Ki-67/MIB-1、MMP-2及其抑制物TIMP-2在膀胱移行细胞癌中的表达及其意义
|
摘要
目的：联合检测细胞核相关抗原（Ki-67/MIB-1）、基质金属蛋白酶2（MMP-2）及其抑制物（TIMP-2）在膀胱癌中的表达以及它们与肿瘤病理因素和复发、预后的关系。
方法：所取42例膀胱移行细胞癌手术后组织及5例正常膀胱组织均用10%福尔马林固定液固定标本，标本固定后，经乙醇梯度脱水，二甲苯透明，浸蜡包埋。做连续组织切片，厚度为4μm，备HE染色及免疫组织化学染色。免疫采用链霉菌过氧化物酶（SP法）染色。一抗分别为鼠抗人Ki-67（MIB-1）、鼠抗人MMP-2和鼠人抗TIMP-2单抗（均购自福建迈新公司）。组织切片脱腊并水化后，3% H2O2处理10min，过氧化酶阻断溶液、室温孵育10min。10%山羊血清室温孵育5min。加入一抗，4℃过液。生物素标记的二抗及SP复合物各10min。DAB显色，苏木素复染，透明封片。以PBS替代-抗作阴性对照，人乳腺癌组织作为阳性对照。镜下观察肿瘤细胞细胞核出现棕黄色（Ki-67/MIB-1）或细胞质出现棕黄色（MMP-2、TIMP-2）为阳性细胞，高倍镜下连续计数5个视野，染色细胞数>25%定为阳性，≤25%为阴性。所有数据输入计算机，用统计软件SPSS10.0处理。计量资料行X2检验，若遇小样本资料采用Fisher精确检验法，以P<0.05为差异有显著性意义。
结果：
1．正常膀胱组织中Ki-67/MIB-1、MMP-2及TIMP-2均无表达。
2．在50例膀胱移行细胞癌中Ki-67/MIB-1、MMP-2、TIMP-2的阳性率分别为50%（21/42）、52.38%（22/42）、59.52%（25/42）。Ki-67/MIB-1和MMP-2的表达率随着肿瘤病理分级，临床分期的升高而增加，而TIMP-2的表达率则呈下降趋势。临床分期、病理分级各组之间Ki-67/MIB-1、MMP-2、TIMP-2的阳性率差异有显著意义（P<0.05）。
3．随访41例病例中Ki-67/MIB-1阳性表达者，肿瘤复发率比无表达者显著升高，复发率分别为52.38%（11/21）和20%（4/20），差异具有显著意义，（P<0.05）。MMP-2阳性表达者肿瘤复发率为47.62%(10/21)，而阴性表达者复发率为25%（5/20），差别无统计学意义（P>0.05）。TIMP2阳性表达者和阴性表达者复发率分别为33.33%（8/24）和41.18%（7/17），差别无统计学意义（P>0.05）。
4．随访41例中死亡病例Ki-67/MIB-1的阳性表达率明显高于存活病例，阳性率分别为100%（7/7）和41.18%（14/34），两者比较差异有显著意义（P<0.05）。MMP-2在死亡者中的阳性表达率为100%（7/7），而存活者中的阳性表达率为44.12%（15/34），两者比较差异有显著性意义（P<0.05）。TIMP-2在死亡者中的阳性率为57.1%（4/7），而存活者中的阳性率为61.76%（21/34），两者比较差异无显著意义（P>0.05）。说明Ki-67（MIB-1）和MMP2的阳性表达与膀胱移行细胞癌的预后呈正相关。
结论
1．Ki-67（MIB-1）、MMP-2、TIMP-2的阳性表达率与膀胱
移行细胞癌的临床分期、病理分级密切相关。
2．Ki-67（MIB-1）的阳性表达率与膀胱移行细胞癌的复发密切相关。MMP-2及TIMP-2的阳性表达率与膀胱移行细胞癌的复发无关。
3．Ki-67（MIB-1）、MMP-2的阳性表达率与膀胱移行细胞癌的预后密切相关，可作为判断预后的指标。
本组资料发现部分膀胱移行细胞癌TIMP-2呈阴性表达和MMP-2、Ki-67（MIB-1）阳性表达，且TIMP-2分别与其它两个蛋白表达呈密切负相关。说明TIMP-2和MMP-2及Ki-67（MIB-1）在膀胱移行细胞癌发生、发展中起重要作用，可能共同影响膀胱移行细胞癌的发生，发展过程，其作用机理尚需进一步研究，同时收集更多的资料，定期随访，也是下一步应用本研究结果为膀胱移行细胞癌的预后进行评估等工作的重点。
Objective: To explore the expression of nuclear associated antigen (Ki-67/MIB-1) and matrix metalloproteinase (MMP-2) and its tissue inhibitor (TIMP-2) in transitional cell cancer of bladder (TCCB) and the relationship between pathologic factor of tumor, relapse and prognosis.
