiliary Pancreat Dis Int.2006 Aug;5(3):409-15.
[36]Murawaki Y,Ikuta Y,Okamoto K,et al.Plasma matrix metalloproteinase-9(gelatinase B)in patients with hepatocellular carcinoma[J].Res Commun Mol Pathol Pharmacol.2000,108:351-357
[37]Kuyvenhoven JP,Van Hoek B,Blom E,et al.Assessment of the clinical significance of serum matrix metalloproteinases MMP-2and MMP-9 in patients with various chronic liver diseases and hepatocellular carcinoma[J].Thromb Haemost.2003,89:718-725
[38]Harada T,Arii S,Mise M,et al.Membrane-type matrix metalloproteinase-1(MT1-MMP)gene is overexpressed in highly invasive hepatocellular carcinomas[J].J Hepatol,1998,28:231-239.
[39]Matrisian LM.The matrix-degrading metalloproteinases[J].Bioessays,1992,14:455-463
[40]Birkedal-Hansen H.Protedylic remodeling of extracelluar matrix[J].Cuur Opin Cell Biol,1995,7:728-735
[41]Hayasaka A,Suzuki N,Fujimoto N,et al.Elevated plasma levels of matrix metallo-proteinase-9(92-kd type Ⅳ collagenase/gelatinase B)in hepatocellular carcinoma.Hepatology,1996;24:1058-1062.
[42]Suzuki K,Enghild JJ,Morodomi T,et al.Mechanisms of activation of tissue procollagenase by metalloproteinase 3(stromelysin) [J].Biochemistry,1990,29:10261-10270
[43]Mazzieri R,Masiero L,Zanetta L,et al.Control of type Ⅳcollagenase activity by components with cell-bound reactant[J].EMBO J,1997,16(9):2319-2332
[44]Rao JS,Gondi C,Chetty C,et al.Inhibition of invasion,angiogenesis,tumor growth,and metastasis by adenovirusmediated transfer of antisense uPAR and MMP-9 in non-small cell lung cancer cells[J].Mol Cancer Zher.2005 Sep;4(9):1399-408.
[45]Gondi CS,Lakka SS,Dinh DH,et al.Downregulation of uPA,uPAR and MMP-9 using small,interfering,hairpin RNA(siRNA)inhibits glioma cell invasion,angiogenesis and tumor growth[J].Neuron Glia Biol.2004 May;1(2):165-176.
[46]Taras D,Blanc JF,Rullier A,et al.Halofuginone suppresses the lung metastasis of chemically induced hepatocellular carcinoma in rats through MMP inhibition[J].Neoplasia.2006 Apr;8(4):312-8.
[47]Taras D,Blanc JF,Rullier A,et al.Pravastatin reduces lung metastasis of rat hepatocellular carcinoma via a coordinated decrease of MMP expression and activity[J].J Hepatol.2007,46(1):69-76.Epub 2006 Jul 28.
[48]Mohanam S,Jasti SL,Kondraganti SR,Chandrasekar N,Kin Y,Fuller GN,Lakka SS,Kyritsis AP,et al.Stable transfection of urokinase-type plasminogen activator antisense construct modulates invasion of human glioblastoma cells[J].Clinical Cancer Research.2001;7:2519-2526.
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16 Rajput B et al.Science[J]1985;230-672.
17 Dano,K.et al.Plasminogen activators,tissuedegradation and cancer[J].Adv.Cancer Res.1985,44,139- 266.
18 Zhou L,Hayashi Y,Itoh T,et al.Expression of urokinase-type plasminogen activator,urokinase-type plasminogen activator receptor,and plasminogen activator inhibitor-1 and -2 in hepatocellular carcinoma[J].Pathol Int.2000;50(5):392-397.
19 Zheng O,Tang ZY,Xue Q,et al.Invasion and metastasis of hepatocellular carcinoma in relation to urokinase-type plasminogen activator,its receptor and inhibitor[J].J Cancer Res Clin Oncol.2000 Nov;126(11):641-645.
20 Okusa Y,Ichikura T,Mochizuki H,et al.Prognotic impact of stromal cell-derived urokinase-tupe plasminogen activator in gstric carcinoma[J].Cancer,1999,85(5):1033-10381.
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22 Zheng Q,Tang ZY,Xue Q,et al.Invasion and metastasis of hepatocellular carcinoma in relation to urokinase-type plasminogen activator,its receptor and inhibitor[J].J Cancer Res Clin Oncol.2000:126(11):641-645.
23 Morgunova E,Tuuttila A,Bergmann U,etal.Structure of human pro-matrix metalloproteinase-2:activation mechanism revealed[J].Science,1999,284:1667-1670.
