MMP-2、MMP-9、TIMP-2在人脑胶质瘤中的表达及意义
摘要
研究MMP-2、MMP-9、TIMP-2在胶质细胞瘤中的蛋白质表达及其意义,探讨MMP-2、MMP-9、TIMP-2与胶质细胞瘤分级的关系及三者之间的相互关系,从而进一步阐明胶质细胞瘤侵袭性的分子机制。MMP-2、MMP-9及TIMP-2的联合检测可能会更有利于对人脑胶质瘤的恶性生物学行为进行评价与判断,为临床提供评价预后、靶向治疗的新思路。材料与方法
本实验收集2006年1月至2008年12月郑州大学第一附属医院神经外科脑胶质瘤手术标本58例,按2000年WHO脑肿瘤分类标准分级：低度恶性组30例(Ⅰ级10例；Ⅱ级20例),高度恶性组28例(Ⅲ级15例；ⅣV级13例)。另取同期急性颅脑损伤内减压时切除的正常脑组织8例。应用免疫组化SP法检测了8例正常脑组织、30例低度恶性脑胶质瘤及28例高度恶性脑胶质瘤组织中MMP-2、MMP-9及TIMP-2蛋白的表达。利用SPSS13.0统计软件处理数据,两样本率的比较采用四格表资料x2检验；多样本率的比较采用行列表资料的x2检验；相关性检验用Spearman相关分析。以α=0.05为显著性检验水准。结果
1.MMP-2在正常脑组织(A)、低度恶性(B)及高度恶性脑胶质瘤组织(C)中的阳性表达率呈逐渐升高趋势(其阳性率分别为25.00%(2／8),66.67%(20／30)和89.29%(25／28),组间比较(A:B X2=4.498 P=0.034；B：C X@=4.261 P=0.039；C：A X2=13.714 P=0.000)均有显著性差异(P值均<0.05)。
2.MMP-9在正常脑组织(A)、低度恶性(B)及高度恶性脑胶质瘤组织(C)中的阳性表达率呈逐渐升高趋势(其阳性率分别为12.50 %(1／8),73.33%(22／30)和96.43%(27／28)),组间比较(A:B X2=9.783 P=0.002；B：C X2=5.893 P=0.015；C：AX2=25.358 P=0.000)均有显著性差异(P值均<0.05)。
3.TIMP-2在正常脑组织(A)、低度恶性(B)及高度恶性脑胶质瘤组织(C)中的阳性表达率呈逐渐升高趋势(其阳性率分别为12.50%%(1／8),56.67%(17／30)和85.71%(24／28)),组间比较(A:B X2=4.942 P=0.026; B：C X2=5.893 P=0.015；C：AX2=15.718 P=0.000)均有显著性差异(P值均<0.05)。
4.MMP-2蛋白的表达和MMP-9蛋白的表达之间呈正相关关系(RS=0.521p<0.05),MMP-2蛋白表达阳性的病例中MMP-9蛋白的阳性表达率为93.33%(42／45),MMP-2蛋白表达阴性的病例中,MMP-9蛋白的阳性表达率为53.85%(7／13)。
5.MMP-2蛋白的表达和TIMP-2蛋白的表达之间呈正相关关系(RS=0.357p<0.05),MMP-2蛋白表达阳性的病例中TIMP-2蛋白的阳性表达率为80.00%(36／45),MMP-2蛋白表达阴性的病例中,TIMP-2蛋白的阳性表达率为38.46%(5／13)。
6.MMP-9蛋白的表达和TIMP-2蛋白的表达之间呈正相关关系(RS=0.331p<0.05),MMP-9蛋白表达阳性的病例中,TIMP-2蛋白的阳性表达率为77.55%(38／49),MMP-9蛋白表达阴性的病例中,TIMP-2蛋白的阳性表达率为33.33%(3／9)。结论
1.在不同脑组织中,从正常脑组织到低度恶性脑胶质瘤、高度恶性脑胶质瘤,MMP-2、MMP-9及TIMP-2蛋白表达的阳性率均呈逐渐升高趋势,提示MMP-2、MMP-9、TIMP-2蛋白的表达与脑胶质瘤的发生发展有关。
2.MMP-2、MMP-9及TIMP-2蛋白的表达与脑胶质瘤的恶性程度呈正相关关系,提示MMP-2、MMP-9、TIMP-2蛋白的高表达均与胶质瘤的恶性程度有关。
3.MMP-2和MMP-9蛋白表达之间呈正相关关系,提示二者表达具有一致性,可能在脑胶质瘤的发生、发展中起协同效应。MMP-2与TIMP-2、MMP-9与TIMP-2蛋白表达之间均呈正相关关系,提示TIMP-2在脑胶质瘤表达调高,并随恶性程度升高而表达增强的机制是一种补偿机制。
Objective
This study was aimed to investigate the expression of MMP-2(matrix metalloproteinase-2),MMP-9(matrix metalloproteinase-2)and TIMP-2(tissue inhibitor of metalloproteinase-2) in the glioma and normal brain tissue, and to clarify the relationship between MMP/TIMP expressions (MMP-2,MMP-9andTIMP-2) and every grade of glioma. Meanwhile, the relationship between the expression of MMP-2,MMP-9 and TIMP-2 in the combined detection could be good to human malignant glioma to evaluate and judge behavior, to provide for the evaluation of clinical prognosis, targeted therapy of new ideas. Materials and methotis
In this study, collected from January 2006 to December 2008, the First Affiliated Hospital of Zhengzhou University, Neurosurgery,58 cases of surgical specimens of glioma, according to 2000 WHO grading classification of brain tumors: low grade 30 cases (grade 110 cases;gradeⅡ20 cases),28 cases were:high potential malignancy (grade III 15 cases; grade IV 13 cases).Also,there were 8 cases of normal brain tissue taken from decompression operation of acute brain injury. The expression of MMP-2,MMP-9 and TIMP-2 protein were detected using immunohistochemical SP method in 58 cases of brain glioma (30 cases of low potential malignancy,28 cases of high potential malignancy) and 8 cases of normal brain tissue. SPSS 13.0 process data using statistical software, and compare the two sample rate using 2X2 tables analysis and chi-square statistics; Diverse line of this list was used to compare the rate of information x2 test; Correlation test with Spearman correlation analysis.To a=0.05 level for the test of significance. Result
