MMP-2和MMP-9在胃癌患者组织和血清中的表达及临床意义
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摘要
为了研究基质金属蛋白酶2(MMP-2)和基质金属蛋白酶9(MMP-9)的血清含量及组织表达的相关性,探讨MMP-2和MMP-9与胃癌侵袭、转移的关系,收集2007年4月～2007年11月吉林大学第二医院普外科住院手术治疗的38例胃癌患者的癌组织和术前血清标本,运用免疫组织化学PV-9000通用型二步法和ELSIA法对胃癌患者组织及血清中MMP-2和MMP-9的含量表达进行检测,结果发现:MMP-2和MMP-9在胃癌组织中的阳性表达率分别为94.7%和86.8%,与淋巴结转移、肿瘤分期显著相关(P<0.05);胃癌患者血清中MMP-2水平与正常对照组比较无显著差异(P>0.05);胃癌患者血清中MMP-9的含量明显高于正常对照组,差异有显著性(P<0.05),且其含量与淋巴结转移、肿瘤分期显著相关(P<0.05)。可得出以下结论:MMP-2和MMP-9在胃癌组织中高表达,且与淋巴结转移、肿瘤分期显著相关;胃癌患者血清中MMP-2的含量与组织中MMP-2的表达没有相关性,血清中MMP-9的含量与组织中MMP-9的表达具有相关性,且与淋巴结转移、肿瘤分期显著相关;检测胃癌患者术前血清中MMP-9的含量有助于预测肿瘤的TNM分期、淋巴结是否发生转移,从而为制定合理的手术方案提供有效的信息。
Gastric carcinoma is one of the most familiar malignant tumors. There is close affinity between its prognosis and the invasion and metastasis of cancer cells.Invasion and metastasis is character of malignant tumor,also is the main cause that leads patients to failure treatment and death.The invasion and metastasis is an extremely complex process controlled by polygene that needs many steps to develop, referring to reciprocity of broad tumor cells–host, cell- matrix.In the process of invasion and metastasis of cancer cells the significance of MMPs is accelerating cancer cells break through the histochemistry barriers through destroying the balance of degradation,then invade tissues around and transfer to tissues beyond.Both MMP-2 and MMP-9 are geltinases which are the most important ones of MMPs. With the effect of fusible medium or adhesion molecules tumor cells can change information with mesenchyma and cooperate with producing and regulating MMP-2 and MMP-9,which has the fatal significance in the mechanism study of tumor cells’invasion and metastasis.
Object: To study the relativity of levels of MMP-2 and MMP-9 in serum and cancer tissues got from gastric carcinoma patients, dicuss relationship between them and clinical pathology parameters.
Methods: 38 gastric carcinoma paraffin embed specimens resected by operation were collected from the second hospital of Jilin University from May to November in 2007.The expression of MMP-2 and MMP-9 in 38 resected specimens was analyed by PV-9000 polymer detection system for immunohistological staining. Immunohistochemistry pigmentation use the proportion of positive cells in all the cancer cells in every slice to estimate,choose randomly 5 fields to account under high power field,absolutely negative or positive rate<5% is (-),5%～25% is (+),26%～75% is (++),>75% is (+++). Enzyme-linked immunosorbent assay was used to detect the preoperative serum level of MMP-2 and MMP-9 in 38 patients with gastric cancer,compared with 20 healthy persons. Used the anthos 2010 to scan immediately after the reaction, elicited the concentration of every pore according to the OD value and calibration concentration. Used the statistic software CS-2000 to make statistics analysis.The result of immunohistochemistry use theχ2 proof-test;the result of ELISA expressed by mean( x)±SD(s) use the t proof-test.And P<0.05 has the statistics significance.
Results: The positive expression of MMP-2 and MMP-9 in gastric carcinoma tissue specimens respectively was 94.7%(36/38)and 86.8%(33/38),there was significant relationship between the expression of MMP-2 and MMP-9 and the lymph node metastasis,TNM stage(P<0.05,respectively);the level of MMP-2 in serum of gastric carcinoma patients and control group respectively was 48.80±22.17ng/ml and 53.02±24.04 ng/ml,there was no significant difference between the gastric patients and the control group(P>0.05); the level of MMP-9 in serum of gastric carcinoma patients and control group respectively was 210.97±94.29 ng/ml and 60.36±25.74 ng/ml,there was significant difference between the gastric patients and the control group (P<0.05),also there was significant relationship between the expression of MMP-9 in serum and the lymph node metastasis,TNM stage(P<0.05,respectively).
