口腔颌面部肉瘤中FAK、MMP-9和uPA的表达及其生物学意义
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摘要
背景和目的：口腔颌面部肉瘤(Oromaxillofacial sarcoma，OMFS)的恶性度较高，发展较快，且综合治疗效果差，预后不良，早期诊断和根治性外科手术是提高生存率的主要途径。因此充分利用现代免疫学和分子生物学理论和技术，探索OMFS的发生发展规律，揭示其生物学特性，为临床诊治提供可靠依据尤为必要。粘着斑激酶(focaladhesion kinase，FAK)是一个胞浆酪氨酸激酶，能激活Src内源性蛋白酪氨酸激酶。癌基因、细胞外基质(extracellular matrix，ECM)、整合素(integrin)刺激后，FAK发生酪氨酸磷酸化。FAK的高表达和酪氨酸磷酸化与肿瘤的生成能力相关。大量文献报道，FAK的高表达与多种恶性肿瘤的侵袭和转移正相关。基质金属蛋白酶-9(matrixmetalloproteinase-9，MMP-9)属于明胶酶类，主要作用是降解ECM，其作用底物主要是明胶和Ⅳ／Ⅴ型胶原，同时在血管生成方面发挥作用，促进肿瘤的侵袭和转移。以往大量的研究表明，MMP-9可在皮肤癌、甲状腺癌、前列腺癌、结肠癌、肺癌、骨肉瘤等肿瘤组织中表达，免疫组化研究表明MMP-9表达部位主要在细胞浆，尤其表达在肿瘤侵袭和转移前沿；而且，MMP-9的表达与多种肿瘤的病理分级正相关，MMP-9的表达可能成为恶性肿瘤预后的一项指标。尿激酶型纤溶酶原激活物(urokinase-typeplasminogen activator，uPA)通过激活纤溶酶原增加纤溶酶的生成，从而促进基底膜和细胞外基质蛋白的降解，影响细胞的迁徙。uPA和其受体的结合启动了蛋白溶解过程，有利于MMP-9的激活，促进ECM的溶解。这些过程在肿瘤细胞的侵袭和转移中发挥重要作用。本课题应用免疫组化方法检测OMFS中FAK、MMP-9和uPA的表
郑州大学20(抖年硕士毕业论文
口腔领面部肉瘤中FAK、MMP一9和证叭的表达及其生物学意义
达，探讨FAK激活及其信号传导在肉瘤发生发展中的作用及其相互关系，为临床评估
OMFS复发、侵袭和转移潜能，进行预后监测提供参考依据。
材料和方法:
1.收集1993年2月至2002年5月郑州大学第一附属医院手术切除并经病理证
实口腔领面部间叶性肿瘤51例。其中OMI.S37例，所有病例术前均未行化疗、放疗
或生物治疗。全部组织均经中性福尔马林液固定，常规脱水后石蜡包埋。口腔正常间
叶组织5例，取自口腔领面部外伤手术病人。
2.应用免疫组化S一P法检测OMF.S中FAK.、MMP一9和uPA的表达。
3.应用SPSslo.0统计软件对FAK、M血于一9和uPA的表达与肉瘤患者临床病
理特征的关系，以及指标间的相关性进行统计分析，检验结果均以Q=0 .05作为有统计
学意义的判断水准。
结果:
1 .FAK阳性信号位于肿瘤细胞胞膜或胞浆内，为弥散性或细颗粒状棕黄色，阳
性表达细胞为非均质性，口腔领面部肉瘤中FAK的阳性表达率为62.16%，而良性间
叶组织肿瘤中阳性表达率为14.29%，两组比较差异有统计学意义(尸<0.05)。在高分
化组、中分化组和低分化组中，FAK的阳性表达率分别为33 .33%、70.00%和80.00%，
统计分析表明，高分化组与低分化组之间差异有统计学意义(尸<0.仍)。发生复发、
淋巴结转移或远处转移的肉瘤中FAK表达明显升高，但差异不具有统计学意义(尸
>0 .05)。与无转移肉瘤相比，转移组FAK表达差异有统寸学意义(尸<0.05)。
2.MMP一9的阳性信号位于肿瘤细胞胞膜或胞浆内，为棕黄色或黄色细颗粒状，
阳性表达细胞为非均质性。口腔领面部肉瘤中M血IP一9的阳性表达率为62.16%，明显
高于良性间叶组织肿瘤(尸<0.05)，并随肉瘤分化程度的降低而呈升高趋势，统计分
析表明，高分化组与低分化组之间差异有统计学意义(尸<0.05)。发生复发、淋巴结
转移或远处转移的肉瘤中M入IP.9表达明显升高，但差异不具有统计学意义(尸>0.05)。
与无转移肉瘤相比，转移组MMP一9表达差异有统计学意义(尸<0.05)。
3 .uPA的阳性信号为棕黄色细颗粒状，位于肿瘤细胞胞膜或胞浆内，阳性表达细
胞为非均质性。口腔领面部肉瘤中uPA的阳性表达率为70.27%，而良性间叶组织肿瘤
中阳性表达率为21.43%，两组比较差异有统计学意义(尸<0.05)。在高分化组、中分
化组和低分化组中，uPA的阳性表达率分别为41.67%、·70.00%和93.33%，统计分析
郑州大学2004举硕士毕业论文
口腔领面部肉瘤中I叭K、M劫P一9和ul叭的表达及其生物学意义
表明，高分化组和中分化组、中分化组和低分化组之间差异不具有统计学意义(尸
>0.05)，而高分化组与低分化组之间差异有统计学意义(尸<0.05)。复发肉瘤中uPA
的阳性表达率明显高于原发肉瘤(尸<0.05)。在发生淋巴结转移或远处转移的肉瘤中
uPA表达有明显升高趋势，但差异不具有统计学意义(尸>0.05)。
4.口腔领面部肉瘤中，FAK的阳性表达和MN[P一9的阳性表达呈显著相关(尸
<0.05);FAK的阳性表达和uPA的阳性表达呈显著相关(尸<0.05);MMP一9的阳性
表达和uPA的阳性表达呈显著相关(P<0 .05)。
5.FAK、Ml田一9和uPA在正常口腔肌肉、脂肪组织中均不表达。
结论:
1 .FAK在口腔领面部肉瘤发生和发展过程中起重要作用;FAK的高表达可能成
为评估口腔领面部肉瘤临床侵袭和转移潜能的有用指标。
2.MMP一9的高表达是反映口腔领面部肉瘤恶性程度评估
Background and Objective: Oromaxillofacial sarcoma(OMFS) is a malignant tumor originated from mesenchymal tissue of oral and maxillofacial region which not only has obvious difference of histology, many kinds and lower incidence rate but also is characterized by high malignant degree, early distant metastasis, insignificant effect for combined therapy and poor prognosis.It is essential for correct treatment decisions and better survival rates to make extensive research on the development mechanisms and the biological character of oromaxillofacial sarcoma, understanding the molecular mechanisms of metastasis is critical with respect to oral tumorigenesis. focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that plays a pivotal role in signal transduction at integrin-linked cellular adhesions, which mediate cell contact with the extracellular matrix. It has been shown to play a role in the survival of anchorage-dependent cells and to be essential for integrin-linked cell migration - processes that ar
e likely to play important roles in the development of malignancies. FAK is an intracellular tyrosine kinase associated with the regulation of cell growth, migration, and survival. The purpose of the current study was to determine whether elevated FAK expression in oromaxillofacial sarcoma was associated with increased invasiveness and metastasis. To detect the expression of FAK and MMP-9 and uPA in oromaxillofacial sarcoma and to study their correlation with clinicopathological data including tumor type, grade and lymph node status.