24 Hayasaka A,Suzuki N,Fujimoto N,et al.Elevated plasma levels of matrix metallo-proteinase-9(92-kd type Ⅳ collagenase/gelatinase B)in hepatocellular carcinoma[J]..Hepatology,1996;24:1058-1062.
25 Ishii Y,Nakasato Y,Kobayashi S,et al.A study on angiogenesis-related matrix metalloproteinase networks in primary hepatocellular carcinoma[J].J Exp Clin Cancer Res 2003 22:461 -470.
26 Arii S,Mise M,Harada T,et al Overexpression of matrix metalloproteinase-9 gene in hepatocellular carcinoma with invasion potential[J].Hepatology,1996,24:316-322.
27 Maatta M,Soini Y,Liakka A,et al.Differential expression of matrix metalloproteinase(MMP)-2,MMP-9,and membrane type 1-MMP in hepatocellular and pancreatic adenocarcinoma:implications for tumor progression and clinical prognosis[J].Clin Cancer Res.2000;6(7):2726-34.
28 Murawaki Y,Ikuta Y,Okamoto K,et al.Plasma matrix metalloproteinase-9(gelatinase B)in patients with hepatocellular carcinoma[J].Res Commun Mol Pathol Pharmacol.2000,108:351-357.
29 Shirabe K,Shimada M,Kajiyama K,et al.Expression of matrix metalloproteinase-9 in surgically resected Intrahepatic cholangiocarcinoma[J].Surgery,1999,126:842-846.
30 Harada T,Arii S,Mise M,et al.Membrane-type matrix metalloproteinase-1(MTl-MMP)gene is overexpressed in highly invasive hepatocelhlar carcinomas[J].J Hepatol,1998,28:231-239.
31 Matrisian LM.The matrix-degrading metalloproteinases[J].Bioessays,1992,14:455-463.
32 Birkedal-Hansen H.Protedylic remodeling of extracelhar matrix[J].Cuur Opin Cell Biol,1995,7:728-735.
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34 Suzuki k,Enghild JJ,Morodomi T,et al.Mechanisms of activation of tissue procollagenase by metalloproteinase 3(stromelysin)[J].Biochemistry,1990,29:10261-10270.
35 Mazzieri R,Masiero L,Zanetta L,et al.Control of type Ⅳcollagenase activity by components with cell-bound reactant[J].EMBO J,1997,16(9):2319-2332.
36 van Hinsbergh VW,Engelse MA,Quax PH.Pericelhlar proteases in angiogenesis and vasculogenesis[J].Arterioscler Thromb Vasc Biol.2006 Apr;26(4):716-28.
37 Reuning U,Magdolen V,Wilhelm O,et al.Multifunctional potential of the plasminogen activation system in tumor invasion andmetastasis[J].Int J 0ncol,1998;13(5):893-906.
38 Zuo YY,Wang JM,et al.Expression and Significance of u-PA and MMP-9in carcinoma of stomach[J].Chin J Hemorh.2003;13(4):352-354.
[1]李玉林主编.病理学第六版[M]。北京:人民卫生出版社,2005:221
[2]Wojtukiewicz M,Sierko E,Zacharski L R,et al.Occurrence of components off fibrinolytic pathways in situ in laryngeal cancer[J].Semin Thromb Hemost,2003,29(3):317-320
[3]Rajput B et al.Science[J]1985;230-672
[4]Dano,K.et al.Plasminogen activators,tissuedegradation and cancer,idv[J].Cancer Res.1985,44,139-266
[5]Beh rendt N,Ploug M,Patthy L,et al.The ligand-binding domain of the cell surface receptor for urokinase-type plasminogen activator[J].JBio l Chem,1991,226:7842-7847
[6]Seetoo DQ,Crowe PJ,Russell PJ,et al.Quantitative expression of protein markers of p lasminogen activation system in prognosis of colorectal cancer[J].J SurgOncol.2003,82(3):184-193
[7]Tanaka N,Fukao H,Ueshima S,et al.Plasminogen activator inhibitor 1 in human carcinoma tissues[J].Int J Cancer.1991,48(4):481-484
[8]Sandstrom M,JohanssonM,Sandstrom J,et al.Expression of the proteolytic factors,tPA and uPA,PAI-1 and VEGF during malignant glioma progression[J].Int J Dev Neurosci,1999,17(5):473-481
[9]Subramanian R,Gondi CS,Lakka SS,et al.siRNA-mediated simultaneous downregulation of uPA and its receptor inhibits angiogenesis and invasiveness triggering apoptosis in breast cancer cells[J].Int J Oncol..2006 Apt;28(4):831-839
[10]Merchan JR,Tang J,Hu G,et al.Protease activity of urokinase and tumor progression in a syngeneic mammary cancer model[J].J Natl Cancer Inst.2006 Jun 7;98(11):756-64.