Discussion: The high expression of MMP-2 and MMP-9 in tissue and the high level of MMP-9 in serum in patients with gastric carcinoma was already approved by many academicians. Basically this became a verdict. And now the controversy is whether there is significant relationship of MMP-2 in serum between the gastric carcinoma patients and the control group. Through this investigation we elicited that the concentration of MMP-2 in serum in gastric carcinoma patients had no significant difference with the control group , the explanation as follows: 1.MMP-2 can be activated by fibroblast,so there is high expression in tissue;MMP-9 can be activated by fibrinoclase,so the level in serum is relatively high.2.Because MMP-2 mainly root in many connective tissue cells , MMP-9 mainly root in neutrophile granulocyte and macrophage.Under the normal condition,there is a small quantity of expression respectively of MMP-2 and MMP-9.And the results of immunohistochemistry told us that there was difference between MMP-2 and MMP-9 in the same gastric carcinoma tissues,more strong positive of MMP-2 and more positive of MMP-9.3.The methods of detecting is different,the different results due to the different reagent and laboratory environment.Especially the reagent, different binding site of antigen and antibody will lead to different results. 4.The content of MMP-2 in serum of gastric carcinoma patients which is detected by the way of ELSIA is gross.This way couldn’t detect simultaneously the active form and the zmogen form of MMP-2.So we couldn’t exclude the active form of MMP-2 has no significant difference with the control group,and the relativity with lymph node metastasis ,TNM stage. In all,this investigation of MMP-2 and MMP-9 offered credible theory gist for clinical effective and reasonable integrative Rx .At the same time,this hinted that people can control the invasion and metastasis of tumor through the interdiction of MMP-2 and MMP-9 to control and treat tumor.This also redound us to understand the molecular mechanism of metastasis of tumor one more step,but the particular mechanism still needs us investigate more thoroughly.
Conclusion: There is high expression of MMP-2 and MMP-9 in gastric carcinoma tissues, and there was significant correlation with metastasis of lymph node and TNM stage. There was relativity of the expression of MMP-9 between the serum and the tissue.In the patients with gastric carcinoma,detecting the level of MMP-9 in serum before operation can prognosticate lymph node metastasis and TNM stage ,and provide useful information for establishing reasonable operation project. This is a good simple way without traumatic occlusion.
Gastric carcinoma is one of the most familiar malignant tumors. There is close affinity between its prognosis and the invasion and metastasis of cancer cells.Invasion and metastasis is character of malignant tumor,also is the main cause that leads patients to failure treatment and death.The invasion and metastasis is an extremely complex process controlled by polygene that needs many steps to develop, referring to reciprocity of broad tumor cells–host, cell- matrix.In the process of invasion and metastasis of cancer cells the significance of MMPs is accelerating cancer cells break through the histochemistry barriers through destroying the balance of degradation,then invade tissues around and transfer to tissues beyond.Both MMP-2 and MMP-9 are geltinases which are the most important ones of MMPs. With the effect of fusible medium or adhesion molecules tumor cells can change information with mesenchyma and cooperate with producing and regulating MMP-2 and MMP-9,which has the fatal significance in the mechanism study of tumor cells’invasion and metastasis.
Object: To study the relativity of levels of MMP-2 and MMP-9 in serum and cancer tissues got from gastric carcinoma patients, dicuss relationship between them and clinical pathology parameters.
Methods: 38 gastric carcinoma paraffin embed specimens resected by operation were collected from the second hospital of Jilin University from May to November in 2007.The expression of MMP-2 and MMP-9 in 38 resected specimens was analyed by PV-9000 polymer detection system for immunohistological staining. Immunohistochemistry pigmentation use the proportion of positive cells in all the cancer cells in every slice to estimate,choose randomly 5 fields to account under high power field,absolutely negative or positive rate<5% is (-),5%～25% is (+),26%～75% is (++),>75% is (+++). Enzyme-linked immunosorbent assay was used to detect the preoperative serum level of MMP-2 and MMP-9 in 38 patients with gastric cancer,compared with 20 healthy persons. Used the anthos 2010 to scan immediately after the reaction, elicited the concentration of every pore according to the OD value and calibration concentration. Used the statistic software CS-2000 to make statistics analysis.The result of immunohistochemistry use theχ2 proof-test;the result of ELISA expressed by mean( x)±SD(s) use the t proof-test.And P<0.05 has the statistics significance.
