摘要
目的:本课题通过免疫组化SP法,检测胰岛素生长因子1受体(IGF-1R)和尿激酶型纤溶酶原活化因子(u-PA)在喉咽癌组织及癌旁喉咽黏膜组织中的表达,并将IGF-1R与u-PA在喉咽癌组织中的表达进行相关性分析,探讨IGF-1R与u-PA在喉咽癌发生、发展、浸润和转移中的作用以及它们在喉咽癌浸润转移中的相互关系,为喉咽癌的诊断、治疗和预后判断提供参考依据。
材料与方法:采用免疫组织化学SP法,分别检测55例喉咽癌组织、42例癌旁喉咽黏膜组织及40例会厌囊肿粘膜组织中IGF-1R蛋白和u-PA蛋白的表达情况。采用SPSS11.0统计学软件对实验数据进行统计学处理,率的比较采用x2检验,检验标准以α=0.05为显著性检验水准。
结果:①IGF-1R在喉咽癌组织、癌旁喉咽粘膜组织及会厌囊肿粘膜组织中的阳性表达率分别为81.82%,52.38%和17.50%,3组间两两比较,差异均有统计学意义(P<0.01);在阳性表达组织中,3组的强阳性率分别为72.72%,30.95%和2.50%,3组间两两比较,差异亦均有统计学意义(P<0.01)。②u-PA在喉咽癌组织、癌旁喉咽粘膜组织及会厌囊肿粘膜组织中的阳性表达率分别为85.45%,42.86%和20.00%,3组间两两比较,差异均有统计学意义(P<0.05);在阳性表达组织中,3组的强阳性率分别为76.36%,23.81%和2.50%,3组间两两比较,差异亦均有统计学意义(P<0.01)。③IGF-1R在喉咽癌有淋巴结转移组和无淋巴结转移组中的强阳性表达率分别为82.61%和22.22%,二者之间差异有统计学意义(P<0.01)。④u-PA蛋白在喉咽癌有淋巴结转移组和无淋巴结转移组中的强阳性表达率分别为78.26%和44.44%,二者之间差异有统计学意义(P<0.01)。⑤IGF-1R在3年内存活组和死亡组中的阳性表达率分别为76.92%和88.89%,二者之间差异没有统计学意义(P>0.05)。⑥u-PA在3年内存活组和死亡组中的阳性表达率分别为84.62%和88.89%,二者之间差异没有统计学意义(P>0.05)。⑦IGF-1R在5年内存活组和死亡组中的阳性表达率分别为75.00%和86.67%,二者之间差异没有统计学意义(P>0.05)。⑧u-PA在5年内存活组和死亡组中的阳性表达率分别为75.00%和80.00%,二者之间差异没有统计学意义(P>0.05)。⑨45例IGF-1R蛋白阳性表达的喉咽癌组织中42例u-PA蛋白呈阳性表达;10例IGF-1R蛋白阴性表达的喉咽癌组织中5例u-PA蛋白亦呈阴性表达,二者在喉咽癌组织中的表达有明显的相关性(P<0.01)。
结论:1.IGF-1R蛋白和u-PA蛋白的阳性表达率在喉咽癌组织中显著增高,在癌旁组中的表达高于在对照组中的表达,提示IGF-1R和u-PA在喉咽癌组织中高表达与喉咽癌的发生发展有关。
2.IGF-1R蛋白和u-PA蛋白的强阳性表达与喉咽癌有无淋巴结转移明显相关,检测喉咽癌组织中IGF-1R和u-PA的表达,可能有助于估计喉咽癌淋巴结转移。
3.喉咽癌组织中IGF-1R表达与u-PA表达呈正相关,推测两者可能在喉咽癌发生、发展以及淋巴结转移中起了协同作用。
Objective:This research subject investigates, through immunohistichemistry SP method, the expressions of IGF-1R protein and u-PA protein in the tissue of laryngopharynx carcinoma and in the tissue adjacent to cancer, so as to discusses its mechanism of pathogenesis, development, invasion and metastasis, to find an useful indicator for early diagnosis of laryngopharynx carcinoma and pxovide the new methods and ideas for therapy and predict the prognosis of laryngopharynx carcinoma.
Materials and methods:By adopting immunohistichemistry SP method, the expressions of IGF-1R protein and u-PA protein in the tissue of 55 laryngopharynx carcinoma cases, 42 adjacent to cancer cases and 40 epiglottis cyst cases were detected. All the datas were analyzed by SPSS 11.0 statistical software. The comparison of positive rates uses the Chi-square and Fisher, Statistically significant level was considered as "alpha equals 0.05".