1.MMP-2 in normal brain tissue (A), low-grade (B) and highly malignant brain gliomas (C).The positive expression rate was gradually increased (the positive rates were 25.00%(2/8),66.67%(20/30) and 89.29%(25/28)), between the two groups (A:B X2=4.498 P=0.034; B:C X2=4.261 P=0.039; C:A X2=13.714 P=0.000),and was significantly different (P<0.05).
2.MMP-9 in normal brain tissue (A), low-grade (B) and highly malignant brain gliomas (C). The positive expression rate was gradually increased (the positive rates were 12.50%(1/8),73.33%(22/30) and 96.43%(27/28)), between the two groups (A: B X2=9.783 P=0.002; B:C X2=5.893 P=0.015; C:A X2=25.358 P=0.000),and was significantly different (P<0.05).
3.TIMP-2 in normal brain tissue (A), low-grade (B) and highly malignant brain gliomas (C) The positive expression rate was gradually increased (the positive rates were 12.50%%(1/8),56.67%(17/30) and 85.71%(24/28)), between the two groups (A:B X2=4.942, P=0.026; B:C X2=5.893, P=0.015; C:A X2=15.718,P= 0.000),and was significantly different (P<0.05).
4.MMP-2 protein expression and protein expression of MMP-9 positive correlation between the(RS=0.521, P<0.05), MMP-2 protein positive cases in the MMP-9 protein expression rate was 93.33%(42/45), MMP-2 protein negative cases, MMP-9 protein expression was 53.85%(7/13).
5. MMP-2 protein expression and protein expression of TIMP-2 showed a positive correlation between (RS=0.357,P<0.05), MMP-2 protein positive cases in TIMP-2 protein expression was 80.00%(36/45), MMP-2 protein negative cases, TIMP-2 protein expression was 38.46%(5/13).
6. MMP-9 protein expression and TIMP-2 protein positive correlation between the expression (RS=0.331,P<0.05), MMP-9 protein expression in positive cases, TIMP-2 protein expression was 77.55%(38/49), MMP-9 protein expression in negative cases, TIMP-2 protein expression was 33.33%(3/9). Conclusions
1. In different brain tissue from normal brain tissue to low-grade malignant gliomas, highly malignant glioma, MMP-2, MMP-9 and TIMP-2 protein expression showed a positive rate increased with, suggesting that MMP-2, MMP-9, TIMP-2 protein expression had relitionship with the incidence of glioma development.
2. MMP-2, MMP-9 and TIMP-2 protein expression and degree of malignant gliomas were positively correlated, suggesting that MMP-2, MMP-9, TIMP-2 protein expression and high degree of malignancy of glioma about.
3. The expression of MMP-2 and MMP-9 protein were positive correlation, suggesting that the expression of consistency between the two may occur in brain gliomas.The development of a synergistic effect.MMP-2 and TIMP-2, MMP-9 and TIMP-2 protein expression showed a positive correlation between, suggesting that TIMP-2 expression increased in glioma, and the degree of malignancy increased with the increase of the mechanism to express akind of compensation mechanism.