Results: The positive expression of MMP-2 and MMP-9 in gastric carcinoma tissue specimens respectively was 94.7%(36/38)and 86.8%(33/38),there was significant relationship between the expression of MMP-2 and MMP-9 and the lymph node metastasis,TNM stage(P<0.05,respectively);the level of MMP-2 in serum of gastric carcinoma patients and control group respectively was 48.80±22.17ng/ml and 53.02±24.04 ng/ml,there was no significant difference between the gastric patients and the control group(P>0.05); the level of MMP-9 in serum of gastric carcinoma patients and control group respectively was 210.97±94.29 ng/ml and 60.36±25.74 ng/ml,there was significant difference between the gastric patients and the control group (P<0.05),also there was significant relationship between the expression of MMP-9 in serum and the lymph node metastasis,TNM stage(P<0.05,respectively).
Discussion: The high expression of MMP-2 and MMP-9 in tissue and the high level of MMP-9 in serum in patients with gastric carcinoma was already approved by many academicians. Basically this became a verdict. And now the controversy is whether there is significant relationship of MMP-2 in serum between the gastric carcinoma patients and the control group. Through this investigation we elicited that the concentration of MMP-2 in serum in gastric carcinoma patients had no significant difference with the control group , the explanation as follows: 1.MMP-2 can be activated by fibroblast,so there is high expression in tissue;MMP-9 can be activated by fibrinoclase,so the level in serum is relatively high.2.Because MMP-2 mainly root in many connective tissue cells , MMP-9 mainly root in neutrophile granulocyte and macrophage.Under the normal condition,there is a small quantity of expression respectively of MMP-2 and MMP-9.And the results of immunohistochemistry told us that there was difference between MMP-2 and MMP-9 in the same gastric carcinoma tissues,more strong positive of MMP-2 and more positive of MMP-9.3.The methods of detecting is different,the different results due to the different reagent and laboratory environment.Especially the reagent, different binding site of antigen and antibody will lead to different results. 4.The content of MMP-2 in serum of gastric carcinoma patients which is detected by the way of ELSIA is gross.This way couldn’t detect simultaneously the active form and the zmogen form of MMP-2.So we couldn’t exclude the active form of MMP-2 has no significant difference with the control group,and the relativity with lymph node metastasis ,TNM stage. In all,this investigation of MMP-2 and MMP-9 offered credible theory gist for clinical effective and reasonable integrative Rx .At the same time,this hinted that people can control the invasion and metastasis of tumor through the interdiction of MMP-2 and MMP-9 to control and treat tumor.This also redound us to understand the molecular mechanism of metastasis of tumor one more step,but the particular mechanism still needs us investigate more thoroughly.
Conclusion: There is high expression of MMP-2 and MMP-9 in gastric carcinoma tissues, and there was significant correlation with metastasis of lymph node and TNM stage. There was relativity of the expression of MMP-9 between the serum and the tissue.In the patients with gastric carcinoma,detecting the level of MMP-9 in serum before operation can prognosticate lymph node metastasis and TNM stage ,and provide useful information for establishing reasonable operation project. This is a good simple way without traumatic occlusion.
引文
1. Liotta LA,Steeg P,Stetler-Stevenson WG,et al. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell,1991,64:327～336.
2. Hrabec E,Strek M,Nowak D,et al. Elevated level of circulating matrix metalloproteinase-9 in patients with lung cancer. Respir Med,2001,95(1):14.
3. 孙书明,周妍,胡志雄等.肺癌病人血清 MMP-2 和 MMP-9的检测[J].中国临床医学,2003,10(5):637～638.
4. 苏亚娟,高玲娟,王淑敏.测定卵巢恶性肿瘤患者血清基质金属蛋白酶-2 的临床价值[J].黑龙江医药科学,2004, 27(2): 3.
5. 王香平,陈升平,周莲娥.血清明胶酶(MMP-2、MMP-9)与子宫内膜癌[J].首都医科大学学报,2005,26(3):356～357.
6. 钟美佐,黄进,翟晓等.非霍奇金淋巴瘤患者血清中 MMP-9和 MMP-2 蛋白的检测及临床意义[J].中华检验医学杂志,2006,29(3):242～243.