Results:①The rates of positive expression of IGF-1R protein in the tissue of laryngopharynx carcinoma, in the tissue adjacent to cancer and in the tissue of epiglottis cyst are 81.82%, 52.38% and 17.50% respectively, the difference between any two group is significant (P<0.01); The rates of powerful positive expression of IGF-1R protein in the positive expression are 72.72%, 30.95% and 2.50% respectively, the difference between any two is significant(P<0.01).②The rates of positive expression of u-PA protein in the tissue of laryngopharynx carcinoma, in the tissue adjacent to cancer and in the tissue of epiglottis cyst are 85.45%, 42.86% and 20.00% respectively,the difference between any two group is significant (P<0.01); The rates of powerful positive expression of u-PA protein in the tissue of laryngopharynx carcinoma, in the tissue adjacent to cancer and in the tissue of epiglottis cyst are 76.36%, 23.81% and 2.50% respectively, the difference between any two group is significant(P<0.01).③The rates of powerful positive expressions of IGF-1R protein in the tissue of metastasis and non-metastasis are 82.61% and 22.22% respectively. The difference in the two groups has statistical significance(P<0.01).④The rates of powerful positive expressions of u-PA protein in the tissue of metastasis and non-metastasis are 78.26% and 44.44% respectively. The difference in the two groups has statistical significance(P<0.01). ⑤The rates of positive expressions of IGF-1R protein in the groups of the 3-year survival and 3-year death are 76.92% and 88.89% respectively. The difference in the two groups has no statistical significance(P>0.05).⑥The rates of positive expressions of u-PA protein in the groups of the 3-year survival and 3-year death are 84.62% and 88.89% respectively. The difference in the two groups has no statistical significance(P>0.05).⑦The rates of positive expressions of IGF-1R protein in the groups of the 5-year survival and 5-year death are 75.00% and 86.67% respectively. The difference in the two groups has no statistical significance(P>0.05).⑧The rates of positive expressions of u-PA protein in the groups of the 5-year survival and 5-year death are 75.00% and 80.00% respectively. The difference in the two groups has no statistical significance(P>0.05).⑨There are 42 positive expressions of u-PA protein cases in the 45 positive expressions of IGF-1R protein cases. There are 5 negative expressions of u-PA protein cases in the 10 negative expressions of IGF-1R protein cases. The IGF-1R expression was closely correlated with the u-PA expression(P<0.01).
Conclusions: 1. The rates of positive expressions of IGF-1R protein and u-PA protein are obviously increase in the tissue of laryngopharynx carcinoma, and in the tissue adjacent to cancer are higher than in the tissue of epiglottis cyst, . It is pointed out that IGF-1R and u-PA take part in the pathogenesis and development of laryngopharynx carcinoma.
2.The powerful positive expressions of IGF-1R protein and u-PA protein obviously concern the lymph node metastasis. It indicated that the detection of IGF-1R and u-PA in the tissue of laryngopharynx carcinoma might be helpful to estimate the lymphatic metastasis of laryngopharynx carcinoma.
3.The IGF-1R expression was closely correlated with the u-PA expression,which suggested that IGF-1R and u-PA played a positive role to each other in course of pathogenesis, development, invasion and metastasis of laryngopharynx carcinoma.
引文
[1] Werner H. Dysregulation of the type 1 IGF receptor as a paradigm in tumor progression. Mol cell endocrinol, 1998, 146(1-2): 213.
[2] Blakesley VA, Stannard BS, Kalebic T, et al. Role of the IGF-1 receptor in mutagensis and tumor promotion. J Endocrin , 1997, 152 (2) :339-334.
[3] Bermont L, Lamiclle F, Fauconnet S, et al. Regulation of vascular endothelial growth factor expression by insulin-like growth factors 1 in endometrial adenocarcinoma cells. Int J Cancer, 2000, 85(1): 117-123.
[4] Dunn SE, Torres JV, Oh JS, et al. Up-regulation of urokinase-type plasminogen activator by insulin-like growth factors 1 depends upon phosphatidylinositol-3. kinase and mitogenactivated protein kinsae.Cancer Res, 2001, 61(4):1367-1374.
[5] Dunn SE, Ehrlich M, Sharp NJ, et al. A dominant negative nutant of the insulin-like growth factors 1 receptor inhibits the adhesion, invasion and metastasis of breast cancer. Cancer Res, 1998, (58):3353-3361.
[6] Roldan AL, Lbbellis MV, Masucci MT, et al. Cloning and expression of the receptor for human urokinase plasminogen activator a central molecule in cell surface plasmin dependent proteolysis. EMBO J, 1990, 9(2) : 467-474.
[7] Bustin SA, Jenkins PJ. The growth hormone-insulin-like growth factor-1 axis and colorectal cancer. Trends Mol Med, 2001, 7(10):447-454.
[8] Daws MR, Westley BR, May FE. Paradoxical effects of overexpression of the type I insulin-like growth factor (IGF) receptor on the responsiveness of human breast cancer cells to IGFs and estradiol. Endocrinology, 1996,137(4): 1177-1186.