本实验收集2006年1月至2008年12月郑州大学第一附属医院神经外科脑胶质瘤手术标本58例,按2000年WHO脑肿瘤分类标准分级：低度恶性组30例(Ⅰ级10例；Ⅱ级20例),高度恶性组28例(Ⅲ级15例；ⅣV级13例)。另取同期急性颅脑损伤内减压时切除的正常脑组织8例。应用免疫组化SP法检测了8例正常脑组织、30例低度恶性脑胶质瘤及28例高度恶性脑胶质瘤组织中MMP-2、MMP-9及TIMP-2蛋白的表达。利用SPSS13.0统计软件处理数据,两样本率的比较采用四格表资料x2检验；多样本率的比较采用行列表资料的x2检验；相关性检验用Spearman相关分析。以α=0.05为显著性检验水准。结果
1.MMP-2在正常脑组织(A)、低度恶性(B)及高度恶性脑胶质瘤组织(C)中的阳性表达率呈逐渐升高趋势(其阳性率分别为25.00%(2／8),66.67%(20／30)和89.29%(25／28),组间比较(A:B X2=4.498 P=0.034；B：C X@=4.261 P=0.039；C：A X2=13.714 P=0.000)均有显著性差异(P值均<0.05)。
2.MMP-9在正常脑组织(A)、低度恶性(B)及高度恶性脑胶质瘤组织(C)中的阳性表达率呈逐渐升高趋势(其阳性率分别为12.50 %(1／8),73.33%(22／30)和96.43%(27／28)),组间比较(A:B X2=9.783 P=0.002；B：C X2=5.893 P=0.015；C：AX2=25.358 P=0.000)均有显著性差异(P值均<0.05)。
3.TIMP-2在正常脑组织(A)、低度恶性(B)及高度恶性脑胶质瘤组织(C)中的阳性表达率呈逐渐升高趋势(其阳性率分别为12.50%%(1／8),56.67%(17／30)和85.71%(24／28)),组间比较(A:B X2=4.942 P=0.026; B：C X2=5.893 P=0.015；C：AX2=15.718 P=0.000)均有显著性差异(P值均<0.05)。
4.MMP-2蛋白的表达和MMP-9蛋白的表达之间呈正相关关系(RS=0.521p<0.05),MMP-2蛋白表达阳性的病例中MMP-9蛋白的阳性表达率为93.33%(42／45),MMP-2蛋白表达阴性的病例中,MMP-9蛋白的阳性表达率为53.85%(7／13)。
5.MMP-2蛋白的表达和TIMP-2蛋白的表达之间呈正相关关系(RS=0.357p<0.05),MMP-2蛋白表达阳性的病例中TIMP-2蛋白的阳性表达率为80.00%(36／45),MMP-2蛋白表达阴性的病例中,TIMP-2蛋白的阳性表达率为38.46%(5／13)。
6.MMP-9蛋白的表达和TIMP-2蛋白的表达之间呈正相关关系(RS=0.331p<0.05),MMP-9蛋白表达阳性的病例中,TIMP-2蛋白的阳性表达率为77.55%(38／49),MMP-9蛋白表达阴性的病例中,TIMP-2蛋白的阳性表达率为33.33%(3／9)。结论
1.在不同脑组织中,从正常脑组织到低度恶性脑胶质瘤、高度恶性脑胶质瘤,MMP-2、MMP-9及TIMP-2蛋白表达的阳性率均呈逐渐升高趋势,提示MMP-2、MMP-9、TIMP-2蛋白的表达与脑胶质瘤的发生发展有关。
2.MMP-2、MMP-9及TIMP-2蛋白的表达与脑胶质瘤的恶性程度呈正相关关系,提示MMP-2、MMP-9、TIMP-2蛋白的高表达均与胶质瘤的恶性程度有关。
3.MMP-2和MMP-9蛋白表达之间呈正相关关系,提示二者表达具有一致性,可能在脑胶质瘤的发生、发展中起协同效应。MMP-2与TIMP-2、MMP-9与TIMP-2蛋白表达之间均呈正相关关系,提示TIMP-2在脑胶质瘤表达调高,并随恶性程度升高而表达增强的机制是一种补偿机制。
Objective
This study was aimed to investigate the expression of MMP-2(matrix metalloproteinase-2),MMP-9(matrix metalloproteinase-2)and TIMP-2(tissue inhibitor of metalloproteinase-2) in the glioma and normal brain tissue, and to clarify the relationship between MMP/TIMP expressions (MMP-2,MMP-9andTIMP-2) and every grade of glioma. Meanwhile, the relationship between the expression of MMP-2,MMP-9 and TIMP-2 in the combined detection could be good to human malignant glioma to evaluate and judge behavior, to provide for the evaluation of clinical prognosis, targeted therapy of new ideas. Materials and methotis
In this study, collected from January 2006 to December 2008, the First Affiliated Hospital of Zhengzhou University, Neurosurgery,58 cases of surgical specimens of glioma, according to 2000 WHO grading classification of brain tumors: low grade 30 cases (grade 110 cases;gradeⅡ20 cases),28 cases were:high potential malignancy (grade III 15 cases; grade IV 13 cases).Also,there were 8 cases of normal brain tissue taken from decompression operation of acute brain injury. The expression of MMP-2,MMP-9 and TIMP-2 protein were detected using immunohistochemical SP method in 58 cases of brain glioma (30 cases of low potential malignancy,28 cases of high potential malignancy) and 8 cases of normal brain tissue. SPSS 13.0 process data using statistical software, and compare the two sample rate using 2X2 tables analysis and chi-square statistics; Diverse line of this list was used to compare the rate of information x2 test; Correlation test with Spearman correlation analysis.To a=0.05 level for the test of significance. Result
1.MMP-2 in normal brain tissue (A), low-grade (B) and highly malignant brain gliomas (C).The positive expression rate was gradually increased (the positive rates were 25.00%(2/8),66.67%(20/30) and 89.29%(25/28)), between the two groups (A:B X2=4.498 P=0.034; B:C X2=4.261 P=0.039; C:A X2=13.714 P=0.000),and was significantly different (P<0.05).