7. 张成武,邹寿椿,徐文鹃等。胃癌 MMP-9 表达的临床意义[J]。中国胃肠外科杂志,2000,3(1):25～27.
8. 孙亚欣,张志超,孙立群等.基质金属蛋白酶含量及表达与膀胱癌侵袭转移的关系[J].吉林大学学报:医学版,2005,31(1):127～129.
9. 赵立阁,安瓦尼尔,祝诚.细胞外基质与基质蛋白酶[J].生物化学与生物物理进展,1999,26(3):224～227.
10. Zucker S,Mirza H,Conner CE,et al.Vascular endothelial growth factor induces tissue factor and matrix metalloproteinase production in endothelial cells: conversion of prothrombin to thrombin results in progelatinase A activation and cell proliferation [J]. Int J,Cancer,1998,75(5):780～786.
11. Poulson R,Pignatelli M,William G,et al.Stromal expression of 72 kda type Ⅳ collagenase and TIMP-2 mRNA in colorectal neoplasia.Am J athol,1992,141:386～396.
12. Grigion WF,D’Errico A,Fiorentino M,et al.Gelatinase A(MMP-2) and its mRNA detected in both neoplastic and stromal cells of tumors with different invasive and metastatic properties.Diagn Mol Pathol,1994,3:163～169.
13. 陈合群,张雪培,申鹏飞等.MMP-2 和 MMP-9 在膀胱癌组织中表达的免疫组化研究[J] .中国现代医学杂志,2003,13 (12):78～80.
14. Liottal Tryg Gvasoank,Garbisa S.Metastatic potential correlates with enzymatic degradation of basement membrane collagen[J].Nature,1980,284:67～68.
15. Sier CF,Kubben FJ,Ganesh S,et al.Tissue levels of matrix metalloproteinase MMP-2 and MMP-9 are related to the overall survival of patients with gastric carcinoma [J].Br J Cancer,1996,74(3):413～417.
16. Parsons SL,Watson SA,Collins HM,et al.Gelatinase (MMP-2 and MMP-9) expression in gastrointestinal malignany [J].Br J Cancer,1998,78(11):1495～1502.
17. Shou Y,Hirano T,Gong Y,et al.Influence f angiogenetic fators and matrix metalloproteinase upon tumor progression in non-small-cell lung cancer [J].Br J Cance,2001,85(11): 1706～1712.
18. Hee J,Soo KB,Ho Y,et al.Anti-invasive activity of ursoliecid correlates with the reduced expression of matrix metalloproteinase-9 (MMP-9) in HT-1080 human fibrosarcoma cells[J].Cancer Res,1996,56(10): 2281～2285.
19. 毛梅,曾群丽,余爱荣.基质金属蛋白酶-2 在肺癌患者血清中的表达及临床意义[J].新乡医学院学报.2006,23(2):151-153.
20. 孙书明,周妍,胡志雄等.肺癌病人血清 MMP-2 和 MMP-9的检测[J].中国临床医学,2003,10(5):637-638.
21. 金钫,段银钟.基质金属蛋白酶与骨改建[J].牙体牙髓牙周病学杂志. 2000,10(4):232-235.
22. RayJ M,Stetler-StevensonWG.The role of matrix metallo- proteases and the irinhibitors in tumour invasion, metastasis and angiogenesis [J].EurRespirJ,1994,7(11):2062 -2072.
23. Koger M, Tschesche H. Cloning expression and action of atruncated 92Kda gelatinase minienzyme[J].Gene,1997,196: 175 -180.
24. Shen KH , Chi CW, Loss , et al.Serum matrix metallo- proteinase-9 level associated with stromal reaction in patients with gastric cancer[J].Anticancer Res, 2000, 20(2B):1307～1310.
25. 李邦涛,汤旭东,文志斌等.中国生理学会论文汇编[A]. 中国生理学会论文汇编 2006 年第二期 [C], 2006.
26. Kabashima A,Maehara Y,Kakeji,etal. linicopathological features and overexpression of matrix metallo- proteinases in intramucosal gastric carcinoma with lymph node metastasis [J].Clin Cancer Res,2000,6(9):3581～3584.
1. Chambers AF,Matrisian LM. Chaning view of the role ofmatrix metalloprotinases in metastasis [J]. J Natl CancerInst,1997, 89(7):1260-1270.