[9] Weber MM, Fottner C, Liu SB, et al. Overexpression of the insulin-like growth factor 1 receptor in human colon carcinomas. Cancer,2002, 95 (10) : 2086-2095.
[10] Favoni RE, de Cupis A, Ravera F, et al. Expression and function of the insulin-like growth factor I system in human non-small-cell lung cancer and normal lung cell lines. Int J Cancer, 1994, 56(6): 858-866.
[11] He C, He P, Liu LP, et al. Analysis of expression of components in the plasminogen activator system in high and low metastasis human lung cancer cells. Cancer Res Clin On, 2001, 127(3): 180-186.
[12] Duggan C, Maguire T, Mcdermott E, et al. Urokinase plasminogen activator andurokinase plasminogen activator receptor in breast cancer.Int J Cancer, 1995, 61(5):597-600.
[13] Yang JL, Seetoo D, Wang Y, et al. Urokinase-type plasminogen activator and its receptor in colorectal cancer : independent prognostic factors of me-tastasis and cancer-specific survival and potential therapeutic targets. Int J Cancer, 2000, 89(5): 431-439.
[14] Gross JL, Behrens DL, Mullins DE, et al. Plasminogen activator and inhibitor activity in human gliomas and modulation by sodium butyrate.Cancer Res, 1998, 48(2): 291-296.
[15] Wu Y, Yakar S, Zhao L, et al. Circulating insulin-like growth factor-1 levels regulate colon cancer growth and metastasis. Cancer Res, 2002,62(4): 1030-1035.
[16] Ullrich A, Gray A, Tam AW, et al. Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity. EMBO J, 1986, 5(10):2503-2512.
[17] Jone JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biologicalactions. Endocrine Review, 1995, 16(1): 3-34.
[18] Navarro M, Baserga R. Limited redundancy of survival signals from the type 1 insulin-like growth factor receptor. Endocrinology, 2001, 142(3) :1073-1081.
[19] Werner H, Woloschak M, Adamo M, et al. Developmental regulation of the rat insulin-like growth factor 1 receptor gene. Proc Natl Acad Sci USA,1989, 86(19) : 7451-7455.
[20] Resnicoff M, Burgaud JL, Rotman HL, et al. Correlation between apoptosis, tumorigenesis,and levels of insulin like growth factor 1 receptors.Cancer Res,1995,55(17):3739-3741.
[21]Rubini M,Hongo A,Dambrosio C,et al.The IGF-1 receptor in mitogenesis and transformation of mouse embryo cells:role of receptor number.Exp Cell Res,1997,230(2):284-292.
[22]Happerfeild LC,Mile DW,Barnes DM,et al.The localization of the insulin-like growth factor receptor 1(IGF-1R) in benign and malignant breast tissue.J Pathol,1997,183(4):412-417.
[23]Antoniades HN,Galanopoulous T,Neville—Golden J,et al.Expression of insulin-like growth factors Ⅰ and Ⅱ and their receptor mRNAs in primary human astrocytomas and meningiomas;in vivo studies using in situ hybridization and immunocytochemistry.Int J Cancer.1992,50(2):215-222.
[24]周平,周子成,陈文生,等.IGF-IR在肝癌及癌旁肝组织中的表达及其临床意义.第三军医大学学报,2001,23(10):1245-1246.
[25]Long L,Rubin R,Brodt P,et al.The localization of the Insuline-like growth factor Ⅰ receptor in benign and malignant breast tissue.Exp Cell Res,1998,58(238):116-121.
[26]赵明东,胡雪梅,孙殿敬,等.胰岛素样生长因子-1及其受体在胃癌发生发展中的作用.肿瘤防治杂志,2004,11(1):46-48.
[27]Kaleko M,Rutter WJ,Miller AD.Overexpression of the human insulin-like growth fact-Ⅰ receptor promotes ligand-dependent neoplastic transformation.Mol Cell Biol,1990,10(2):463-473.
[28]Prater D,Li HL,Asa S,et al.Dominant negative inhibition of tumorigenesis in vivo by human insuline-like growth factor 1 receptor mutant.Proc Natl Acad Sci USA,1994,91(6):2181-2185.
[29]Yee D,Favoni RE,Levovic GS,et al.Insulin-like factor Ⅰ expression by tumors of neuroectodermal origin with the t(11;22) chromosomal translocation.A potential autocrine factor.J Clin Invest,1990,86(6):1806-1814.
[30] Happerfield LC, Miles DW, Barnes DM, et al. The localization of the insulin-like growth factor receptor I (IGFR-I)in benign and malignant breast tissues. Pathol, 1997, 183(4): 412-417.