Material and Method:
1. Thirty-seven cases of OMFS samples, 14 cases of benign mesenchymal tumors and 5 cases of normal mesenchymal tissues of oral and maxillofacial region were collected at the first teaching hospital of zhengzhou university, patients hadn't received preoperative chemotherapy or radiation therapy.the tissues were fixed in 10% formalin and embedded in paraffin.
2. Immunohistochemical streptavidin peroxidase method was used to detect the expression of FAK and MMP-9 and uPA in OMFS and benign mesenchymal tumors.
3. The results were analyzed by SPSS 10.0 software wrap, and a P value of less than 0.05 was considered to be statistically significant.
Results
1 . In oromaxillofacial sarcomas,positive staining for FAK was mainly observed in the cytoplasm and/or on the membrane of tumour cells as well as some mesenchymal cells, and its positive rate was 62.16% (23/37);FAK express was detected in 14.29% (2/14) of benign tumors,and a significant diffenence was found between the two groups (P <0.05) .in the there groups of highly, moderately and poorly differentiated of OMFS,the positive rates of FAK were 33.33% (4/12), 70.00% (7/10) and 80.00% (12/15) .respectively .There was a significant difference between highly differentiated group and poorly differentiated group
(P <0.05) .the expression level of FAK was significantly higher in locally recurrent sarcomas than that in primary sarcomas, while no statistical significance was found (P >0.05) . There was a significant difference between sarcomas with distant metastasis and lymph node metastasis and the other sarcomas (P <0.05 ) .
2. In OMFS ,the positive rate of uPA is 70.27 % (26/37), while the positive rate is 21.43 % (3/14) in benign tumors, There was a significant difference between the two groups
(P <0.05 ) .in the there groups of highly, moderately and poorly differentiated of OMFS,the positive rates of uPA were 41.67% (5/12) and 70.00%(7/10) and 93.33%(14/15), respectively. There was a significant difference between highly differentiated group and poorly differentiated group (P <0.05 ) . the expression level of uPA was significantly higher in locally recurrent sarcomas than in primary sarcomas (P <0.05) .in sarcomas with distant
metastasis and/or lymph node metastasis,the positive expression of uPA tended to increase compared to the other sarcomas, while no statistical significance was found (P >0.05 ) .
3. In OMFS , the positive rate of MMP-9 is 62. 16% (23/37);while the positive rate is 21.
郑州大学20(抖年硕士毕业论文
口腔领面部肉瘤中FAK、MMP一9和证叭的表达及其生物学意义
达，探讨FAK激活及其信号传导在肉瘤发生发展中的作用及其相互关系，为临床评估
OMFS复发、侵袭和转移潜能，进行预后监测提供参考依据。
材料和方法:
1.收集1993年2月至2002年5月郑州大学第一附属医院手术切除并经病理证
实口腔领面部间叶性肿瘤51例。其中OMI.S37例，所有病例术前均未行化疗、放疗
或生物治疗。全部组织均经中性福尔马林液固定，常规脱水后石蜡包埋。口腔正常间
叶组织5例，取自口腔领面部外伤手术病人。
2.应用免疫组化S一P法检测OMF.S中FAK.、MMP一9和uPA的表达。
3.应用SPSslo.0统计软件对FAK、M血于一9和uPA的表达与肉瘤患者临床病
理特征的关系，以及指标间的相关性进行统计分析，检验结果均以Q=0 .05作为有统计
学意义的判断水准。
结果:
1 .FAK阳性信号位于肿瘤细胞胞膜或胞浆内，为弥散性或细颗粒状棕黄色，阳
性表达细胞为非均质性，口腔领面部肉瘤中FAK的阳性表达率为62.16%，而良性间
叶组织肿瘤中阳性表达率为14.29%，两组比较差异有统计学意义(尸<0.05)。在高分
化组、中分化组和低分化组中，FAK的阳性表达率分别为33 .33%、70.00%和80.00%，
统计分析表明，高分化组与低分化组之间差异有统计学意义(尸<0.仍)。发生复发、
淋巴结转移或远处转移的肉瘤中FAK表达明显升高，但差异不具有统计学意义(尸
>0 .05)。与无转移肉瘤相比，转移组FAK表达差异有统寸学意义(尸<0.05)。
2.MMP一9的阳性信号位于肿瘤细胞胞膜或胞浆内，为棕黄色或黄色细颗粒状，
阳性表达细胞为非均质性。口腔领面部肉瘤中M血IP一9的阳性表达率为62.16%，明显
高于良性间叶组织肿瘤(尸<0.05)，并随肉瘤分化程度的降低而呈升高趋势，统计分
析表明，高分化组与低分化组之间差异有统计学意义(尸<0.05)。发生复发、淋巴结
转移或远处转移的肉瘤中M入IP.9表达明显升高，但差异不具有统计学意义(尸>0.05)。
与无转移肉瘤相比，转移组MMP一9表达差异有统计学意义(尸<0.05)。
3 .uPA的阳性信号为棕黄色细颗粒状，位于肿瘤细胞胞膜或胞浆内，阳性表达细
胞为非均质性。口腔领面部肉瘤中uPA的阳性表达率为70.27%，而良性间叶组织肿瘤
中阳性表达率为21.43%，两组比较差异有统计学意义(尸<0.05)。在高分化组、中分
化组和低分化组中，uPA的阳性表达率分别为41.67%、·70.00%和93.33%，统计分析
郑州大学2004举硕士毕业论文
口腔领面部肉瘤中I叭K、M劫P一9和ul叭的表达及其生物学意义
表明，高分化组和中分化组、中分化组和低分化组之间差异不具有统计学意义(尸
>0.05)，而高分化组与低分化组之间差异有统计学意义(尸<0.05)。复发肉瘤中uPA
的阳性表达率明显高于原发肉瘤(尸<0.05)。在发生淋巴结转移或远处转移的肉瘤中
uPA表达有明显升高趋势，但差异不具有统计学意义(尸>0.05)。
4.口腔领面部肉瘤中，FAK的阳性表达和MN[P一9的阳性表达呈显著相关(尸
<0.05);FAK的阳性表达和uPA的阳性表达呈显著相关(尸<0.05);MMP一9的阳性
表达和uPA的阳性表达呈显著相关(P<0 .05)。
5.FAK、Ml田一9和uPA在正常口腔肌肉、脂肪组织中均不表达。
结论:
1 .FAK在口腔领面部肉瘤发生和发展过程中起重要作用;FAK的高表达可能成
为评估口腔领面部肉瘤临床侵袭和转移潜能的有用指标。
2.MMP一9的高表达是反映口腔领面部肉瘤恶性程度评估
Background and Objective: Oromaxillofacial sarcoma(OMFS) is a malignant tumor originated from mesenchymal tissue of oral and maxillofacial region which not only has obvious difference of histology, many kinds and lower incidence rate but also is characterized by high malignant degree, early distant metastasis, insignificant effect for combined therapy and poor prognosis.It is essential for correct treatment decisions and better survival rates to make extensive research on the development mechanisms and the biological character of oromaxillofacial sarcoma, understanding the molecular mechanisms of metastasis is critical with respect to oral tumorigenesis. focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that plays a pivotal role in signal transduction at integrin-linked cellular adhesions, which mediate cell contact with the extracellular matrix. It has been shown to play a role in the survival of anchorage-dependent cells and to be essential for integrin-linked cell migration - processes that ar
e likely to play important roles in the development of malignancies. FAK is an intracellular tyrosine kinase associated with the regulation of cell growth, migration, and survival. The purpose of the current study was to determine whether elevated FAK expression in oromaxillofacial sarcoma was associated with increased invasiveness and metastasis. To detect the expression of FAK and MMP-9 and uPA in oromaxillofacial sarcoma and to study their correlation with clinicopathological data including tumor type, grade and lymph node status.