Methods: Applying S-P immunohistochemical technique to detect the expression of Ki-67/ MIB-1, MMP-2 and TIMP-2 at 50 urine bladders cancer specimens ,and analyse clinical data. The yellow particles inside cell plasma under microscope were positive cell, count five sight continuously, Number of positive cell>25% was positive and <25% was negative. statistic treatment: all data were input computer and were treated with SPSS10.0stastic software。Calculated data were with X2 test or FISHER test and there was significantly difference when P<0.05.
Results:
1. The expression of Ki-67/MIB-1, MMP-2 and TIMP-2s is negative in normal bladder tissue.
2. The positive expression rate of Ki-67/ MIB-1, MMP-2 and TIMP-2s is 52% (26/50), 48% (24/50) and 58% respectively. (29/50). The expression rate of Ki-67/ MIB-1, MMP-2 increased along with pathnological stage and grade while TIMP-2 expression rate tend to
decrease. There was significantly difference between pathnological stage and grade of the expression of Ki-67/MIB-1, MMP-2, TIMP-2 (P<0.05).
3. In 45 case, the tumor relapse rate of Ki-67/MIB-1 positive expression is higher than negative expression, the relapsing rate is 54.2% (13/24) and 23.7% (5/21) 34.7% (8/23) respectuvely. the relapsing rate of TIMP-2 positive expression is 37% (10/27), and the relapseing rate of TIMP-2 negative expression is 44.4% (8/18). there was no significant difference between MMP-2 positive expression and MMP-2 negative expression patients.
4. In 45 case, ththe positive expression rate of MMP-2 in those cases whos died and survived is 75% (6/8) and 43.2% (16/37) respectively. there was significantly difference between them (P<0.05). the positive expression rate of TIMP-2 in those cases who died and survived is 50% (4/8) and 62.2% (23/37) respectively. Ther were no significantly difference between them (P>0.05). that indicated that the positive expression of Ki-67 (MIB-1) and MMP-2 is correlation with the prognosis of transitional cell cancer of bladder (TCCB).
Conclusion
1. Expression rate of Ki-67 (MIB-1), MMP-2, TIMP-2 were closely correlated with pathological stage and tissue grade of TCCB.
2. the Ki-67 (MIB-1) expression rate were closely associated with recurrence of TCCB.
3. Ki-67 (MIB-1)and MMP-2 expression rates were closely associated with prognosis of TCCB.that indicated that Ki-67 (MIB-1) and MMP-2 expression rates will be a factor to judge the prognosis of TCCB.
These data demonstrated that parts of transitional cell cancer of bladders were negatively express of TIMP-2 and positively express of MMP-2and Ki-67 (MIB-1)。Moreover, the TIMP-2 were closely negative related with the expression of two. others protein. That indicated TIMP-2 MMP-2 and Ki-67 (MIB-1)s played an important role in occurrence and development of transitional cell cancer of bladder, and may affect the process of occurrence and development of transitional cell cancer of bladder together. Its function mechanism needs further research still, and more data will be collected at the same time. Periodically visit is also a focus of next study to evaluate the prognosis of TCCB applied with this result.