[31] Liotta L, Sterler-Stevenson W. Tumor invasion and matastasis: an imbalance of positive and negative regulation. Cancer Res, 1991, 51(18):5054-5059.
[32]Dunn SE, Torres JV, Oh JS, et al. Up-regulation of urokinase-type plasminogen activator by insulin-like growth factor-I depends upon phosphatidylinositol-3 kinase and mitogen-activated protein kinase kinase. Cancer Res, 2001, 61(4): 1367-1374.
[33] Bennont L, Lamielle F, Fauconnet S, et al. Regulation of vascular endothelial growth factor expression by insulin-like growth factor-1 in endometrial adenocarcionma cells. Int J Cancer, 2000, 85(1): 117-123.
[34]Dunn SE, Ehrlich M, Sharp NJ, et al .A dominant negative mutant of the insulin-like growth factor-I receptor inhibits the adhesion, invasion,and metastasis of breast cancer. Cancer Res, 1998, 58(15): 3353-3361.
[35] Peter B, Van Waarde MA, Vissink A, et al. Degranulation of rat salivary glands following treatment with receptor-selective agonists. Clin Exp Pharmacol Physiol, 1995, 22(5):330-336.
[36] Long L, Rubin R, Brodt P. Enhanced invasion and liver colonization by lung carcinoma cells overexpressing the type 1 insulin-like growth factor receptor. Exp Cell Res, 1998, 238(1): 116-121.
[37] Rajput B, Degen SF, Reich E, et al .Chromosomal locations of human tissue plasminogen activator and urokinase genes. Science, 1985, 230(4726):672-674.
[38] Pannell R, Gurewich V. Activation of plasminogen by single-chain urokinase or by two-chain urokinase a demonstration that single-chain urokinase has a low catalytic activity (pro-urokinase). Blood, 1987,69(1) : 22-26.
[39] Appella E, Robinson EA, Ullrich SJ, et al. The receptor-binding sequence of urokinase.A biological function for the growth-factor module of proteases.J Biol them,1987,262(10):4437-4440.
[40]Patthy L.Evolution of the proteases of blood coagulation and fibrinolysis by assembly from modules.Cell,1985,41(3):657-663.
[41]Bowen RM,Hoidal JR,Estensen RD.Urokinase-type plasminogen activator in alveolar macrophages and bronchoalveolar lavage fluid from normal and smoke-exposed hamsters and humans.J Lab Clin Med,1985,106(6):667-673.
[42]Roldan AL,Cubellis MV,Masucci MT,et al.Cloning and expression of the receptor for human urokinase plasminogen activator,a central molecule in cell surface plasmin dependent proteolysis.EMBO J,1990,9(2):467-474.
[43]Visscher DW,Sarkar F,Lorusso P,et al.Immunohistologic evaluation of invasion—associated proteases in breast carcinoma.Mod Pathol,1993,6(3):302-306.
[44]Solomayer EF,Diel IJ,Wallwiener D,et al.Prognostic relevance of urokinase plasminogen activator detection in micrometastatic cells in the bone marrow of patients with primary breast cancer.Br J Cancer,1997,76(6):812-818.
[45]Tanaka N,Fukao H,Ueshima S,et al.Plasminogen activator inhibitor Ⅰ in human carcinoma tissues.Int Cancer,1991,48(4):481-484.
[46]Kohler L,Hiller K,Martin R,et al.Tumor-associated proteolytic factors uPA and PAI-1 in endometrial carcinoma Eur[J].Gynecol Oncol,1997,66(2):268-274.
[47]步星耀,章翔,陈恩志,等.尿激酶型纤溶酶原激活因子基因与胶质瘤的侵袭及预后的关系.肿瘤,1999,19(4):223-225.
[48]刘大林,陈国玉,夏建国,等.尿激酶型纤溶酶原激活物与胃癌侵袭及转移关系的研究.南京医科大学学报,2001,21(5):393-395.
[49]杨进益,李韶,周荣祥,等.尿激酶型纤溶原激活物及其受体在膀跳移行细胞癌中表达的意义.中华泌尿外科杂志,2000,21(8):465-466.
[50]陈淑勤,黄培生,李一伟,等.尿激酶型纤溶原激活物在鼻咽癌的表达及临床意义.福建医科大学学报,2002,36(1):36-38.
[51]Volm M,Mattern J,Koomagi R.Relationship of urokinase and urokinase receptor in non-small cell lung cancer to proliferation,angiogenesis,metastasis and patient survival.Oncol Rep,1999,6(3):611-615.
[52]孙达春,刘文励.恶性肿瘤患者血液中尿激酶型纤溶酶原激活物系统测定的临床意义.临床内科杂志,2000,17(3):157-158.
[53]端木建华,庞琦,徐广明.脑膜瘤周血管源性脑水肿与血管内皮细胞生长因子的关系.齐鲁医学杂志,2002,17(1):7-9.