Material and Method:
1. Thirty-seven cases of OMFS samples, 14 cases of benign mesenchymal tumors and 5 cases of normal mesenchymal tissues of oral and maxillofacial region were collected at the first teaching hospital of zhengzhou university, patients hadn't received preoperative chemotherapy or radiation therapy.the tissues were fixed in 10% formalin and embedded in paraffin.
2. Immunohistochemical streptavidin peroxidase method was used to detect the expression of FAK and MMP-9 and uPA in OMFS and benign mesenchymal tumors.
3. The results were analyzed by SPSS 10.0 software wrap, and a P value of less than 0.05 was considered to be statistically significant.
Results
1 . In oromaxillofacial sarcomas,positive staining for FAK was mainly observed in the cytoplasm and/or on the membrane of tumour cells as well as some mesenchymal cells, and its positive rate was 62.16% (23/37);FAK express was detected in 14.29% (2/14) of benign tumors,and a significant diffenence was found between the two groups (P <0.05) .in the there groups of highly, moderately and poorly differentiated of OMFS,the positive rates of FAK were 33.33% (4/12), 70.00% (7/10) and 80.00% (12/15) .respectively .There was a significant difference between highly differentiated group and poorly differentiated group
(P <0.05) .the expression level of FAK was significantly higher in locally recurrent sarcomas than that in primary sarcomas, while no statistical significance was found (P >0.05) . There was a significant difference between sarcomas with distant metastasis and lymph node metastasis and the other sarcomas (P <0.05 ) .
2. In OMFS ,the positive rate of uPA is 70.27 % (26/37), while the positive rate is 21.43 % (3/14) in benign tumors, There was a significant difference between the two groups
(P <0.05 ) .in the there groups of highly, moderately and poorly differentiated of OMFS,the positive rates of uPA were 41.67% (5/12) and 70.00%(7/10) and 93.33%(14/15), respectively. There was a significant difference between highly differentiated group and poorly differentiated group (P <0.05 ) . the expression level of uPA was significantly higher in locally recurrent sarcomas than in primary sarcomas (P <0.05) .in sarcomas with distant
metastasis and/or lymph node metastasis,the positive expression of uPA tended to increase compared to the other sarcomas, while no statistical significance was found (P >0.05 ) .
3. In OMFS , the positive rate of MMP-9 is 62. 16% (23/37);while the positive rate is 21.
引文
1 张永福，杜舜颖，蒋泽先，等．口腔颌面部间叶组织恶性肿瘤(附31例报告)．华西口腔医学杂志，1986，4(4)：244-246
2 李新明，张永福．口腔颌面部间叶组织恶性肿瘤细胞DNA含量的流式细胞分析．华西口腔医学杂志，1993，11(3)：173-175
3 Sieg DJ, Hauck CR, Schlaepfer DD. Required role of focal adhesion kinase (FAK) for integrin-stimulated cell migration. J Cell Sci, 1999, 112 (16): 2677-2691
4 Hauck CR, Hsia DA, Schlaepfer DD.The focal adhesion kinase--a regulator of cell migration and invasion. IUBMB Life, 2002, 53 (2): 115-119
5 Hauck CR, Hsia DA, Puente XS, et al. FRNK blocks v-Src-stimulated invasion and experimental metastases without effects on cell motility or growth. EMBO J, 2002,21 (23): 6289-6302
6 Hauck CR, Sieg DJ, Hsia DA, et al. Inhibition of focal adhesion kinase expression or activity disrupts epidermal growth factor-stimulated signaling promoting the migration of invasive human carcinoma cells. Cancer Res,2001,61 (19): 7079-7090
7 Oktay MH, Oktay K, Hamele-Bena D, et al.Focal adhesion kinase as a marker of malignant phenotype in breast and cervical carcinomas. Hum Pathol, 2003, 34(3): 240-245
8 Miyazaki T, Kato H, Nakajima M, et al. FAK overexpression is correlated with tumour inv-asiveness and lymph node metastasis in oesophageal squamous cell carcinoma. Br J Cancer, 2003, 89(1): 140-5
9 Cance WG, Harris JE, Iacocca MV, et al. Immunohistochemical analyses of focal adhesion kinase expression in benign and malignant human breast and colon tissues: correlation with preinvasive and invasive phenotypes. Clin Cancer Res, 2000,6(6): 2417-23
10 Yu Q, Stamenkovie I.Cell surfaeeloealized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev, 2000,14(2): 163-176
11 Kurizaki T, Toi M, Tominaga T.Relationship between matrix metalloproteinase expression and tumor angiogenesis in human breast carcinoma.Oncol Rep, 1998,5(3):673-677
12 Kornberg LJ. Focal adhesion kinase and its potential involvement in tumor invasion and metastasis. Head Neck, 1998, 20(8): 745-752
13 Owens LV, Xu L, Dent GA, et al. Focal adhesion kinase as a marker of invasive potential in differentiated human thyroid cancer. Ann Surg Oncol, 1996,3(1): 100-105.