方法：所取42例膀胱移行细胞癌手术后组织及5例正常膀胱组织均用10%福尔马林固定液固定标本，标本固定后，经乙醇梯度脱水，二甲苯透明，浸蜡包埋。做连续组织切片，厚度为4μm，备HE染色及免疫组织化学染色。免疫采用链霉菌过氧化物酶（SP法）染色。一抗分别为鼠抗人Ki-67（MIB-1）、鼠抗人MMP-2和鼠人抗TIMP-2单抗（均购自福建迈新公司）。组织切片脱腊并水化后，3% H2O2处理10min，过氧化酶阻断溶液、室温孵育10min。10%山羊血清室温孵育5min。加入一抗，4℃过液。生物素标记的二抗及SP复合物各10min。DAB显色，苏木素复染，透明封片。以PBS替代-抗作阴性对照，人乳腺癌组织作为阳性对照。镜下观察肿瘤细胞细胞核出现棕黄色（Ki-67/MIB-1）或细胞质出现棕黄色（MMP-2、TIMP-2）为阳性细胞，高倍镜下连续计数5个视野，染色细胞数>25%定为阳性，≤25%为阴性。所有数据输入计算机，用统计软件SPSS10.0处理。计量资料行X2检验，若遇小样本资料采用Fisher精确检验法，以P<0.05为差异有显著性意义。
结果：
1．正常膀胱组织中Ki-67/MIB-1、MMP-2及TIMP-2均无表达。
2．在50例膀胱移行细胞癌中Ki-67/MIB-1、MMP-2、TIMP-2的阳性率分别为50%（21/42）、52.38%（22/42）、59.52%（25/42）。Ki-67/MIB-1和MMP-2的表达率随着肿瘤病理分级，临床分期的升高而增加，而TIMP-2的表达率则呈下降趋势。临床分期、病理分级各组之间Ki-67/MIB-1、MMP-2、TIMP-2的阳性率差异有显著意义（P<0.05）。
3．随访41例病例中Ki-67/MIB-1阳性表达者，肿瘤复发率比无表达者显著升高，复发率分别为52.38%（11/21）和20%（4/20），差异具有显著意义，（P<0.05）。MMP-2阳性表达者肿瘤复发率为47.62%(10/21)，而阴性表达者复发率为25%（5/20），差别无统计学意义（P>0.05）。TIMP2阳性表达者和阴性表达者复发率分别为33.33%（8/24）和41.18%（7/17），差别无统计学意义（P>0.05）。
4．随访41例中死亡病例Ki-67/MIB-1的阳性表达率明显高于存活病例，阳性率分别为100%（7/7）和41.18%（14/34），两者比较差异有显著意义（P<0.05）。MMP-2在死亡者中的阳性表达率为100%（7/7），而存活者中的阳性表达率为44.12%（15/34），两者比较差异有显著性意义（P<0.05）。TIMP-2在死亡者中的阳性率为57.1%（4/7），而存活者中的阳性率为61.76%（21/34），两者比较差异无显著意义（P>0.05）。说明Ki-67（MIB-1）和MMP2的阳性表达与膀胱移行细胞癌的预后呈正相关。
结论
1．Ki-67（MIB-1）、MMP-2、TIMP-2的阳性表达率与膀胱
移行细胞癌的临床分期、病理分级密切相关。
2．Ki-67（MIB-1）的阳性表达率与膀胱移行细胞癌的复发密切相关。MMP-2及TIMP-2的阳性表达率与膀胱移行细胞癌的复发无关。
3．Ki-67（MIB-1）、MMP-2的阳性表达率与膀胱移行细胞癌的预后密切相关，可作为判断预后的指标。
本组资料发现部分膀胱移行细胞癌TIMP-2呈阴性表达和MMP-2、Ki-67（MIB-1）阳性表达，且TIMP-2分别与其它两个蛋白表达呈密切负相关。说明TIMP-2和MMP-2及Ki-67（MIB-1）在膀胱移行细胞癌发生、发展中起重要作用，可能共同影响膀胱移行细胞癌的发生，发展过程，其作用机理尚需进一步研究，同时收集更多的资料，定期随访，也是下一步应用本研究结果为膀胱移行细胞癌的预后进行评估等工作的重点。
Objective: To explore the expression of nuclear associated antigen (Ki-67/MIB-1) and matrix metalloproteinase (MMP-2) and its tissue inhibitor (TIMP-2) in transitional cell cancer of bladder (TCCB) and the relationship between pathologic factor of tumor, relapse and prognosis.
Methods: Applying S-P immunohistochemical technique to detect the expression of Ki-67/ MIB-1, MMP-2 and TIMP-2 at 50 urine bladders cancer specimens ,and analyse clinical data. The yellow particles inside cell plasma under microscope were positive cell, count five sight continuously, Number of positive cell>25% was positive and <25% was negative. statistic treatment: all data were input computer and were treated with SPSS10.0stastic software。Calculated data were with X2 test or FISHER test and there was significantly difference when P<0.05.