[11]Chapman HA,Wei Y,et al.Role of urokinase receptor andcaveolin in regulation of integrin signaling[J].Thromb Haemostasis,1999,82:291
[12]Ghosh S,Munshi HG,Sen R,et al.Loss of adhesion-regulated proteinase production is correlated with invasive activity in oral squamous cell carcinoma[J].Cancer.2002 Dec 15;95(12):2524-33.
[I3]Mitra SK,Lim ST,Chi A,et al.Intrinsic focal adhesion kinase activity controls orthotopic breast carcinoma metastasis via the regulation of urokinase plasminogen activator expression in a syngeneic tumor model[J].Oncogene.2006 Mar 20;Epub ahead of print.
[14]Zheng Q,Tang ZY,Xue Q,et al.Invasion and metastasis of hepatocellular carcinoma in relation to urokinase-type plasminogen activator,its receptor and inhibitor[J].J Cancer Res Clin Oncol.2000;126(11):641-645.
[15]Maatta M,Soini Y,Liakka A,et al.Differential expression of matrix metalloproteinase(MMP)-2,MMP-9,and membrane type 1-MMP in hepatocellular and pancreatic adenocarcinoma:implications for tumor progression and clinical prognosis[J].Clin Cancer Res.2000;6(7):2726-34.
[16]Itoh T,Hayashi Y,Kanamaru T,et al.Clinical significance of urokinase-type plasminogen activator activity in hepatocellular carcinoma[J].J Gastroenterol Hepatol 2000b 15:422-430.
[17]Zhou L,Hayashi Y,Itoh T,et al.Expression of urokinase-type plasminogen activator,urokinase-type plasminogen activator receptor,and plasminogen activator inhibitor-1 and -2 in hepatocellular carcinoma[J].Pathol Int.2000;50(5):392-397.
[18]Nieto-Rodriguez A,Hernandez-Pando R,Kershenobich D,et al.Expression of urokinase-type plasminogen activator in an experimental model of hepatocarcinoma[J].Toxicology:2001 Mar 21;161(1-2):13-23.
[19]Zheng Q,Tang ZY,Xue Q,et al.Invasion and metastasis of hepatocellular carcinoma in relation to urokinase-type plasminogen activator,its receptor and inhibitor[J].J Cancer Res Clin Oncol.2000 Nov;126(11):641-6.
[20]Jouce ER.Mat fix M etalloproteinases.Angiogenesis,and Cancer Clinical[J].Cancer Research,2003;9:551
[21]Nagase H,Woessner J F,J r.Matrix metalloproteinases[J].J BiolChem,1999,274(31):21491-21494
[22]Massova I,Kotra L P,Fridman R,et al.Matrix metalloproteinases:structure,evolution and diversification[J].FASEB,1998,12:1075-1095
[23]Morgunova E,Tuuttila i,Bergmann U,et al.Structure of human pro-matrix metalloproteinase-2:activation mechanism revealed [J].Science,1999,284:1667-1670
[24]Woessner JF.Matrix metalloproteinases and their inhibitors in connective tissue remodeling[J].FA SEB,1991;5:2145
[25]Kleiner D,Stetler2Stevenson W.Matrix metalloproteinase and metastasis[J].Cancer Chemother Phamacol,1999,43:42.
[26]Goregory J M,YongLiang C,Smith RM,et al.A role for matrix metalloDroteinases and tumor host interaction in hepatocellular carcinomas[J]. AmJ Sury , 2002 ,183 :588-594.
[27]Powell WC , Knox JD , Navre M, et al. Expression of the metallopro-teinases matrilysis in Dn - 145 cells increases their invasive poteontial insevere combined immunodeficient mice [J]. Cancer Res , 1993 , 53 :417 - 4221
[28]Puli S, Lai JC, Bhushan A, Inhibition of matrix degrading enzymes and invasion in human glioblastoma (U87MG) Cells by isoflavones [J]. J Neurooncol. 2006 Apr 6; Epub ahead of print
[29]van Hinsbergh VW, Engelse MA, Quax PH. Pericellular proteases in angiogenesis and vasculogenesis[J]. Arterioscler Thromb Vasc Biol. 2006 Apr; 26(4):716-28.