[54]He C,He P,Liu LP,et al.Analysis of expression of components in the plasminogen activator system in high and low metastasis human lung cancer cells.Cancer Res Clin Onc,2001,127(3):180-186.
[55]Duggan C,Maguirer,Mcdermott E,et al.Urokinase plasminogenactivator and urokinase plasminogen activator receptor in breast cancer.Int J Cancer,1995,61(5):597-600.
[56]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.
[57]Gross JL,Behrens DL,Mullins DE,et al.Plasminogen activator and inhibitor activity in human gliomas and modulation by sodium butyrate.Cancer Res,1998,48(2):291-296.
[58]Festuccia C,Dolo V,Gueerra F,et al.Plasminogen activator system modulates invasive capacity and proliferation in prostatic tumor cells.Clin Exp Metastasis,1998,16(6):513-528.
[59]梁新华,毛祖彝,何永文,等.尿激酶型纤溶酶原激活物在口腔鳞癌中的表达及意义.华西口腔医学杂志,2003,21(2):147-149.
[60]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 therapentic targets. Int Cancer,2000,89(5):431-439.
[61]Peverali FA,Mandriota SJ,Ciana P,et al.Tumoa cells secret an angiogenis factor that stimulates basic fibroblast growth factor and urokinase expression invascular endothelial cell.J Cell Physiol,1994,161(1):1-4.
[62]Hsu DW,Efird Jr,Hedley-Whyte ET.Prognostic role of urokinase type plasminogen activator in human gliomas.Am J Pathol,1995,147(1):114-123.
[63]Dunn SE,rorres JV,Oh JS,et al.Up-regulation of urokinase-type plasminogen activator by insulin-like growth factor-1 depends upon phosphatidylinositol-3 kinase and mitogen-activated protein kinase kinase.Cancer Res,2001,61(4):1367-1374.
[64]Peter B,Van Waarde MA,Vissink A,et al.Degranulation of rat salivary glands following treatment with receptor-selective agonists.Clin Exp Pharmacol Physiol,1995,22(5):330-336.
[65]郑新华,赵秋民,陈奎生,等.食管鳞癌组织中胰岛素样生长因子-1受体的表达.郑州大学杂志,2005,40(2):273-275.
[66]闫亮,张云汉,陈奎生,等.食管鳞癌中uPA,P-选择素、nm23,p27的表达及其与浸润转移关系的研究.郑州大学学报(医学版),2004,39(2):202-204.
[67]Farinati F,Herszenyi L,Plebani M,et al.Increased levels of cathepsin B and L,urokinase-type plasminogen activator and its inhibitor type-1 as an early event in gastric carcinogenesis.Carcinogenesis,1996,17(12):2581-2587.
[68]Yamamoto M,Sawaya R,Mohanam S,et al.Expression and localization of urokinase-type plasminogen activator in human astrocytomas in vivo.Cancer Res,1994,54(14):3656-3661.
[1]刘宝英.胰岛素样生长因子研究进展.国外医学分子生物学分册,1996,18(3):103-108.
[2]Rajaram S,Baylink DJ,Mohan S.Insulin-like growth factor-binding proteins in serum and other binlogical fluids:regulation and functions.Endocr Rev,1997,18(6):801-831.
[3]张力,李树浓.胰岛素样生长因子-1.国外医学、生理、病理科学与临床分期,1997,17(2):174-177.
[4]周最明.IGF-2在肝癌中的异常表达及其意义.临床肝胆病杂志,1997,13(1):12-14.
[5]Akmal SN,Yun K,Higami Y,et al.Insulin-like growth factor 2 and insulin-like growth factor binging protein 2 expression in hepatoblastoma.Hum Pathol,1995,26(8):846-851.
[6]潘世扬.胰岛素样生长因子受体表达与肿瘤细胞生长和转移.国外医学生理、病理科学与临床分册,1999,19(4):304-306.
[7]Favoni RE,de Cupis A,Revere F et al.Expression and function of the insulin-like growth factor 1 system in human non-small-cell lung cancer and normal lung cell lines.Int J Cancer,1994,56(6):858-866.
[8]Su Q,Liu YF,Zhang JF et al.Expression of insulin-like growth factor Ⅱ in hepatitis B,liver cirrhosis and hepatocellular carcinoma,its relationship with hepatitis B virus antigen expression.Hepatology,1994,20(4):788-799.
[9]than JM,Stampfer MJ,Ma J,et al.Insulin-like growth factor-Ⅰ(IGF-Ⅰ) and IGF binding protein-3 as predictors of advanced-stage prostate cancer.Natl Cancer Inst,2002,94(14):1099-1106.