Results:
1. The expression of Ki-67/MIB-1, MMP-2 and TIMP-2s is negative in normal bladder tissue.
2. The positive expression rate of Ki-67/ MIB-1, MMP-2 and TIMP-2s is 52% (26/50), 48% (24/50) and 58% respectively. (29/50). The expression rate of Ki-67/ MIB-1, MMP-2 increased along with pathnological stage and grade while TIMP-2 expression rate tend to
decrease. There was significantly difference between pathnological stage and grade of the expression of Ki-67/MIB-1, MMP-2, TIMP-2 (P<0.05).
3. In 45 case, the tumor relapse rate of Ki-67/MIB-1 positive expression is higher than negative expression, the relapsing rate is 54.2% (13/24) and 23.7% (5/21) 34.7% (8/23) respectuvely. the relapsing rate of TIMP-2 positive expression is 37% (10/27), and the relapseing rate of TIMP-2 negative expression is 44.4% (8/18). there was no significant difference between MMP-2 positive expression and MMP-2 negative expression patients.
4. In 45 case, ththe positive expression rate of MMP-2 in those cases whos died and survived is 75% (6/8) and 43.2% (16/37) respectively. there was significantly difference between them (P<0.05). the positive expression rate of TIMP-2 in those cases who died and survived is 50% (4/8) and 62.2% (23/37) respectively. Ther were no significantly difference between them (P>0.05). that indicated that the positive expression of Ki-67 (MIB-1) and MMP-2 is correlation with the prognosis of transitional cell cancer of bladder (TCCB).
Conclusion
1. Expression rate of Ki-67 (MIB-1), MMP-2, TIMP-2 were closely correlated with pathological stage and tissue grade of TCCB.
2. the Ki-67 (MIB-1) expression rate were closely associated with recurrence of TCCB.
3. Ki-67 (MIB-1)and MMP-2 expression rates were closely associated with prognosis of TCCB.that indicated that Ki-67 (MIB-1) and MMP-2 expression rates will be a factor to judge the prognosis of TCCB.
These data demonstrated that parts of transitional cell cancer of bladders were negatively express of TIMP-2 and positively express of MMP-2and Ki-67 (MIB-1)。Moreover, the TIMP-2 were closely negative related with the expression of two. others protein. That indicated TIMP-2 MMP-2 and Ki-67 (MIB-1)s played an important role in occurrence and development of transitional cell cancer of bladder, and may affect the process of occurrence and development of transitional cell cancer of bladder together. Its function mechanism needs further research still, and more data will be collected at the same time. Periodically visit is also a focus of next study to evaluate the prognosis of TCCB applied with this result.
引文
郭应禄主编. 泌尿男生殖系肿瘤. 北京人民出版社, 2000; 25~43.
kruger S, Muller H, Br J urol, 1995, Apr; 75(4): 480~4.
wright C, Thomas D, Mellon K, et al. Br J urol, 1995 Teb: 75[2]: 173~179.
Gonlero P, Casetta G, zitellaA,etal eur urol 2000jep;(38):287-296
5. Bei B, Bucana CD, Fidler IJ, Density-dependent induction of 92-kd type IV collagenase acitivity in chultures of A 431 human epidermoid carcinoma cells. Am J pathogy, 1994, 114: 1058~ 1067
6. Oniso M, Riccio MP, scannapiecop, atal Gelatinase A/TIMP-Z im balance in tymph-node positive breast carcmomas by RT-PCR. Int J cancer, 1995, 3:621~626.