14 Fukai Y, Masuda N, Manda R, et al. FAK overexpression is correlated with tumour invasiveness and lymph node metastasis in oesophageal squamous cell carcinoma. Br J Cancer, 2003, 89(1): 140-145
15 Hsia DA, Mitra SK, Hauck CR, et al. Differential regulation of cell motility and invasion by FAK. J Cell Biol, 2003, 160(5): 753-767
16 Schneider GB, Kurago Z, Zaharias R, et al. Elevated focal adhesion kinase expression facilitates oral tumor cell invasion. Cancer, 2002, 95(12): 2508-2515
17 weiner TM, Liu ET, Craven RJ, et al. Expression of focal adhesion kinase gene and invasive cancer. Lancet, 1993, 342(8878): 1024-1025
18 Michael DS.Biochemical signals and biological responses elicited by the focal adhesion kinase.Biochimica et Biophysica Acta, 2001, 1540 (1): 1—21
19 Owens LV, Xu L, Craven RJ, et al.Overexpression of the focal adhesion kinase (p125FAK) in invasive human tumors. Cancer Res, 1995, 55(13): 2752-2755
20 Kahana O,Micksche M,Witz IP, et al.The focal adhesion kinase (P125FAK)is constitutively active in human malignant melanoma. Oncogene,2002,21(25):3969—3977
21 Rodina A, Schramm K, Musatkina E,et al.Phosphorylation of p125FAK and paxillin focal adhesion proteins in src-transformed cells with different metastatic capacity. FEBS Lett, 1999, 455(1-2): 145-148
22 Moritake H, Sugimoto T, Kuroda H, et al. Newly established Askin tumor cell line and overexpression of focal adhesion kinase in Ewing sarcoma family of tumors cell lines. Cancer Genet Cytogenet, 2003,146(2): 102-109
23 苏剑敏，桂律．周逸平．等．粘着斑激酶在肿瘤中的表达及其临床意义．中国肿瘤，2002，11(11)：670—672
24 Ruest PJ,Roy S,Shi E, et al. Phosphospecific antibodies reveal focal adhesion kinase activation loop phosphorylation in nascent and mature focal adhesion and requirement for the autophosphorylation site. Cell Growth Differ, 2000,11 (1): 41-48
25 Cary LA, Chang JF, Guan JL. Stimulation of cell migration by overexpression of focal adhesion kinase and its association with Src and Fyn. J Cell Sci, 1996,109 (7): 1787-1794
26 Hauck CR, Hunter T, Schlaepfer DD. The v-Src SH3 domain facilitates a cell adhesion-independent association with focal adhesion kinase. J Biol Chem, 2001, 276(21): 17653-17662
27 Walsh MF, Thamilselvan V, Grotelueschen R, et al. Absence of adhesion triggers differential FAK and SAPKp38 signals in SW620 human colon cancer cells that may inhibit adhesiveness and lead to cell death. Cell Physiol Biochem, 2003,13(3): 135-146
28 Sonoda Y, Matsumoto Y, Funakoshi M, et al. Anti-apoptotic role of focal adhesion kinase (FAK). Induction of inhibitor-of-apoptosis proteins and apoptosis suppression by the overexpression of FAK in a human leukemic cell line, HL-60. J Biol Chem, 2000, 275(21): 16309-16315
29 Matter ML, Ruoslahti E. A signaling pathway from the alpha5betal and alpha(v)beta3 integrins that elevates bc1-2 transcription. J Biol Chem, 2001, 276(30): 27757-27763
30 Jones RJ, Brunton VG, Frame MC.Adhesion-linked kinases in cancer; emphasis on src, focal adhesion kinase and PI 3-kinase. Eur J Cancer, 2000, 6(13): 1595-1606
31 Zhao JH, Guan JL. Role of focal adhesion kinase in signaling by the extracellular matrix. Prog Mol Subcell Biol, 2000, 25:37-55
32 Mardinger O, Givol N, Talmi YP, et al. Osteosarcoma of the jaw. The Chaim Sheba Medical Center experience. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 2001, 91(4): 445-451
33 Hsia DA, Mitra SK, Hauck CR, et al. Differential regulation of cell motility and invasion by FAK.J Cell Biol, 2003, 160(5): 753-767
34 Thant AA, Nawa A, Kikkawa F, et al. Fibronectin activates matrix metalloproteinase-9 secretion via the MEK1-MAPK and the PI3K-Akt pathways in ovarian cancer cells. Clin Exp Metastasis, 2000,18(5): 423-428
35 Irigoyen JP, Nagamine Y.Cytoskeletal reorganization leads to induction of the
urokinase-type plasminogen activator gene by activating FAK and Src and subsequently the Ras/Erk signaling pathway. Biochem Biophys Res Commun, 1999,262(3): 666-670
36 Kim I, Kim HG, Moon SO, et al. Angiopoietin-1 induces endothelial cell sprouting through the activation of focal adhesion kinase and plasmin secretion. Circ Res, 2000, 86(9): 952-959
37 Besson A, Robbins SM, Yong VW. PTEN/MMAC1/TEP1 in signal transduction and tumorigenesis. Eur J Biochem, 1999,263(3): 605-611
38 Tamura M, Gu J, Takino T. Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: differential involvement of focal adhesion kinase and p130Cas. Cancer Res, 1999, 9(2): 442-449
39 Gautam A, Li ZR, Bepler G. RRMl-induced metastasis suppression through PTEN-regulated pathways. Oncogene, 2003, 2(14): 2135-2142
40 Gu Y, Chen. JS, Zhou XD. Inhibitory effects of antisense focal adhesion kinase oligodeoxynucleotides on the invasion of Bel 7402 hepatocellular carcinoma cells. Zhonghua Gan Zang Bing Za Zhi, 2003,11(10):612-615.