2. Bar-OrA,Nuttall R K,Duddy M,etal. Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis [J]. Brain,2003,126:2738-2749.
3. 金钫,段银钟.基质金属蛋白酶与骨改建[J].牙体牙髓牙周病学杂志. 2000,10(4):232-235.
4. RayJ M,Stetler-Stevenson WG.The role of matrix metallo- proteases and the irinhibitors in tumour invasion, metastasis and angiogenesis [J].EurRespirJ,1994,7(11):2062 -2072.
5. Koger M,Tschesche H. Cloning expression and action of atruncated 92Kda gelatinase minienzyme[J]. Gene,1997,196: 175-180.
6. Mac Dougal JR.Contributions of tumor and stromal matrix metallopreteinases to Tumor progression.Cancer Metastasis,Rev,1995,14:351.
7. Roshimoto M,Itoh F.Expression of MMP-7 mRNA in humancolorectal cancer.Int J Cancer,1993,54:614.
8. Gillec C.High level of MT-MMP expression is associated with invasiveness of cervical cancer cells.Int J Cancer,1996,65:209.
9. Liotta LA,Tryggvason K,Garbisa S et al.Metastatic potential correlates with enzymatic degradation of basement membrane collargen. Mature,1980;284:67.
10. Airola K , Karonen T , Vaalamo Met al. Expression of collagenas-es-1 and-3 and their inhibitors TIMP-1 and-3 correlates with thelevel of invasion in malignant melanomas. British Journal of Cancer,1999;80(5,6):733-743.
11. Chamber AF , Matrisian LM.Changing views of matrix metalloproteinase in metastasis[J].Natl Cancer Inst 1997. 89(6): 1260-1265.
12. Parsons SL,Watson SA,Collins HM,et al Gelatianse(MMP-2 and MMP-9) expression in gastrointestinal malingancy [J].Br J Cancer 1998. 78(11):1495-1502.
13. 赵立阁,安瓦尼尔,祝诚.细胞外基质与基质蛋白酶[J].生物化学与生物物理进展,1999,26(3):224-227.
14. Zucker S , Mirza H , Conner CE , et al. Vascular endothelialgrowth factor induces tissue factor and matrixmetallopro-teinase production in endothelial cells: conversion of pro-thrombin to thrombin results in progelatinase A activationand cell proliferation [J].Int J Cancer ,1998,75(5): 780-786.
15. Forsyth PA,Wong H,Laing TD,et al. Gelatinase-A(MMP-2), gelatinase-B(MMP-9) and membrane type matrix metalloproteinase-1(MT1-MMP) are involved in different aspects of the pathophysiology of malignantgliomas[J]. Br J Cancer,1999,79 (11-12): 1828-1835.
16. Huo N,Ichikawa Y,Kamiyama M,et al.MMP-7(matrilysin) accelerated growth of human umbilical vein endothelial cells[J]. CancerLett,2002,177(1):95-100.
17. Ray JM , Stetler R , Stevenson W G.The role of matrix matalloproteases and their inhibitors in tumour invasion, metastasis and angiogenesis. Eur Respir J,1994;7:2062.
18. Deryugina EI,Bourdon MA,Jungwirth K,et al.Fuctional activation of integrin alpha V beta in tumor cells expressing membrane-type 1 matrix metallo- preteinase.Int J Cancer,2000,86(1):15.
19. O’Reilly M S,Holmgren L,Shing et al.A novel angiogenesisinhibitor that mediates the suppression of metastases by a Lew is lung carcinoma.Cell,1994;79:315.
20. David L ,Nesland J,Holm R,et al. Expression of lamin,collagen Ⅳ , fibronectin and type Ⅳ collagenase in gastric carcinoma[J]. Cancer,1994,13:518-527.
21. Nomura H,Fujimoto N,Seiki,etal. Enhanced production of matrix metalloproteinases activation of matrix metalloproteinase2 (gelatinase A) in human gastric carcinomas. Int J Cancer,1996,69(1):9-16.
22. Inoue T,Yashiro M,Nishimura S,et al.Prognostic Matrix metalloproteinase-1 expression in a factor for patients with advanced gastric cancer[J].Int J Mol Med,1999,4(1):73-77.
23. 李楠,徐采朴,房殿春,等.人胃癌 MMP-2、MMP-9及MT1-MMP 基因的过度表达-免疫组织化学和原位杂交研究[J].中国肿瘤临床,1998,25(11):806-809.