[30]Birchmeier W, Behrens J. Cadherin expression in carcinomas: role in the formation of cell junctions and the p revention of invasiveness[J]. Biochim BiophysActa, 1994, 1198(1): 11-26.
[31]Zhang JF , Zhang YP, Hao FY, et al. DNA ploidy analysis and expression of MMP-9, TIMP-2, and E-cadherin in gastric carcinoma[J]. World J Gastroenterol, 2005, 11 (36) :5592 —5600
[32]Gao ZH, Tretiakova MS, Liu WH, et al. Association of E-cadherin, matrix metalloproteinases, and tissue inhibitors of metalloproteinases with the progression and metastasis of hepatocellular carcinoma [J]. Mod Pathol. 2006 Apr; 19(4) : 533-40.
[33] Ishii Y, Nakasato Y, Kobayashi S, et al. A study on angiogenesis-related matrix metalloproteinase networks in primary hepatocellular carcinoma [J]. J Exp Clin Cancer Res. 2003 Sep; 22 (3): 461-70.
[34]Arii S , Mise M, Harada T , et al . Overexpression of matrix metalloproteinase-9 gene in hepatocellular carcinoma with invasion potential[J].Hepatology,1996,24:316-322.
[35]Xia D,Yan LN,Xie JG,et al.Overexpression of TIMP-1 mediated by recombinant adenovirus in hepatocellular carcinoma cells inhibits proliferation and invasion in vitro[J].Hepatobiliary Pancreat Dis Int.2006 Aug;5(3):409-15.
[36]Murawaki Y,Ikuta Y,Okamoto K,et al.Plasma matrix metalloproteinase-9(gelatinase B)in patients with hepatocellular carcinoma[J].Res Commun Mol Pathol Pharmacol.2000,108:351-357
[37]Kuyvenhoven JP,Van Hoek B,Blom E,et al.Assessment of the clinical significance of serum matrix metalloproteinases MMP-2and MMP-9 in patients with various chronic liver diseases and hepatocellular carcinoma[J].Thromb Haemost.2003,89:718-725
[38]Harada T,Arii S,Mise M,et al.Membrane-type matrix metalloproteinase-1(MT1-MMP)gene is overexpressed in highly invasive hepatocellular carcinomas[J].J Hepatol,1998,28:231-239.
[39]Matrisian LM.The matrix-degrading metalloproteinases[J].Bioessays,1992,14:455-463
[40]Birkedal-Hansen H.Protedylic remodeling of extracelluar matrix[J].Cuur Opin Cell Biol,1995,7:728-735
[41]Hayasaka A,Suzuki N,Fujimoto N,et al.Elevated plasma levels of matrix metallo-proteinase-9(92-kd type Ⅳ collagenase/gelatinase B)in hepatocellular carcinoma.Hepatology,1996;24:1058-1062.
[42]Suzuki K,Enghild JJ,Morodomi T,et al.Mechanisms of activation of tissue procollagenase by metalloproteinase 3(stromelysin) [J].Biochemistry,1990,29:10261-10270
[43]Mazzieri R,Masiero L,Zanetta L,et al.Control of type Ⅳcollagenase activity by components with cell-bound reactant[J].EMBO J,1997,16(9):2319-2332
[44]Rao JS,Gondi C,Chetty C,et al.Inhibition of invasion,angiogenesis,tumor growth,and metastasis by adenovirusmediated transfer of antisense uPAR and MMP-9 in non-small cell lung cancer cells[J].Mol Cancer Zher.2005 Sep;4(9):1399-408.
[45]Gondi CS,Lakka SS,Dinh DH,et al.Downregulation of uPA,uPAR and MMP-9 using small,interfering,hairpin RNA(siRNA)inhibits glioma cell invasion,angiogenesis and tumor growth[J].Neuron Glia Biol.2004 May;1(2):165-176.
[46]Taras D,Blanc JF,Rullier A,et al.Halofuginone suppresses the lung metastasis of chemically induced hepatocellular carcinoma in rats through MMP inhibition[J].Neoplasia.2006 Apr;8(4):312-8.
[47]Taras D,Blanc JF,Rullier A,et al.Pravastatin reduces lung metastasis of rat hepatocellular carcinoma via a coordinated decrease of MMP expression and activity[J].J Hepatol.2007,46(1):69-76.Epub 2006 Jul 28.
[48]Mohanam S,Jasti SL,Kondraganti SR,Chandrasekar N,Kin Y,Fuller GN,Lakka SS,Kyritsis AP,et al.Stable transfection of urokinase-type plasminogen activator antisense construct modulates invasion of human glioblastoma cells[J].Clinical Cancer Research.2001;7:2519-2526.