41 Saito Y, Swanson X, Mhashilkar AM, et al. Adenovirus-mediated transfer of the PTEN gene inhibits human coiorectal cancer growth in vitro and in vivo. Gene Ther, 2003, 10(23): 1961-1969
42 官国先，寿楠海．粘着斑激酶反义寡核苷酸与胃癌细胞生长及凋亡的关系．山东医药，2001，041(014)：1-3
43 Bezzi M, Hasmim M, Bieler G, et al. Zoledronate sensitizes endothelial cells to tumor necrosis factor-induced programmed cell death: evidence for the suppression of sustained activation of focal adhesion kinase and protein kinase B/Akt. J Biol Chem, 2003,278(44): 43603-43614
44 Arii S, Mise M, Harada T, et al. Overexpression of matrix metalloproteinase 9 gene in hepatocellular carcinoma with invasive potential. Hepatology, 1996, 24(2): 316-322
45 Gokaslan ZL, Chintala SK, York JE, et al. Expression and role of matrix metalloproteinases MMP-2 and MMP-9 in human spinal column tumors. Clin Exp Metastasis, 1998,16(8): 721-728
46 Davies B, Waxman J, Wasan H, et al. Levels of matrix metalloproteases in bladder cancer correlate with tumor grade and invasion. Cancer Res, 1993, 53(22): 5365-5369
47 许克新，侯树坤，杜志军．检测金属基质蛋白酶及其抑制物对判断膀胱癌浸润和转移的意义．中华泌尿外科杂志，2002,23(4)：231-233
48 张云锋，王作仁，牛新捷．胆囊癌中基质金属蛋白酶-9、粘附分子CD44变构体6表达及其临床意义．中华泌尿外科杂志，2002，23(4)：405-406
49 郭文忠，冉宇靓，王贵齐．VEGF和MMP-9在食管癌中的表达及低氧调节．中华肿瘤杂志，2002，24(1)：44-47
50 Sopata I, Dancewicz AM. Presence of a gelatin-specific proteinase and its latent form in human leucocytes. Biochim Biophys Acta, 1974,370(2): 510-523
51 Iwata H, Kobayashi S, Iwase H, et al. Production of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human breast carcinomas. Jpn J Cancer Res, 1996,87(6): 602-611
52 Ueda Y, Imai K, Tsuchiya H, et al. Matrix metalloproteinase 9 (gelatinase B) is expressed in multinucleated giant cells of human giant cell tumor of bone and is associated with vascular invasion. Am J Pathol, 1996, 148(2): 611-622
53 Schoedel KE, Greco MA, Stetler-Stevenson WG, et al. Expression of metalloproteinases and tissue inhibitors of metalloproteinases in giant cell tumor of bone: an immunohistochemical study with clinical correlation. Hum Pathol, 1996, 27(11): 1144-1148
54 Nakano A, Tani E, Miyazaki K, et al. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in human gliomas. J Neurosurg, 1995, 83(2): 298-307
55 Ashida K, Nakatsukasa H, Higashi T, et al. Cellular distribution of 92-kd type Ⅳ collagenase/gelatinase B in human hepatocellular carcinoma. Am J Pathol, 1996, 149(6): 1803-1811
56 Bernhard EJ, Gruber SB, Muschel RJ. Direct evidence linking expression of matrix metalloproteinase 9 (92-kDa gelatinase/collagenase) to the metastatic phenotype in transformed rat embryo cells. Proc Natl Acad Sci U S A, 1994, 91(10): 4293-4297
57 Itoh T, Tanioka M, Matsuda H, et al. Experimental metastasis is suppressed in MMP-9-deficient mice. Clin Exp Metastasis, 1999, 17(2): 177-181
58 Himelstein BP, Asada N, Carlton MR, et at Matrix metalloproteinase-9 (MMP-9) expression in childhood osseous osteosarcoma. Med Pediatr Oncol, 1998, 31(6): 471-474
59 Soderstrom M, Aro HT, Ahonen M, et al. Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human chondrosarcomas. APMIS, 2001, 109(4): 305-315
60 Kido A, Tsutsumi M, Iki K, et al. Overexpression of matrix metalloproteinase (MMP)-9 correlates with metastatic potency of spontaneous and 4-hydroxyaminoquinoline 1-oxide (4-HAQO)-induced transplantable osteosarcomas in rats. Cancer Lett, 1999, 137(2): 209-216
61 Rechberger T, Postawski K, Skorupski P, et al. Local activity of matrix metalloproteinases in a case of botryoid sarcoma. Eur J Obstet Gynecol Reprod Biol, 1996,67(2): 169-172
62 Kawashima A, Nakanishi I, Tsuchiya H, et al. Expression of matrix metalloproteinase 9 (92-kDa gelatinase/type Ⅳ collagenase) induced by tumour necrosis factor alpha correlates with metastatic ability in a human osteosarcoma cell line. Virchows Arch, 1994, 424(5): 547-552
63 Lakka SS, Gondi CS, Yanamandra N, et al. Synergistic down-regulation of urokinase plasminogen activator receptor and matrix metalloproteinase-9 in SNB19 glioblastoma cells efficiently inhibits glioma cell invasion, angiogenesis, and tumor growth, Cancer Res, 2003, 63(10): 2454-2461
64 Liu G, Shuman MA, Cohen RL. Co-expression of urokinase, urokinase receptor and PAI-1 is necessary for optimum invasiveness of cultured lung cancer cells. Int J Cancer, 1995, 60(4): 501-506
65 Schmalfeldt B, Kuhn W, Reuning U, et al. Primary tumor and metastasis in ovarian cancer differ in their content of urokinase-type plasminogen activator, its receptor, and inhibitors types 1 and 2. Career Res, 1995,55(18): 3958-3963
66 Achbarou A, Kaiser S, Tremblay G, et al. Urokinase overproduction results in increased skeletal metastasis by prostate cancer cells in vivo. Cancer Res, 1994, 54(9): 2372-2377
67 Foekens JA, Peters HA, Look MP, et al. The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients. Cancer Res, 2000,60(3): 636-643
68 Yang JL, Seetoo D, Wang Y, et al. Urokinase-type plasminogen activator and its receptor in colorectal cancer: independent prognostic factors of metastasis and cancer-specific survival and potential therapeutic targets. Int J Cancer, 2000, 89(5): 431-439
69 He C, He P, Liu LP, et al. Analysis of expressions of components in the plasminogen activator system in high-and low-metastatic human lung cancer cells. J Cancer Res Clin Oncol, 2001, 127(3): 180-186
70 刘刚，李金荣．口腔鳞癌组织中尿激酶型纤溶酶原激活剂及其抑制剂活性与颈淋巴结转移的关系．临床口腔医学杂志，1999，15(1)：12-13
71 李杰恩，徐志文，陈显新．鼻咽癌尿激酶型纤溶酶原激活物及VEGF表达与侵袭转移关系．肿瘤防治研究，2001，28(5)：359-360
72 肖继平，张广德，夏文华，等．乳腺瘤中尿激酶型纤溶酶原激活物的过度表达．实用癌症杂志，1999，14(4)：261-262