24. 梁雨荣,赵涛,何尔斯泰,等.基质金属蛋白酶 MMP-2、MMP-9与胃癌转移的关系[J].中华普通外科杂志,2000,15(2):119
25. Ko B K,Cho H R,Choi D W,et al .Reduced expression of tissue inhibitor of metalloproteinase in nodal metastasis of stomach cancer. J Korean Med Sci, 1998,13(3):286-290.
26. Otani Y.The collagenase activities,interstitial collagenase and type IV collagenase in human stomach cancer with special reference to local spreading and lymphnode metastasis. Keio J Med,1990,39:159-167.
27. Lichtinghagen R,Helmbrecht T,Arndt B,et al. Expression pattern of matrix metalloproteinases in human liver.Eur J Clin Chem Clin Biochem,1995,33(2):65-71.
28. Wang XH. Relationship of HAB18 and MMP-2 expression with human hepatocarcinoma cell differentiation [J]. Chin JClinic Hepatol,2002,18 (1): 55-56.
29. 刘瑾,杨青,王绵珍等.基质金属蛋白酶与肺癌的侵袭和转移[J]. 现代预防医学 2004,31(2):164-166.
30. Gonzalez AG,Irurrea C,Vadillo F,et al.72kD(MMP-2) and 92kD(MMP-9) type Ⅳ collagenase production and activity in different histologic types of lung cancer. Pathobiology,1998,66(1):5.
31. Ylisimio S,Hoyhtya M,Trupeenniemi HT,et al.Serum MMP-2,-9 and TIMP-1,-2 in lung cancer--TIMP-1 as a porgnostic marker. Anticancer Res,2000,20(2B):1311.
2. Hrabec E,Strek M,Nowak D,et al. Elevated level of circulating matrix metalloproteinase-9 in patients with lung cancer. Respir Med,2001,95(1):14.
3. 孙书明,周妍,胡志雄等.肺癌病人血清 MMP-2 和 MMP-9的检测[J].中国临床医学,2003,10(5):637～638.
4. 苏亚娟,高玲娟,王淑敏.测定卵巢恶性肿瘤患者血清基质金属蛋白酶-2 的临床价值[J].黑龙江医药科学,2004, 27(2): 3.
5. 王香平,陈升平,周莲娥.血清明胶酶(MMP-2、MMP-9)与子宫内膜癌[J].首都医科大学学报,2005,26(3):356～357.
6. 钟美佐,黄进,翟晓等.非霍奇金淋巴瘤患者血清中 MMP-9和 MMP-2 蛋白的检测及临床意义[J].中华检验医学杂志,2006,29(3):242～243.
7. 张成武,邹寿椿,徐文鹃等。胃癌 MMP-9 表达的临床意义[J]。中国胃肠外科杂志,2000,3(1):25～27.
8. 孙亚欣,张志超,孙立群等.基质金属蛋白酶含量及表达与膀胱癌侵袭转移的关系[J].吉林大学学报:医学版,2005,31(1):127～129.
9. 赵立阁,安瓦尼尔,祝诚.细胞外基质与基质蛋白酶[J].生物化学与生物物理进展,1999,26(3):224～227.
10. Zucker S,Mirza H,Conner CE,et al.Vascular endothelial growth factor induces tissue factor and matrix metalloproteinase production in endothelial cells: conversion of prothrombin to thrombin results in progelatinase A activation and cell proliferation [J]. Int J,Cancer,1998,75(5):780～786.
11. Poulson R,Pignatelli M,William G,et al.Stromal expression of 72 kda type Ⅳ collagenase and TIMP-2 mRNA in colorectal neoplasia.Am J athol,1992,141:386～396.
12. Grigion WF,D’Errico A,Fiorentino M,et al.Gelatinase A(MMP-2) and its mRNA detected in both neoplastic and stromal cells of tumors with different invasive and metastatic properties.Diagn Mol Pathol,1994,3:163～169.
13. 陈合群,张雪培,申鹏飞等.MMP-2 和 MMP-9 在膀胱癌组织中表达的免疫组化研究[J] .中国现代医学杂志,2003,13 (12):78～80.
14. Liottal Tryg Gvasoank,Garbisa S.Metastatic potential correlates with enzymatic degradation of basement membrane collagen[J].Nature,1980,284:67～68.