[10]Manousos O,Souglakos J,Bosetti C,et al.IGF-1 and I6F-2 in relation to colorectal cancer.Int J Cancer,1999,83(1):15-17.
[11]Wang ZH,Ma JX,Zeng BJ,et al.Correlation of glioma cell regression with inhitition of insulin-like growth factor 1 and insulin-like growth factor-hinging protein 2expression.Neuroendocrinology,1997,66(1):203-211.
[12]Kappel CC,Velez Yanguas MC,Hirschfeid S,et al.Human osteosarcoma cell lines are dependent on insulin-like growth factor 1 for in vitro growth.Cancer Res,1994,54(13):2803-2807.
[13]周廷冲,马贤凯,唐佩弦,等.多肽生长因子基础与临床.北京:中国科学技术出版社,1992,187-205.
[14]徐军,罗南萍,杨道理,等.IGF-2与TGF-a变化对肝癌与肝硬化的诊断价值.放射免疫学杂志,1999,12(4):199-201.
[15]Norstedt G,Levinovitz A,Mdler C,et al.Expression of insuline-like growth factor 1 and 2 mRNA during hepatic development proliferation and carcinogenesis in the rat.Carcinogenesis,1988,9(2):209-213.
[16]Muller S,Zirkel D,Westphal M,et al.Genomic imprinting of IGF2 and H19 in human meningiomas.Eur J Cancer,2000,36(5):651-655.
[17]覃汉荣,杨冬华,范子荣,等.改良胶体金免疫电镜技术检测IGF-2在肝癌组织中的表达.中华消化杂志,1999,19(2):128-129.
[18]Manousos O,Souglakos J,Bosetti C,et al.IGF-1 and IGF-2 in relation to colorectal cancer.Int J Cancer,1999,83(1):15-17.
[19]陈春生,刘恩卿,王宇令.结直肠癌患者血清IGF-Ⅱ和TGF-a水平变化的研究.中国医科大学报,2001,30(3):197-198.
[20]周平,周子成,陈文生,等.IGF-IR在肝癌及癌旁组织中的表达及其临床意义.第三军医大学学报,2001,23(10):1245-1246.
[21]Stewart CE,Rotwein P.Growth,differentiation,and survival:multiple physiological functions for insulin-like growth factors.Physiol Rev,1996,76(4):1005-1026.
[22]Grimberg A,Cohen P.Role of insulin-like growth factors and their binding proteins in growth control and carcinogenesis.J Cell Physiol,2000,183(1):1-9.
[23]牛朝诗.IGF-IR与细胞增殖、凋亡和肿瘤.国外医学.生理、病理科学与临床分册,2000,20(3):212-215.
[24]Coppola D,Saunders B,Fu I,et al.The insulin-like growth factor Ⅰ receptor induces transformation and tumorigenicity of ovarian mesothelial cells and down-regulates their fas-receptor expression.Cancer Res,1999,59(13):3264-3270.
[25]Kaleko M,Rutter WJ,Miller AD.Overexpression of the human insulinlike growth factor Ⅰ receptor promotes ligand-dependent neoplastic transformation.Mol Cell Biol,1990,10(2):464-473.
[26]Prager D,Li HL,Asa S,Melmed S.Dominant negative inhibition of tumorigenesis in vivo by human insulin-like growth factor Ⅰ receptor mutant.Proc Natl Acad Sci U S A,1994,91(6):2181-2185.
[27]Blakesley VA,Stannard BS,Kalebic T.Role of the IGF-1R in mutagensis and tumor promotion.J Endocrin,1997,152(3):339-344.
[28]Travali S,Reiss K,Ferber A,et al.Constitutively expressed c-myb abrogates the requirement for Insulin-like Growth Factor 1 in 3T3 fibroblasts.Mol Cell Biol,1991,11(2):731-735.
[29]Reiss K,Fer A,Travali S,et al.The protooncogene c-myb increases the expression of Insulin-like Growth Factor 1 and Insulin-like Growth Factor 1 Receptor messenger RNAs by a transcriptional mechanism.Cancer Res,1991,51(21):5997-6000.
[30]Larsson O,Gimita A,Gimita I.Role of insulin-like growth factor 1 receptor signalling in cancer. Br J Cancer, 2005, 92(2):2097-2101.
[31] Gimita L, Gimita A, Larsson O. Mdm2-dependent ubiquitination and degradation of the insulin-like growth factor I receptor. Proc Natl Acad Sci USA, 100(14): 8247-8252.
[32]Ahlen J, Wejde J, Brosjo O, et al. Insulin-like growth factor type I receptor expression correlates to good prognosis in highly malignant soft tissue sarcoma. Clin Cancer Res,2005, 11(1):206-216.
[33] Sun HZ, Wu SF, Tu ZH. Blockage of IGF-IR signaling sensitizes urinary bladder cancer cells to mitomycin- mediated cytotoxicity. Cell Res, 2001, Jun, 11(2): 107-115.