73 Choong PF, Ferno M, Akerman M, et al. Urokinase-plasminogen-activator levels and prognosis in 69 soft-tissue sarcomas. Int J Cancer ,1996, 69 (4):268-272
74 Hackel C, Czerniak B, Ayala AG, et al. Expression of plasminogen activators and plasminogen activator inhibitor 1 in dedifferentiated chondrosarcoma. Cancer, 1997, 79(1): 53-58
75 Gokaslan ZL, Chintala SK, York JE, et al. Expression and localization of urokinase-type plasminogen activator in human spinal column tumors. Clin Exp Metastasis, 1998, 16(8): 713-719
76 Meade-Tollin LC, Way D, Witte MH.Expression of multiple matrix metalloproteinases and urokinase type plasminogen activator in cultured Kaposi sarcoma cells. Acta Histochem, 1999, 101(3): 305-316
77 Fisher JL, Mackie PS, Howard Ml et al. The expression of the urokinase plasminogen activator system in metastatic murine osteosarcoma: an in vivo mouse model. Clin Cancer Res, 2001, 7(6): 1654-1660
78 Morii T, Yabe H, Morioka H, et al. Prognostic relevance of urokinase type plasminogen activator, its receptor and inhibitors in chondrosarcoma. Anticancer Res, 2000, 20(5A): 3031-3036
79 McCawley LJ, Matrisian LM. Matrix metalloproteinases: multifunctional contributors to
tumor progression. Mol Med Today, 2000, 6(4): 149-156
80 Irigoyen JP, Munoz-Canoves P, Montero L, et al. The plasminogen activator system: biology and regulation. Cell Mol Life Sci, 1999, 56(1-2): 104-132
81 Irigoyen JP, Besser D, Nagamine Y. Cytoskeleton reorganization induces the urokinase-type plasminogen activator gene via the Ras/extracellular signal-regulated kinase (ERK) signaling pathway. J Biol Chem, 1997, 272(3): 1904-1909
82 Shin M, Yan C, Boyd D. An inhibitor of c-jun amino terminal kinase (SP600125) represses c-Jun activation, DNA-binding and PMA-inducible 92-kDa type Ⅳ collagenase expression. Biochim Biophys Acta, 2002, 1589(3):311-316
83 Sein TT, Thant AA, Hiraiwa Y, et al. A role for FAK in the Concanavalin A-dependent secretion of matrix metalloproteinase-2 and-9. Oncogene, 2000, 19(48): 5539-5542
84 Shibata K, Kikkawa F, Nawa A, et al. Both focal adhesion kinase and c-Ras are required for the enhanced matrix metalloproteinase 9 secretion by fibronectin in ovarian cancer cells. Cancer Res, 1998, 58(5): 900-903
2 李新明，张永福．口腔颌面部间叶组织恶性肿瘤细胞DNA含量的流式细胞分析．华西口腔医学杂志，1993，11(3)：173-175
3 Sieg DJ, Hauck CR, Schlaepfer DD. Required role of focal adhesion kinase (FAK) for integrin-stimulated cell migration. J Cell Sci, 1999, 112 (16): 2677-2691
4 Hauck CR, Hsia DA, Schlaepfer DD.The focal adhesion kinase--a regulator of cell migration and invasion. IUBMB Life, 2002, 53 (2): 115-119
5 Hauck CR, Hsia DA, Puente XS, et al. FRNK blocks v-Src-stimulated invasion and experimental metastases without effects on cell motility or growth. EMBO J, 2002,21 (23): 6289-6302
6 Hauck CR, Sieg DJ, Hsia DA, et al. Inhibition of focal adhesion kinase expression or activity disrupts epidermal growth factor-stimulated signaling promoting the migration of invasive human carcinoma cells. Cancer Res,2001,61 (19): 7079-7090
7 Oktay MH, Oktay K, Hamele-Bena D, et al.Focal adhesion kinase as a marker of malignant phenotype in breast and cervical carcinomas. Hum Pathol, 2003, 34(3): 240-245
8 Miyazaki T, Kato H, Nakajima M, et al. FAK overexpression is correlated with tumour inv-asiveness and lymph node metastasis in oesophageal squamous cell carcinoma. Br J Cancer, 2003, 89(1): 140-5
9 Cance WG, Harris JE, Iacocca MV, et al. Immunohistochemical analyses of focal adhesion kinase expression in benign and malignant human breast and colon tissues: correlation with preinvasive and invasive phenotypes. Clin Cancer Res, 2000,6(6): 2417-23
10 Yu Q, Stamenkovie I.Cell surfaeeloealized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev, 2000,14(2): 163-176
11 Kurizaki T, Toi M, Tominaga T.Relationship between matrix metalloproteinase expression and tumor angiogenesis in human breast carcinoma.Oncol Rep, 1998,5(3):673-677
12 Kornberg LJ. Focal adhesion kinase and its potential involvement in tumor invasion and metastasis. Head Neck, 1998, 20(8): 745-752
13 Owens LV, Xu L, Dent GA, et al. Focal adhesion kinase as a marker of invasive potential in differentiated human thyroid cancer. Ann Surg Oncol, 1996,3(1): 100-105.
14 Fukai Y, Masuda N, Manda R, et al. FAK overexpression is correlated with tumour invasiveness and lymph node metastasis in oesophageal squamous cell carcinoma. Br J Cancer, 2003, 89(1): 140-145
15 Hsia DA, Mitra SK, Hauck CR, et al. Differential regulation of cell motility and invasion by FAK. J Cell Biol, 2003, 160(5): 753-767
16 Schneider GB, Kurago Z, Zaharias R, et al. Elevated focal adhesion kinase expression facilitates oral tumor cell invasion. Cancer, 2002, 95(12): 2508-2515
17 weiner TM, Liu ET, Craven RJ, et al. Expression of focal adhesion kinase gene and invasive cancer. Lancet, 1993, 342(8878): 1024-1025
18 Michael DS.Biochemical signals and biological responses elicited by the focal adhesion kinase.Biochimica et Biophysica Acta, 2001, 1540 (1): 1—21
19 Owens LV, Xu L, Craven RJ, et al.Overexpression of the focal adhesion kinase (p125FAK) in invasive human tumors. Cancer Res, 1995, 55(13): 2752-2755
20 Kahana O,Micksche M,Witz IP, et al.The focal adhesion kinase (P125FAK)is constitutively active in human malignant melanoma. Oncogene,2002,21(25):3969—3977
21 Rodina A, Schramm K, Musatkina E,et al.Phosphorylation of p125FAK and paxillin focal adhesion proteins in src-transformed cells with different metastatic capacity. FEBS Lett, 1999, 455(1-2): 145-148