15. Sier CF,Kubben FJ,Ganesh S,et al.Tissue levels of matrix metalloproteinase MMP-2 and MMP-9 are related to the overall survival of patients with gastric carcinoma [J].Br J Cancer,1996,74(3):413～417.
16. Parsons SL,Watson SA,Collins HM,et al.Gelatinase (MMP-2 and MMP-9) expression in gastrointestinal malignany [J].Br J Cancer,1998,78(11):1495～1502.
17. Shou Y,Hirano T,Gong Y,et al.Influence f angiogenetic fators and matrix metalloproteinase upon tumor progression in non-small-cell lung cancer [J].Br J Cance,2001,85(11): 1706～1712.
18. Hee J,Soo KB,Ho Y,et al.Anti-invasive activity of ursoliecid correlates with the reduced expression of matrix metalloproteinase-9 (MMP-9) in HT-1080 human fibrosarcoma cells[J].Cancer Res,1996,56(10): 2281～2285.
19. 毛梅,曾群丽,余爱荣.基质金属蛋白酶-2 在肺癌患者血清中的表达及临床意义[J].新乡医学院学报.2006,23(2):151-153.
20. 孙书明,周妍,胡志雄等.肺癌病人血清 MMP-2 和 MMP-9的检测[J].中国临床医学,2003,10(5):637-638.
21. 金钫,段银钟.基质金属蛋白酶与骨改建[J].牙体牙髓牙周病学杂志. 2000,10(4):232-235.
22. RayJ M,Stetler-StevensonWG.The role of matrix metallo- proteases and the irinhibitors in tumour invasion, metastasis and angiogenesis [J].EurRespirJ,1994,7(11):2062 -2072.
23. Koger M, Tschesche H. Cloning expression and action of atruncated 92Kda gelatinase minienzyme[J].Gene,1997,196: 175 -180.
24. Shen KH , Chi CW, Loss , et al.Serum matrix metallo- proteinase-9 level associated with stromal reaction in patients with gastric cancer[J].Anticancer Res, 2000, 20(2B):1307～1310.
25. 李邦涛,汤旭东,文志斌等.中国生理学会论文汇编[A]. 中国生理学会论文汇编 2006 年第二期 [C], 2006.
26. Kabashima A,Maehara Y,Kakeji,etal. linicopathological features and overexpression of matrix metallo- proteinases in intramucosal gastric carcinoma with lymph node metastasis [J].Clin Cancer Res,2000,6(9):3581～3584.
1. Chambers AF,Matrisian LM. Chaning view of the role ofmatrix metalloprotinases in metastasis [J]. J Natl CancerInst,1997, 89(7):1260-1270.
2. Bar-OrA,Nuttall R K,Duddy M,etal. Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis [J]. Brain,2003,126:2738-2749.
3. 金钫,段银钟.基质金属蛋白酶与骨改建[J].牙体牙髓牙周病学杂志. 2000,10(4):232-235.
4. RayJ M,Stetler-Stevenson WG.The role of matrix metallo- proteases and the irinhibitors in tumour invasion, metastasis and angiogenesis [J].EurRespirJ,1994,7(11):2062 -2072.
5. Koger M,Tschesche H. Cloning expression and action of atruncated 92Kda gelatinase minienzyme[J]. Gene,1997,196: 175-180.
6. Mac Dougal JR.Contributions of tumor and stromal matrix metallopreteinases to Tumor progression.Cancer Metastasis,Rev,1995,14:351.
7. Roshimoto M,Itoh F.Expression of MMP-7 mRNA in humancolorectal cancer.Int J Cancer,1993,54:614.
8. Gillec C.High level of MT-MMP expression is associated with invasiveness of cervical cancer cells.Int J Cancer,1996,65:209.
9. Liotta LA,Tryggvason K,Garbisa S et al.Metastatic potential correlates with enzymatic degradation of basement membrane collargen. Mature,1980;284:67.
10. Airola K , Karonen T , Vaalamo Met al. Expression of collagenas-es-1 and-3 and their inhibitors TIMP-1 and-3 correlates with thelevel of invasion in malignant melanomas. British Journal of Cancer,1999;80(5,6):733-743.
11. Chamber AF , Matrisian LM.Changing views of matrix metalloproteinase in metastasis[J].Natl Cancer Inst 1997. 89(6): 1260-1265.