2.MMP-9 in normal brain tissue (A), low-grade (B) and highly malignant brain gliomas (C). The positive expression rate was gradually increased (the positive rates were 12.50%(1/8),73.33%(22/30) and 96.43%(27/28)), between the two groups (A: B X2=9.783 P=0.002; B:C X2=5.893 P=0.015; C:A X2=25.358 P=0.000),and was significantly different (P<0.05).
3.TIMP-2 in normal brain tissue (A), low-grade (B) and highly malignant brain gliomas (C) The positive expression rate was gradually increased (the positive rates were 12.50%%(1/8),56.67%(17/30) and 85.71%(24/28)), between the two groups (A:B X2=4.942, P=0.026; B:C X2=5.893, P=0.015; C:A X2=15.718,P= 0.000),and was significantly different (P<0.05).
4.MMP-2 protein expression and protein expression of MMP-9 positive correlation between the(RS=0.521, P<0.05), MMP-2 protein positive cases in the MMP-9 protein expression rate was 93.33%(42/45), MMP-2 protein negative cases, MMP-9 protein expression was 53.85%(7/13).
5. MMP-2 protein expression and protein expression of TIMP-2 showed a positive correlation between (RS=0.357,P<0.05), MMP-2 protein positive cases in TIMP-2 protein expression was 80.00%(36/45), MMP-2 protein negative cases, TIMP-2 protein expression was 38.46%(5/13).
6. MMP-9 protein expression and TIMP-2 protein positive correlation between the expression (RS=0.331,P<0.05), MMP-9 protein expression in positive cases, TIMP-2 protein expression was 77.55%(38/49), MMP-9 protein expression in negative cases, TIMP-2 protein expression was 33.33%(3/9). Conclusions
1. In different brain tissue from normal brain tissue to low-grade malignant gliomas, highly malignant glioma, MMP-2, MMP-9 and TIMP-2 protein expression showed a positive rate increased with, suggesting that MMP-2, MMP-9, TIMP-2 protein expression had relitionship with the incidence of glioma development.
2. MMP-2, MMP-9 and TIMP-2 protein expression and degree of malignant gliomas were positively correlated, suggesting that MMP-2, MMP-9, TIMP-2 protein expression and high degree of malignancy of glioma about.
3. The expression of MMP-2 and MMP-9 protein were positive correlation, suggesting that the expression of consistency between the two may occur in brain gliomas.The development of a synergistic effect.MMP-2 and TIMP-2, MMP-9 and TIMP-2 protein expression showed a positive correlation between, suggesting that TIMP-2 expression increased in glioma, and the degree of malignancy increased with the increase of the mechanism to express akind of compensation mechanism.
引文
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[32]Nordqvist AC, Smurawa H, Mathiesen T. Expression of matrix metalloproteinases 2 and 9 in meningiomas associated with different degrees of brain invasiveness and edema [J].J Neurosurg,2001,95(5):839-844
[33]康春生,浦佩玉,李捷等,人脑胶质瘤AKT2表达与细胞增殖和侵袭性的关系[J].中华病理学杂志,2004,33(5)：464--465
[34]Rothhut B,Ghoneinm C,Antonicelli F,et al.Epidermal growth factor stimulates matrix metalloproteinase-9 expression and invasion in human follicular thvroid carcinoma cells through Focal adhesionkinase [J].Biochimie,2007,89(5):613-624.