22 Moritake H, Sugimoto T, Kuroda H, et al. Newly established Askin tumor cell line and overexpression of focal adhesion kinase in Ewing sarcoma family of tumors cell lines. Cancer Genet Cytogenet, 2003,146(2): 102-109
23 苏剑敏，桂律．周逸平．等．粘着斑激酶在肿瘤中的表达及其临床意义．中国肿瘤，2002，11(11)：670—672
24 Ruest PJ,Roy S,Shi E, et al. Phosphospecific antibodies reveal focal adhesion kinase activation loop phosphorylation in nascent and mature focal adhesion and requirement for the autophosphorylation site. Cell Growth Differ, 2000,11 (1): 41-48
25 Cary LA, Chang JF, Guan JL. Stimulation of cell migration by overexpression of focal adhesion kinase and its association with Src and Fyn. J Cell Sci, 1996,109 (7): 1787-1794
26 Hauck CR, Hunter T, Schlaepfer DD. The v-Src SH3 domain facilitates a cell adhesion-independent association with focal adhesion kinase. J Biol Chem, 2001, 276(21): 17653-17662
27 Walsh MF, Thamilselvan V, Grotelueschen R, et al. Absence of adhesion triggers differential FAK and SAPKp38 signals in SW620 human colon cancer cells that may inhibit adhesiveness and lead to cell death. Cell Physiol Biochem, 2003,13(3): 135-146
28 Sonoda Y, Matsumoto Y, Funakoshi M, et al. Anti-apoptotic role of focal adhesion kinase (FAK). Induction of inhibitor-of-apoptosis proteins and apoptosis suppression by the overexpression of FAK in a human leukemic cell line, HL-60. J Biol Chem, 2000, 275(21): 16309-16315
29 Matter ML, Ruoslahti E. A signaling pathway from the alpha5betal and alpha(v)beta3 integrins that elevates bc1-2 transcription. J Biol Chem, 2001, 276(30): 27757-27763
30 Jones RJ, Brunton VG, Frame MC.Adhesion-linked kinases in cancer; emphasis on src, focal adhesion kinase and PI 3-kinase. Eur J Cancer, 2000, 6(13): 1595-1606
31 Zhao JH, Guan JL. Role of focal adhesion kinase in signaling by the extracellular matrix. Prog Mol Subcell Biol, 2000, 25:37-55
32 Mardinger O, Givol N, Talmi YP, et al. Osteosarcoma of the jaw. The Chaim Sheba Medical Center experience. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 2001, 91(4): 445-451
33 Hsia DA, Mitra SK, Hauck CR, et al. Differential regulation of cell motility and invasion by FAK.J Cell Biol, 2003, 160(5): 753-767
34 Thant AA, Nawa A, Kikkawa F, et al. Fibronectin activates matrix metalloproteinase-9 secretion via the MEK1-MAPK and the PI3K-Akt pathways in ovarian cancer cells. Clin Exp Metastasis, 2000,18(5): 423-428
35 Irigoyen JP, Nagamine Y.Cytoskeletal reorganization leads to induction of the
urokinase-type plasminogen activator gene by activating FAK and Src and subsequently the Ras/Erk signaling pathway. Biochem Biophys Res Commun, 1999,262(3): 666-670
36 Kim I, Kim HG, Moon SO, et al. Angiopoietin-1 induces endothelial cell sprouting through the activation of focal adhesion kinase and plasmin secretion. Circ Res, 2000, 86(9): 952-959
37 Besson A, Robbins SM, Yong VW. PTEN/MMAC1/TEP1 in signal transduction and tumorigenesis. Eur J Biochem, 1999,263(3): 605-611
38 Tamura M, Gu J, Takino T. Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: differential involvement of focal adhesion kinase and p130Cas. Cancer Res, 1999, 9(2): 442-449
39 Gautam A, Li ZR, Bepler G. RRMl-induced metastasis suppression through PTEN-regulated pathways. Oncogene, 2003, 2(14): 2135-2142
40 Gu Y, Chen. JS, Zhou XD. Inhibitory effects of antisense focal adhesion kinase oligodeoxynucleotides on the invasion of Bel 7402 hepatocellular carcinoma cells. Zhonghua Gan Zang Bing Za Zhi, 2003,11(10):612-615.
41 Saito Y, Swanson X, Mhashilkar AM, et al. Adenovirus-mediated transfer of the PTEN gene inhibits human coiorectal cancer growth in vitro and in vivo. Gene Ther, 2003, 10(23): 1961-1969
42 官国先，寿楠海．粘着斑激酶反义寡核苷酸与胃癌细胞生长及凋亡的关系．山东医药，2001，041(014)：1-3
43 Bezzi M, Hasmim M, Bieler G, et al. Zoledronate sensitizes endothelial cells to tumor necrosis factor-induced programmed cell death: evidence for the suppression of sustained activation of focal adhesion kinase and protein kinase B/Akt. J Biol Chem, 2003,278(44): 43603-43614
44 Arii S, Mise M, Harada T, et al. Overexpression of matrix metalloproteinase 9 gene in hepatocellular carcinoma with invasive potential. Hepatology, 1996, 24(2): 316-322
45 Gokaslan ZL, Chintala SK, York JE, et al. Expression and role of matrix metalloproteinases MMP-2 and MMP-9 in human spinal column tumors. Clin Exp Metastasis, 1998,16(8): 721-728
46 Davies B, Waxman J, Wasan H, et al. Levels of matrix metalloproteases in bladder cancer correlate with tumor grade and invasion. Cancer Res, 1993, 53(22): 5365-5369
47 许克新，侯树坤，杜志军．检测金属基质蛋白酶及其抑制物对判断膀胱癌浸润和转移的意义．中华泌尿外科杂志，2002,23(4)：231-233
48 张云锋，王作仁，牛新捷．胆囊癌中基质金属蛋白酶-9、粘附分子CD44变构体6表达及其临床意义．中华泌尿外科杂志，2002，23(4)：405-406
49 郭文忠，冉宇靓，王贵齐．VEGF和MMP-9在食管癌中的表达及低氧调节．中华肿瘤杂志，2002，24(1)：44-47
50 Sopata I, Dancewicz AM. Presence of a gelatin-specific proteinase and its latent form in human leucocytes. Biochim Biophys Acta, 1974,370(2): 510-523
51 Iwata H, Kobayashi S, Iwase H, et al. Production of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human breast carcinomas. Jpn J Cancer Res, 1996,87(6): 602-611
52 Ueda Y, Imai K, Tsuchiya H, et al. Matrix metalloproteinase 9 (gelatinase B) is expressed in multinucleated giant cells of human giant cell tumor of bone and is associated with vascular invasion. Am J Pathol, 1996, 148(2): 611-622
53 Schoedel KE, Greco MA, Stetler-Stevenson WG, et al. Expression of metalloproteinases and tissue inhibitors of metalloproteinases in giant cell tumor of bone: an immunohistochemical study with clinical correlation. Hum Pathol, 1996, 27(11): 1144-1148
54 Nakano A, Tani E, Miyazaki K, et al. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in human gliomas. J Neurosurg, 1995, 83(2): 298-307