12. Parsons SL,Watson SA,Collins HM,et al Gelatianse(MMP-2 and MMP-9) expression in gastrointestinal malingancy [J].Br J Cancer 1998. 78(11):1495-1502.
13. 赵立阁,安瓦尼尔,祝诚.细胞外基质与基质蛋白酶[J].生物化学与生物物理进展,1999,26(3):224-227.
14. Zucker S , Mirza H , Conner CE , et al. Vascular endothelialgrowth factor induces tissue factor and matrixmetallopro-teinase production in endothelial cells: conversion of pro-thrombin to thrombin results in progelatinase A activationand cell proliferation [J].Int J Cancer ,1998,75(5): 780-786.
15. Forsyth PA,Wong H,Laing TD,et al. Gelatinase-A(MMP-2), gelatinase-B(MMP-9) and membrane type matrix metalloproteinase-1(MT1-MMP) are involved in different aspects of the pathophysiology of malignantgliomas[J]. Br J Cancer,1999,79 (11-12): 1828-1835.
16. Huo N,Ichikawa Y,Kamiyama M,et al.MMP-7(matrilysin) accelerated growth of human umbilical vein endothelial cells[J]. CancerLett,2002,177(1):95-100.
17. Ray JM , Stetler R , Stevenson W G.The role of matrix matalloproteases and their inhibitors in tumour invasion, metastasis and angiogenesis. Eur Respir J,1994;7:2062.
18. Deryugina EI,Bourdon MA,Jungwirth K,et al.Fuctional activation of integrin alpha V beta in tumor cells expressing membrane-type 1 matrix metallo- preteinase.Int J Cancer,2000,86(1):15.
19. O’Reilly M S,Holmgren L,Shing et al.A novel angiogenesisinhibitor that mediates the suppression of metastases by a Lew is lung carcinoma.Cell,1994;79:315.
20. David L ,Nesland J,Holm R,et al. Expression of lamin,collagen Ⅳ , fibronectin and type Ⅳ collagenase in gastric carcinoma[J]. Cancer,1994,13:518-527.
21. Nomura H,Fujimoto N,Seiki,etal. Enhanced production of matrix metalloproteinases activation of matrix metalloproteinase2 (gelatinase A) in human gastric carcinomas. Int J Cancer,1996,69(1):9-16.
22. Inoue T,Yashiro M,Nishimura S,et al.Prognostic Matrix metalloproteinase-1 expression in a factor for patients with advanced gastric cancer[J].Int J Mol Med,1999,4(1):73-77.
23. 李楠,徐采朴,房殿春,等.人胃癌 MMP-2、MMP-9及MT1-MMP 基因的过度表达-免疫组织化学和原位杂交研究[J].中国肿瘤临床,1998,25(11):806-809.
24. 梁雨荣,赵涛,何尔斯泰,等.基质金属蛋白酶 MMP-2、MMP-9与胃癌转移的关系[J].中华普通外科杂志,2000,15(2):119
25. Ko B K,Cho H R,Choi D W,et al .Reduced expression of tissue inhibitor of metalloproteinase in nodal metastasis of stomach cancer. J Korean Med Sci, 1998,13(3):286-290.
26. Otani Y.The collagenase activities,interstitial collagenase and type IV collagenase in human stomach cancer with special reference to local spreading and lymphnode metastasis. Keio J Med,1990,39:159-167.
27. Lichtinghagen R,Helmbrecht T,Arndt B,et al. Expression pattern of matrix metalloproteinases in human liver.Eur J Clin Chem Clin Biochem,1995,33(2):65-71.
28. Wang XH. Relationship of HAB18 and MMP-2 expression with human hepatocarcinoma cell differentiation [J]. Chin JClinic Hepatol,2002,18 (1): 55-56.
29. 刘瑾,杨青,王绵珍等.基质金属蛋白酶与肺癌的侵袭和转移[J]. 现代预防医学 2004,31(2):164-166.
30. Gonzalez AG,Irurrea C,Vadillo F,et al.72kD(MMP-2) and 92kD(MMP-9) type Ⅳ collagenase production and activity in different histologic types of lung cancer. Pathobiology,1998,66(1):5.
31. Ylisimio S,Hoyhtya M,Trupeenniemi HT,et al.Serum MMP-2,-9 and TIMP-1,-2 in lung cancer--TIMP-1 as a porgnostic marker. Anticancer Res,2000,20(2B):1311.