Gerdes J, schwab o , lemke H, et al. Int J cancer, 1983; 31:13~15
Fontana D, Bellina M, Gubetta L, et al, J urol, 1992, 148: 1149~1151
Tsuji M, lcojima K, Murakam; Y, et al, Br J urol, 1997, 79:367~372
10. Rey A, Lara pc, Redondo E, efal urol. 1998;51:204~210
11. Tsuji M, kojima k, murami Y et al, BrJurol 1997:367~372
WUTT chen JH, lee YH, et al J urol; 2000 Man 163:758~760
Mitsiades N, poulaki V, koloula V, etal Fas: and is present in tum ors of the Ewing s, sarcom a family and is cleaved into asoluble form by a metal proteinase [J]. Am J pathol, 1998, 153(6):1947~1956
Mitsiades N, poulaki V, Koloukla V, etal Fasligandis, present in tum ors of the Wwing s larcom a family and is cleaved in to asoluble form by a metal oproteinase [J]. Am J pathol, 1998, 153(6):1947~1956
宋波, 金锡御, 潘进洪, 等. MMP-2及MMP-9在膀胱癌中的表达及在侵袭转移中的作用, 中华泌尿外科杂志, 1997, 20:400~402
LEVY AT， Cioce V, Sobel, ME, et al. Increased ex pressio adenocarcinoma cancer Res 1991;51:439~444
Vaisanen A, Kallioinen M, Jaskinen Jaskinen PJ, et al. prognostic Calue of MMP-2 irn munoreactive protein RKD Type collagenase in primary skin melanoma Jpathol 1998, 186:51~58
Davies B, waxonan J, wasan H, et al. levele of matrix metal oproteinases in bldder cancer correlate with tumor grade and invasion. Cancer Res, 1993, 5363~5369
Moses MA, wieders chain D, LoughlmKR, et al. Increased inci dence of matyix metal oproteinases in urine of cancer patients cannier Res, 1998, 58:1395~1399
strongin AY, collier I, BannkvoCT, et al. Mechanisin of cell
surface activation of 72kd, type IV collagenase. J Biol chem. 1995 270:5331~5338
张坚, 唐孝达. 膀胱癌中MMP-2, TIMP-2的表达及其与膀胱肿瘤复发的关系. 临床泌尿外科杂志, 2002;17(9):484~489
loakin liossi A, pantazo poulos D, karakitsosp, et al. Analouant cyolHistol, 2000, Jun;22(3):223~228
Azavorian S, Murphy AN, steter-stevenson WG, et al. mole cular as pects of tumor cell in vasion and metastasis., cancer, 1993,17(4):1368~1383
Zhao SZ, cohen AM, Guillem JG, loss of base ment me mbrane type IV collagen is associated withincreased expression of matrix mtallo proteinase Z and 9 during human colorectal tumor, genesis carcino genesis, 1999, 20:749~755
parsons SL, Watson SA,Brown PD, et al. martrix metallopro- feinases Br J Surg, 1997, 84:160~166
Grignon DJ, sakr w, toth M, et al. High levels of tissue inh; bitor of matrix metalloproteinases Z expression are assiociated with poor outcome in invasive bladder cancer. Cancer Res, 1996, 56:1654~1659
Davies B, Waxman J, wasan H, et al. levels of mafrix metallopro-teinases in bladder cancer correlate with tumor grade an invasion. Cancer Res, 1993, 53:5365~5369
Kanayama H, Yokotal K, kurokawa Y, et al. prognost; valuer of
matrix metal oproteimase I and tissue inhibitor of matrix metal oproteinase I expression bladder lancer. Cancer, 1998, 82: 1359~1366
Moses MA,wiederschain D,loughlm KR, et al. Increased inci dence of matrix metal oproteinasesin urine of cancer patients cancer Res, 1998,58:1395~1399
Lokeshwar BL, Selzer MG, block NL, et al secretion of materx metal oproteinases and their inhibitors by human prostatein explant cultures: reduced tissue inhibitor of metal oproteinases secretion by malignant tissues. Canser Ret, 1993,53:4493~4498
Kikuchi R, Nogu chi T, Takeno S, et al. Im munohisto che mical defe ction of me mbrane-type-1-matrix metal oproteinase in colorectal carcinoma br j cancer, 2000, 83:215~218
I mai K, ohuchi E, Aoki T, et al. membrane type-matrix me tall oproteinase 1 is a ge latinolytic enxy me and is secreted in a complex with tissue inhbitor of metalloproteinase2. cancer Res, 1996,56:2707~2710
kruger S, Muller H, Br J urol, 1995, Apr; 75(4): 480~4.
wright C, Thomas D, Mellon K, et al. Br J urol, 1995 Teb: 75[2]: 173~179.
Gonlero P, Casetta G, zitellaA,etal eur urol 2000jep;(38):287-296
5. Bei B, Bucana CD, Fidler IJ, Density-dependent induction of 92-kd type IV collagenase acitivity in chultures of A 431 human epidermoid carcinoma cells. Am J pathogy, 1994, 114: 1058~ 1067
6. Oniso M, Riccio MP, scannapiecop, atal Gelatinase A/TIMP-Z im balance in tymph-node positive breast carcmomas by RT-PCR. Int J cancer, 1995, 3:621~626.