55 Ashida K, Nakatsukasa H, Higashi T, et al. Cellular distribution of 92-kd type Ⅳ collagenase/gelatinase B in human hepatocellular carcinoma. Am J Pathol, 1996, 149(6): 1803-1811
56 Bernhard EJ, Gruber SB, Muschel RJ. Direct evidence linking expression of matrix metalloproteinase 9 (92-kDa gelatinase/collagenase) to the metastatic phenotype in transformed rat embryo cells. Proc Natl Acad Sci U S A, 1994, 91(10): 4293-4297
57 Itoh T, Tanioka M, Matsuda H, et al. Experimental metastasis is suppressed in MMP-9-deficient mice. Clin Exp Metastasis, 1999, 17(2): 177-181
58 Himelstein BP, Asada N, Carlton MR, et at Matrix metalloproteinase-9 (MMP-9) expression in childhood osseous osteosarcoma. Med Pediatr Oncol, 1998, 31(6): 471-474
59 Soderstrom M, Aro HT, Ahonen M, et al. Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human chondrosarcomas. APMIS, 2001, 109(4): 305-315
60 Kido A, Tsutsumi M, Iki K, et al. Overexpression of matrix metalloproteinase (MMP)-9 correlates with metastatic potency of spontaneous and 4-hydroxyaminoquinoline 1-oxide (4-HAQO)-induced transplantable osteosarcomas in rats. Cancer Lett, 1999, 137(2): 209-216
61 Rechberger T, Postawski K, Skorupski P, et al. Local activity of matrix metalloproteinases in a case of botryoid sarcoma. Eur J Obstet Gynecol Reprod Biol, 1996,67(2): 169-172
62 Kawashima A, Nakanishi I, Tsuchiya H, et al. Expression of matrix metalloproteinase 9 (92-kDa gelatinase/type Ⅳ collagenase) induced by tumour necrosis factor alpha correlates with metastatic ability in a human osteosarcoma cell line. Virchows Arch, 1994, 424(5): 547-552
63 Lakka SS, Gondi CS, Yanamandra N, et al. Synergistic down-regulation of urokinase plasminogen activator receptor and matrix metalloproteinase-9 in SNB19 glioblastoma cells efficiently inhibits glioma cell invasion, angiogenesis, and tumor growth, Cancer Res, 2003, 63(10): 2454-2461
64 Liu G, Shuman MA, Cohen RL. Co-expression of urokinase, urokinase receptor and PAI-1 is necessary for optimum invasiveness of cultured lung cancer cells. Int J Cancer, 1995, 60(4): 501-506
65 Schmalfeldt B, Kuhn W, Reuning U, et al. Primary tumor and metastasis in ovarian cancer differ in their content of urokinase-type plasminogen activator, its receptor, and inhibitors types 1 and 2. Career Res, 1995,55(18): 3958-3963
66 Achbarou A, Kaiser S, Tremblay G, et al. Urokinase overproduction results in increased skeletal metastasis by prostate cancer cells in vivo. Cancer Res, 1994, 54(9): 2372-2377
67 Foekens JA, Peters HA, Look MP, et al. The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients. Cancer Res, 2000,60(3): 636-643
68 Yang JL, Seetoo D, Wang Y, et al. Urokinase-type plasminogen activator and its receptor in colorectal cancer: independent prognostic factors of metastasis and cancer-specific survival and potential therapeutic targets. Int J Cancer, 2000, 89(5): 431-439
69 He C, He P, Liu LP, et al. Analysis of expressions of components in the plasminogen activator system in high-and low-metastatic human lung cancer cells. J Cancer Res Clin Oncol, 2001, 127(3): 180-186
70 刘刚，李金荣．口腔鳞癌组织中尿激酶型纤溶酶原激活剂及其抑制剂活性与颈淋巴结转移的关系．临床口腔医学杂志，1999，15(1)：12-13
71 李杰恩，徐志文，陈显新．鼻咽癌尿激酶型纤溶酶原激活物及VEGF表达与侵袭转移关系．肿瘤防治研究，2001，28(5)：359-360
72 肖继平，张广德，夏文华，等．乳腺瘤中尿激酶型纤溶酶原激活物的过度表达．实用癌症杂志，1999，14(4)：261-262
73 Choong PF, Ferno M, Akerman M, et al. Urokinase-plasminogen-activator levels and prognosis in 69 soft-tissue sarcomas. Int J Cancer ,1996, 69 (4):268-272
74 Hackel C, Czerniak B, Ayala AG, et al. Expression of plasminogen activators and plasminogen activator inhibitor 1 in dedifferentiated chondrosarcoma. Cancer, 1997, 79(1): 53-58
75 Gokaslan ZL, Chintala SK, York JE, et al. Expression and localization of urokinase-type plasminogen activator in human spinal column tumors. Clin Exp Metastasis, 1998, 16(8): 713-719
76 Meade-Tollin LC, Way D, Witte MH.Expression of multiple matrix metalloproteinases and urokinase type plasminogen activator in cultured Kaposi sarcoma cells. Acta Histochem, 1999, 101(3): 305-316
77 Fisher JL, Mackie PS, Howard Ml et al. The expression of the urokinase plasminogen activator system in metastatic murine osteosarcoma: an in vivo mouse model. Clin Cancer Res, 2001, 7(6): 1654-1660
78 Morii T, Yabe H, Morioka H, et al. Prognostic relevance of urokinase type plasminogen activator, its receptor and inhibitors in chondrosarcoma. Anticancer Res, 2000, 20(5A): 3031-3036
79 McCawley LJ, Matrisian LM. Matrix metalloproteinases: multifunctional contributors to
tumor progression. Mol Med Today, 2000, 6(4): 149-156
80 Irigoyen JP, Munoz-Canoves P, Montero L, et al. The plasminogen activator system: biology and regulation. Cell Mol Life Sci, 1999, 56(1-2): 104-132
81 Irigoyen JP, Besser D, Nagamine Y. Cytoskeleton reorganization induces the urokinase-type plasminogen activator gene via the Ras/extracellular signal-regulated kinase (ERK) signaling pathway. J Biol Chem, 1997, 272(3): 1904-1909
82 Shin M, Yan C, Boyd D. An inhibitor of c-jun amino terminal kinase (SP600125) represses c-Jun activation, DNA-binding and PMA-inducible 92-kDa type Ⅳ collagenase expression. Biochim Biophys Acta, 2002, 1589(3):311-316
83 Sein TT, Thant AA, Hiraiwa Y, et al. A role for FAK in the Concanavalin A-dependent secretion of matrix metalloproteinase-2 and-9. Oncogene, 2000, 19(48): 5539-5542
84 Shibata K, Kikkawa F, Nawa A, et al. Both focal adhesion kinase and c-Ras are required for the enhanced matrix metalloproteinase 9 secretion by fibronectin in ovarian cancer cells. Cancer Res, 1998, 58(5): 900-903