[34] Resnicoff M, Burgaud JL, Rotman HL, et al. Correlation between apoptosis,tumorigenesis, and levels of insulin-like growth factor I receptors. Cancer Res, 1995,55(17):3739-3741.
[35] Liu Y, Lehar S, Corvi C, et al. Expression of the insulin-like growth factor I receptor C terminus as a myristylated protein leads to induction of apoptosis in tumor cells.Cancer Res, 1998,58(3):570-576.
[36] Hongo A, Yumet G, Resnicoff M, et al. Inhibition of tumorigenesis and induction of apoptosis in human tumor cells by the stable expression of a myristylated COOH terminus of the insulin-like growth factor I receptor. Cancer Res, 1998, 58(11):2477-2484.
[37]Pezzino V, Papa V, Milazzo G, et al. Insulin-like growth factor-I (IGF-I) receptors in breast cancer. Ann N Y Acad Sci, 1996, 784:189-201.
[38] Gebauer G, Jager W, Lang N. mRNA expression of components of the insulin-like growth factor system in breast cancer cell lines, tissues, and metastatic breast cancer cells.Anticancer Res, 1998, 18 (2A):1191-1195.
[39] Long L, Rubin R, Baserga R, et al. Loss of the Metastatic phenotype in Murine Carcinoma Cells Expressing an antisene RNA to the insulin-like growth factors 1 receptor. Cancer Res, 1995, 55(5):1006-1009.
[40] Lopez T, Hanahan D. Elevated levels of IGF-1 receptor convey invasive and metastatic capability in a mouse model of pancreatic islet tumorigenesis. Cancer Cell, 2002, 1(4):339-353.
[41] Bennont L, Lamielle F, Fauconnet S, et al. Regulation of vascular endothelial growth factor expression by insulin- like growth factor-1 in endometrial adenocarcionma cells. Int J Cancer, 2000, 85(1):117-123.
[42]DunnSE, Torres JV, Oh JS, et al. Up-regulation of urokinase-type plasminogen activator by insulin-like growth factor-ldepends upon phosphatidylinositol-3 kinase and mitogen-activated protein kinase. Cancer Res, 2001, 61(4): 1367-1374.
[43] Dunn SE, Ehrlich M, Sharp NJ, et al. A dominant negative mutant of the insulin- like growth factor-I receptor inhibits the adhesion, invasion, and metastasis of breast cancer. Cancer Res, 1998, 58(15):3353-3361.
[44] Sachdev D, Li SL, Hartell JS, et al. A chimeric humanized single-chain antibody against the type 1 insulin-like growth factors receptor renders breast cancer cells refractory to the mitogenic effects of IGF-1. Cancer Res, 2003, 63(3):627-635.
[45] Benini S, Manara MC, Baldini N et al. Inhibition of insulin-like growth factors 1 receptor increases the antitumor activity of doxorubicin and vincristine against Ewing's sarcoma cells. Clin Cancer Res, 2001, 7(6):1790-1797.
[46] Gimita A, Gimita I, del Prete F, et al. Cyclolignans as inhibitors of the insulin-like growth factor 1 receptor and malignant cell growth. Cancer Res, 2004, 64(1):236-242.
[47] Camirand A, Lu Y, Pollak M. Co-targeting HER2/ErbB2 and insulin-like growth factors 1 receptor causes synergistic inhibition of growth in HER2-overexpressing breast cancer cells. Med Sci Monit, 2002, 8(12):BR521-526.
[48] Brodt P, Samani A, Navab R. Inhibition of the type I insulin-like growth factor receptor expression and signaling novel strategies for antinestatic therapy. Biochem Phamacol,2000, 60(8):1101-1107.
[49] Macaulay VM. The IGF receptor as anticancer treatment target. Novartis Found Symp,2004, 262: 235-243.
[50] Killian JK, Jirtle RL. Genomic structure of the human M6P/IGF2 receptor. Mamm Genome,1999, 10(1): 74-77.
[51] Morgan DO, Edman JC, Standring DN, et al. Insulin-like growth factor II receptor as a multifunctional binding protein. Nature, 1987, 329(6137): 301-307.
[52] Costello M, Baxter RC, Scott CD. Regulation of soluble insulin-like growth factor II/mannose 6-phosphate receptor in human serum: measurement by enzyme-linked immunosorbent assay. J Clin Endocrinol Metab, 1999, 84(2):611-617.
[53]Dahms NM, Rose PA, Molkentin JD, et al. The bovine mannose 6-phosphate/insulin-like growth factor II receptor. The role of arginine residues in mannose 6-phosphate binding. Biol Chem, 1993, 268(8):5457-5463.