[35]Greene J,Wang M,Liu YE,et al.Molecular cloning and characterization of human tissue inhibitor of metalloproteinase-4 [J].J Biol Chem,2006,271 (48:30375-30380)
[36]. M. Margarida Bernardo. Design, Synthesis, and Characterization of Potent Slow-binding Inhibitors that are selective for Gelatinases[J]. Jorney of biology chemistry,2002; 277(13): 11201-11207
[37].Robert Visse, Hideaki Nagase. Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases[DB]. Circulation Research,2003;92:827.
[38]Mohanam S, Wang SW, Rayford A, Yamamoto M, Sawaya R, Nakajima M, Liotta LA, Nicolson GL, Stetler-Stevenson WG, Rao JS:Expression of tissue inhibitors of metalloproteinases:negative regulators of human glioblastoma invasion in vivo. [J].Clin Exp Metastasis,2005 Jan,13(1):57-62.
[39]Li M, Xie J, Cheng L, et al.uppression of invasive properties of colorectal carcinoma SW480 cells by 15-hydroxyprostaglandin dehydrogenase gene[J].CancerInvest.2008,26(9): 905-12.
[40]Schwardt O, Kolb H, Ernst B.Drug discovery today [J]. Current Topics in Medicinal Chemistry 2003;3:1-9
[41]Nuttall RK, Pennington CJ, Taplin J, Wheal A, Yong VW, Forsyth PA, Edwards DR:Elevated membrane-type matrix metalloproteinases in gliomas revealed by profiling proteases and inhibitors in human cancer cells. [J].Mol Cancer Res,2003, Mar,1(5):333-45.
[42].Mizumoto H, Saito T. Ashihara K. et al.Expression of matrix metalloproteinases in ovarian endometriomas:immunohistochemical study and enzyme immunoassay[J].Life Sci,2002, 71(3):259-273
[1]章薇,费舟,章翔.基质金属蛋白酶在脑胶质细胞瘤研究中的应用前景[J].中华神经外科疾病研究杂志,2006,5(2)：183-187.
[2]Wai PY,Kuo PC.The role of osteopontin in tumor metastasis[J].J of Surg Res,2004,121(2):228-241.
[3]Deryugina EI, Quigley JP. Matrix metalloproteinases and tumor metastasis [J]. Cancer Metastasis Rev,2006.25 (1):9-34.
[4]Sato H, Takino T, Okaada Y, Cao J,et al. A matrix metalloproteinase expressed on the surface of invasive tumor cells[J]. Nature,2004,370:61-65
[5]Matrisian I.M. The matrix-degrading metalloproteinase[M].Bioessays1992,14:455-463
[6]Banda MJ, Howard EW, Herron GS,et al.Secreted inhibitors of metalloproteinase(IMPs) that are distinct from TIMP[J]. Matrix-Suppl,1992,1:294-8
[7].李慧梅.基质金属蛋白酶及其组织抑制因子与肿瘤侵袭转移关系研究进展.中国医学文摘.内科学,2005(26)：1
[8]Bode W, Fernandez-Catalan C, Tschesche H,et al. Insights into MMP-TIMP inter actions [J]. Cell Mol Life Sci,1999,55(44):639-652.
[9]Massova I, Kotra LP, Fridman R, et al. Matrix metalloproteinases structures ev olution, and diversification [J]. FASEB J,2008,12 (12):1075-1095.
[10]王守彪,基质金属蛋白酶与组织金属蛋白酶抑制因子在肾细胞癌中的研究进展[J].首都医药,2006：p.36-38.
[11]Sounni NE, Devy L, Hajitou A,et al.MT1-MMP experssion promotes tumor growth and angiogenesis through an up-regulation of vascular endothelial growth factor expression [J].2002,16(6):555-546
[12]Hajitou A, Sounni NE, Devy L, et al Down-regulation of vascular endothelial growth factor by tissue inhibitor of metalloproteinase-2:effect on in vivo mammary tumor growth and angiogenesis [J].Cancer Res,2001,61(6):3450-3457.
[13]Kitamura H,Oosawa Y,Kawano N,et al.Basement membrane patterns,gelatinase A and tissue inhibitor of metalloproteinase-2 expressions,and stromal fibrosis during the development of peripheral lung adenocarcinoma[J].Hum Pathol,2009,30(3):331-338.
[14]李保林,林丛尧,冯茂辉,等.大肠癌组织中基质金属蛋白酶-2／9、基质金属蛋白酶抑制剂-1的表达及对微血管生成和肿瘤转移的影响[J].临床外科杂志,2004,12(11)：6642666.
[15]梁君,刘铭球,谢梅,等.肺癌组织中MMP-9及TIMP-1的表达与转移、预后相关性研究[J].中国肺癌杂志,2003,6(1)：46-50.
[16]Murphy AN,Unsworth EJ, Stetler-Stevenson WG Tissue inhibitor of metalloproteinases-2 inhibits bFGF-induced human microvascular endothelial cell proliferation[J].Cell Physiol,1993,157(2):351-358.