Gerdes J, schwab o , lemke H, et al. Int J cancer, 1983; 31:13~15
Fontana D, Bellina M, Gubetta L, et al, J urol, 1992, 148: 1149~1151
Tsuji M, lcojima K, Murakam; Y, et al, Br J urol, 1997, 79:367~372
10. Rey A, Lara pc, Redondo E, efal urol. 1998;51:204~210
11. Tsuji M, kojima k, murami Y et al, BrJurol 1997:367~372
WUTT chen JH, lee YH, et al J urol; 2000 Man 163:758~760
Mitsiades N, poulaki V, koloula V, etal Fas: and is present in tum ors of the Ewing s, sarcom a family and is cleaved into asoluble form by a metal proteinase [J]. Am J pathol, 1998, 153(6):1947~1956
Mitsiades N, poulaki V, Koloukla V, etal Fasligandis, present in tum ors of the Wwing s larcom a family and is cleaved in to asoluble form by a metal oproteinase [J]. Am J pathol, 1998, 153(6):1947~1956
宋波, 金锡御, 潘进洪, 等. MMP-2及MMP-9在膀胱癌中的表达及在侵袭转移中的作用, 中华泌尿外科杂志, 1997, 20:400~402
LEVY AT， Cioce V, Sobel, ME, et al. Increased ex pressio adenocarcinoma cancer Res 1991;51:439~444
Vaisanen A, Kallioinen M, Jaskinen Jaskinen PJ, et al. prognostic Calue of MMP-2 irn munoreactive protein RKD Type collagenase in primary skin melanoma Jpathol 1998, 186:51~58
Davies B, waxonan J, wasan H, et al. levele of matrix metal oproteinases in bldder cancer correlate with tumor grade and invasion. Cancer Res, 1993, 5363~5369
Moses MA, wieders chain D, LoughlmKR, et al. Increased inci dence of matyix metal oproteinases in urine of cancer patients cannier Res, 1998, 58:1395~1399
strongin AY, collier I, BannkvoCT, et al. Mechanisin of cell
surface activation of 72kd, type IV collagenase. J Biol chem. 1995 270:5331~5338
张坚, 唐孝达. 膀胱癌中MMP-2, TIMP-2的表达及其与膀胱肿瘤复发的关系. 临床泌尿外科杂志, 2002;17(9):484~489
loakin liossi A, pantazo poulos D, karakitsosp, et al. Analouant cyolHistol, 2000, Jun;22(3):223~228
Azavorian S, Murphy AN, steter-stevenson WG, et al. mole cular as pects of tumor cell in vasion and metastasis., cancer, 1993,17(4):1368~1383
Zhao SZ, cohen AM, Guillem JG, loss of base ment me mbrane type IV collagen is associated withincreased expression of matrix mtallo proteinase Z and 9 during human colorectal tumor, genesis carcino genesis, 1999, 20:749~755
parsons SL, Watson SA,Brown PD, et al. martrix metallopro- feinases Br J Surg, 1997, 84:160~166
Grignon DJ, sakr w, toth M, et al. High levels of tissue inh; bitor of matrix metalloproteinases Z expression are assiociated with poor outcome in invasive bladder cancer. Cancer Res, 1996, 56:1654~1659
Davies B, Waxman J, wasan H, et al. levels of mafrix metallopro-teinases in bladder cancer correlate with tumor grade an invasion. Cancer Res, 1993, 53:5365~5369
Kanayama H, Yokotal K, kurokawa Y, et al. prognost; valuer of
matrix metal oproteimase I and tissue inhibitor of matrix metal oproteinase I expression bladder lancer. Cancer, 1998, 82: 1359~1366
Moses MA,wiederschain D,loughlm KR, et al. Increased inci dence of matrix metal oproteinasesin urine of cancer patients cancer Res, 1998,58:1395~1399
Lokeshwar BL, Selzer MG, block NL, et al secretion of materx metal oproteinases and their inhibitors by human prostatein explant cultures: reduced tissue inhibitor of metal oproteinases secretion by malignant tissues. Canser Ret, 1993,53:4493~4498
Kikuchi R, Nogu chi T, Takeno S, et al. Im munohisto che mical defe ction of me mbrane-type-1-matrix metal oproteinase in colorectal carcinoma br j cancer, 2000, 83:215~218
I mai K, ohuchi E, Aoki T, et al. membrane type-matrix me tall oproteinase 1 is a ge latinolytic enxy me and is secreted in a complex with tissue inhbitor of metalloproteinase2. cancer Res, 1996,56:2707~2710