[17]Brand K, Baker AH,Peerz-Canto A,et al. Treatment of colorectal liver metastases by adenoviral transfer of tissue inhibitor of metalloproteinases-2 into the liver tissue[G]. Cancer Res,2000,60(20):5723-5730
[18]Kinoshita T,Sato H,Okada A,et al.TIMP-2 promotes activation of progelatinase A by membrane-type 1 matrix metalloproteinase immobilized on agarose beads[J].J Biol Chem,1998,273(26):16098-16103.
[19]kurschat P,ZigrinoP,NischtR,et al.TIMP-2 regulates matrix metalloproteinase-2 activation by modulation of membrane-type 1 matrix metallproteinase activity in high and low invasive melanima cell lines.J Biol Chem,1999,274(30):21056-21062.
[20]Moses, M.A., J. Sudhalter&R.Linger.1990.1dentifiction of an inhibitor of neovascularization from.Science 248:1408-1410
[21]Mauviel A. Cytokine regulation of metalloproteinase gene expression. [J] Cell Biochem, 1993,53:288-295.
[22]Their M, Roeb E, Breuer B, et al.Expression of matrix metalloproteinas-2 in glial and neuronal tumor cell lines:inverse correlation with proliferation rate [J].Cancer Lett,2000,149(1-2):163-170
[23]Hur JH, Prak MJ, Prka IC, et al. Matrix metalloproteinase-2 in human glioamas:
activation of matrix metalloproteinase-2(MMP-2) may be correlated with membrane-typ-1 matrix metalloporteinase(MM1-MMP)expression[J].Kreona Med Sci,2000,15(3):309-314
[24]Nabeshima K.Stimulation of TIMP-1 and MMPs production in cocultures of human tumor cell and human fibroblast[J]. Cancer Lett,2004,78(1-3):133-140
[25]Sugiura Y, Shimada H, Seeger RC, et al.Matrix metalloproteinase-2 and-9 are expressed in human neuroblastoma contribution of stromal cell to their production and correlation with metastasis[DB]. Cancer Res,1998 May 15;58(10):09-16
[26]Reiehenberger F, Eiekelberg O, Wyser C, et al. Distinet endobronelial expression of matrix metalloproteinases(MMP) and their endogenous inhibitors in lung cancer [J].Swiss Med Wkly,2001 May 19:131(19-20):273-9
[27]Papathoma AS,Zoumpourlis V, Balmain A,et al. Role of matrix metalloproteinase-9 in progression of mouse skin carcinogenesis [J]. Mol Carcinog,2001 Jun:31(2):74-82
[28]Sawaya-RE,Mohanam S,Sawaya Petal.Expression and localization of 72kDa type IV collagnase(MMP-2)in human maligrant giomas in viov.[J]Ciln Exp Metastasis,1996 Jan,14(1):35-42.
[29]Mohanam S, Wang SW, et, al. Expression of tissue inhibitors of metalloproteinases:negative regulators of human glioblastoma invasion in vivo[M]. Clin Exp Metastasis, 2005,13(1):57-62
[30]Roderfeld M, Henunann S, Roeb E. Mechanisms of fibrinolysis in chronic liver injury (with special emphasis on MMPs and TIMPs).Z Gastroenterol,2006,45(1):25-33.
[31]Nakano A, Tani E, et, al. Matrix metalloproteinases and tissue inhibitors ofmetalloproteinases in human gliomas[J]. Neurosurg,1995,83(2):298-307
[32]Nakano A, Tani E, et, al. Increased expression of gelatinases A and B, matrilysin and TIMP-1 genes in human malignant gliomas[J]. Nippon Rinsho,2005,53 (7):1816-1821
[33]王建宁,门同义,李广云,等.基质金属蛋白酶2,9及金属蛋白酶组织抑制剂1在肾盂移行细胞癌中的表达及意义[J].中华泌尿外科杂志,2006,27(2)：114-117.
[34]杨明,侯巍,王丽萍,等.MMP-2、MMP-9在乳腺癌组织中的表达及临床意义[J]. Chin J Lab Diagn, October,2004,8(5):520-522.
[35]Lam P, Sian Lim K, Mei Wang S, Hui KM. A microarray study to characterize the molecular mechanism of TIMP-3-mediated tumor rejection[J].Mol Ther.2005,12(1):144-152.
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[31]Romanic AM, White RF, Arleth AJ, et al. Matrix metalloproteinase expression increases after cerebral focal ischemia in rats[J]. Strock,2008,29(5):1020-1030
[32]Nordqvist AC, Smurawa H, Mathiesen T. Expression of matrix metalloproteinases 2 and 9 in meningiomas associated with different degrees of brain invasiveness and edema [J].J Neurosurg,2001,95(5):839-844
[33]康春生,浦佩玉,李捷等,人脑胶质瘤AKT2表达与细胞增殖和侵袭性的关系[J].中华病理学杂志,2004,33(5)：464--465
[34]Rothhut B,Ghoneinm C,Antonicelli F,et al.Epidermal growth factor stimulates matrix metalloproteinase-9 expression and invasion in human follicular thvroid carcinoma cells through Focal adhesionkinase [J].Biochimie,2007,89(5):613-624.
[35]Greene J,Wang M,Liu YE,et al.Molecular cloning and characterization of human tissue inhibitor of metalloproteinase-4 [J].J Biol Chem,2006,271 (48:30375-30380)
[36]. M. Margarida Bernardo. Design, Synthesis, and Characterization of Potent Slow-binding Inhibitors that are selective for Gelatinases[J]. Jorney of biology chemistry,2002; 277(13): 11201-11207
[37].Robert Visse, Hideaki Nagase. Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases[DB]. Circulation Research,2003;92:827.
[38]Mohanam S, Wang SW, Rayford A, Yamamoto M, Sawaya R, Nakajima M, Liotta LA, Nicolson GL, Stetler-Stevenson WG, Rao JS:Expression of tissue inhibitors of metalloproteinases:negative regulators of human glioblastoma invasion in vivo. [J].Clin Exp Metastasis,2005 Jan,13(1):57-62.
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[40]Schwardt O, Kolb H, Ernst B.Drug discovery today [J]. Current Topics in Medicinal Chemistry 2003;3:1-9
[41]Nuttall RK, Pennington CJ, Taplin J, Wheal A, Yong VW, Forsyth PA, Edwards DR:Elevated membrane-type matrix metalloproteinases in gliomas revealed by profiling proteases and inhibitors in human cancer cells. [J].Mol Cancer Res,2003, Mar,1(5):333-45.
[42].Mizumoto H, Saito T. Ashihara K. et al.Expression of matrix metalloproteinases in ovarian endometriomas:immunohistochemical study and enzyme immunoassay[J].Life Sci,2002, 71(3):259-273
[1]章薇,费舟,章翔.基质金属蛋白酶在脑胶质细胞瘤研究中的应用前景[J].中华神经外科疾病研究杂志,2006,5(2)：183-187.
[2]Wai PY,Kuo PC.The role of osteopontin in tumor metastasis[J].J of Surg Res,2004,121(2):228-241.
[3]Deryugina EI, Quigley JP. Matrix metalloproteinases and tumor metastasis [J]. Cancer Metastasis Rev,2006.25 (1):9-34.
[4]Sato H, Takino T, Okaada Y, Cao J,et al. A matrix metalloproteinase expressed on the surface of invasive tumor cells[J]. Nature,2004,370:61-65
[5]Matrisian I.M. The matrix-degrading metalloproteinase[M].Bioessays1992,14:455-463
[6]Banda MJ, Howard EW, Herron GS,et al.Secreted inhibitors of metalloproteinase(IMPs) that are distinct from TIMP[J]. Matrix-Suppl,1992,1:294-8
[7].李慧梅.基质金属蛋白酶及其组织抑制因子与肿瘤侵袭转移关系研究进展.中国医学文摘.内科学,2005(26)：1
[8]Bode W, Fernandez-Catalan C, Tschesche H,et al. Insights into MMP-TIMP inter actions [J]. Cell Mol Life Sci,1999,55(44):639-652.
[9]Massova I, Kotra LP, Fridman R, et al. Matrix metalloproteinases structures ev olution, and diversification [J]. FASEB J,2008,12 (12):1075-1095.
[10]王守彪,基质金属蛋白酶与组织金属蛋白酶抑制因子在肾细胞癌中的研究进展[J].首都医药,2006：p.36-38.
[11]Sounni NE, Devy L, Hajitou A,et al.MT1-MMP experssion promotes tumor growth and angiogenesis through an up-regulation of vascular endothelial growth factor expression [J].2002,16(6):555-546
[12]Hajitou A, Sounni NE, Devy L, et al Down-regulation of vascular endothelial growth factor by tissue inhibitor of metalloproteinase-2:effect on in vivo mammary tumor growth and angiogenesis [J].Cancer Res,2001,61(6):3450-3457.
[13]Kitamura H,Oosawa Y,Kawano N,et al.Basement membrane patterns,gelatinase A and tissue inhibitor of metalloproteinase-2 expressions,and stromal fibrosis during the development of peripheral lung adenocarcinoma[J].Hum Pathol,2009,30(3):331-338.
[14]李保林,林丛尧,冯茂辉,等.大肠癌组织中基质金属蛋白酶-2／9、基质金属蛋白酶抑制剂-1的表达及对微血管生成和肿瘤转移的影响[J].临床外科杂志,2004,12(11)：6642666.
[15]梁君,刘铭球,谢梅,等.肺癌组织中MMP-9及TIMP-1的表达与转移、预后相关性研究[J].中国肺癌杂志,2003,6(1)：46-50.
[16]Murphy AN,Unsworth EJ, Stetler-Stevenson WG Tissue inhibitor of metalloproteinases-2 inhibits bFGF-induced human microvascular endothelial cell proliferation[J].Cell Physiol,1993,157(2):351-358.
[17]Brand K, Baker AH,Peerz-Canto A,et al. Treatment of colorectal liver metastases by adenoviral transfer of tissue inhibitor of metalloproteinases-2 into the liver tissue[G]. Cancer Res,2000,60(20):5723-5730
[18]Kinoshita T,Sato H,Okada A,et al.TIMP-2 promotes activation of progelatinase A by membrane-type 1 matrix metalloproteinase immobilized on agarose beads[J].J Biol Chem,1998,273(26):16098-16103.
[19]kurschat P,ZigrinoP,NischtR,et al.TIMP-2 regulates matrix metalloproteinase-2 activation by modulation of membrane-type 1 matrix metallproteinase activity in high and low invasive melanima cell lines.J Biol Chem,1999,274(30):21056-21062.
[20]Moses, M.A., J. Sudhalter&R.Linger.1990.1dentifiction of an inhibitor of neovascularization from.Science 248:1408-1410
[21]Mauviel A. Cytokine regulation of metalloproteinase gene expression. [J] Cell Biochem, 1993,53:288-295.
[22]Their M, Roeb E, Breuer B, et al.Expression of matrix metalloproteinas-2 in glial and neuronal tumor cell lines:inverse correlation with proliferation rate [J].Cancer Lett,2000,149(1-2):163-170
[23]Hur JH, Prak MJ, Prka IC, et al. Matrix metalloproteinase-2 in human glioamas:
activation of matrix metalloproteinase-2(MMP-2) may be correlated with membrane-typ-1 matrix metalloporteinase(MM1-MMP)expression[J].Kreona Med Sci,2000,15(3):309-314
[24]Nabeshima K.Stimulation of TIMP-1 and MMPs production in cocultures of human tumor cell and human fibroblast[J]. Cancer Lett,2004,78(1-3):133-140
[25]Sugiura Y, Shimada H, Seeger RC, et al.Matrix metalloproteinase-2 and-9 are expressed in human neuroblastoma contribution of stromal cell to their production and correlation with metastasis[DB]. Cancer Res,1998 May 15;58(10):09-16
[26]Reiehenberger F, Eiekelberg O, Wyser C, et al. Distinet endobronelial expression of matrix metalloproteinases(MMP) and their endogenous inhibitors in lung cancer [J].Swiss Med Wkly,2001 May 19:131(19-20):273-9
[27]Papathoma AS,Zoumpourlis V, Balmain A,et al. Role of matrix metalloproteinase-9 in progression of mouse skin carcinogenesis [J]. Mol Carcinog,2001 Jun:31(2):74-82
[28]Sawaya-RE,Mohanam S,Sawaya Petal.Expression and localization of 72kDa type IV collagnase(MMP-2)in human maligrant giomas in viov.[J]Ciln Exp Metastasis,1996 Jan,14(1):35-42.
[29]Mohanam S, Wang SW, et, al. Expression of tissue inhibitors of metalloproteinases:negative regulators of human glioblastoma invasion in vivo[M]. Clin Exp Metastasis, 2005,13(1):57-62
[30]Roderfeld M, Henunann S, Roeb E. Mechanisms of fibrinolysis in chronic liver injury (with special emphasis on MMPs and TIMPs).Z Gastroenterol,2006,45(1):25-33.
[31]Nakano A, Tani E, et, al. Matrix metalloproteinases and tissue inhibitors ofmetalloproteinases in human gliomas[J]. Neurosurg,1995,83(2):298-307
[32]Nakano A, Tani E, et, al. Increased expression of gelatinases A and B, matrilysin and TIMP-1 genes in human malignant gliomas[J]. Nippon Rinsho,2005,53 (7):1816-1821
[33]王建宁,门同义,李广云,等.基质金属蛋白酶2,9及金属蛋白酶组织抑制剂1在肾盂移行细胞癌中的表达及意义[J].中华泌尿外科杂志,2006,27(2)：114-117.
[34]杨明,侯巍,王丽萍,等.MMP-2、MMP-9在乳腺癌组织中的表达及临床意义[J]. Chin J Lab Diagn, October,2004,8(5):520-522.
[35]Lam P, Sian Lim K, Mei Wang S, Hui KM. A microarray study to characterize the molecular mechanism of TIMP-3-mediated tumor rejection[J].Mol Ther.2005,12(1):144-152.
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