[54] Ludwig T, Eggenschwiler J, Fisher P, et al. Mouse mutants lacking the type 2 IGF receptor(IGF2R) and IGF 1R null background. Dev Biol, 1996, 177(2):517-535.
[55] De Souza AT, Hankins GR, Washington MK, et al. M6P/insuline-like growth factor receptor gene is mutated in human hepatocellular carcinomas with loss of heterozygoslty. Nat Genet, 1995, 11(4):447-449.
[56] O'Gorman DB, Costello M, Weiss J, et al. Decreased insulin-like growth factor-2/mannose 6-phosphate receptor expression enhances tumorigenicity in JEG-3 Cells. Cancer Res, 1999, 59(22): 5692-5694.
[57] Linnell J, Groeger G, Hassan AB, et al. Real time kinetics of insulin-like growth factor 2(IGF-2)interaction with the IGF-2/mannose-6-phosphate receptor:the effects of demain 13 and pH.Biol Chem,2001,276(26):23986-23991.
[58]Hancock MK,Haskins DJ,Sun G,et al.Identification of residues essential for carbohydrate recongnition by the insulin-like growth factor 2/ mannose-6-phosphate receptor.Biol Chem,2002,277(13):11255-11264.
I59]Yamada T,De Souza AT,Finkelstein S,et al.Loss of the gene encoding mannose-6-phosphate/insulin-like growth factor 2 receptor is an early event in liver carcinogenesis.Proc Natl Acad Sci USA,1997,94(2):10351-10355.
[60]Devi GR,De SouzaAT,Byrd JC,et al.Altered ligand binding by insulin-like growth factor 2/mannose 6-phosphate receptor bearing missense mutations in human cancer.Cancer Res,1999,59(1):4314-4319.
[61]Twigg SM,Kiefer MC,Zapf J,et al.A central domain binding site in insulin-like growth factor binding protein-5 for the acid-labile subunit.Endocrinology,2000,141(1):454-457.
[62]Chang YS,Gong K,Sun S,et al.Clinical significance of insulin-like growth factor-binding protein-3 expression in stage Ⅰ non-small cell lung cancer.Clin Cancer Res,2002,8(12):3796-3802.
[63]Chang YS,Wang L,Liu D,et al.Correlation between insulin-like growth factor-binding protein-3 promoter methylation and prognosis of patients with stage Ⅰ non-small cell lung cancer.Clin Cancer Res,2002,8(12):3669-3675.
[64]Lee HY,Chun KH,Liu B,et al.Insulin-like growth factor binding protein-3 inhibits the growth of non-small cell lung cancer.Cancer Res,2002,62(12):3530-3537.
[65]yon Wichert G,Jehle PM,Hoeflich A,et al.Inhibition of tumor growth by a dominant negative mutant of the insuline-like growth factor Ⅰ receptor.Cancer Res,2000,60(16):4573-4581.
[66]Richardsen E,Ukkonen T,Bjomsen,et al.Overexpression of IGFBP2 is a marker for malignant transformation in prostate eprithelion.Virchows Arch,2003,442(4):229-335.
[67]邓星辉.胰岛素样生长因子结合蛋白2与肿瘤发生.国外医学临床生物化学与检验学分册,2003,24(1):12-13.
[68]Hoeflich A,Fettscher O,Lahm H,et al.Overexpression of insulin-like growth factor-binding protein-2 results in tumorigenic potential in Y-1 adrenocortical tumor cells.Cancer Res,2000,60(4):834-838.
[69]Isozaki O.Mechanism of abnormal thyroid cell proliferation in normal and tumor tissues.Nippon Rinsho,2005,63(10):153-158.
[70]Ciampolillo A,De Tullio C,Giorgino F.The IGF-I/IGF-I receptor pathway:Implications in the Pathophysiology of Thyroid Cancer. Curr Med Chem, 2005, 12(24): 2881-2891.
[71] Wasko R, Michalek K, Pacholska J, et al. Clinical significance of the insulin like growth factor I gene promoter(P1) polymorphism in thyroid nodular diseased. Neuro Endocrinol Lett, 2005, 26(6):699-703.
[72] Jamieson TA, Brizel DM, Killian JK, et al. M6P/IGF-2R loss of heterozygosity in head and neck cancer associated with poor patient prognosis. BMC Cancer, 2003, 13(3): 4.
[73] Kishimoto Y, Morisawa T, Kitano M, et al. Loss of heterozygosity of the mannose 6-phosphate/ insulin-like growth factor II receptor and p53 Genes in human hepatocellular carcinoma. Hepatol Res, 2001, 20(1): 68-83.
[74] ShibataH, MatsubabaO, Wakiyama H, et al. The role of cyclin dependent kinase inhibitor p27 in squamous cell carcinoma of the esophagus. Pathol Res Pract, 2001, 197(3):157-164.
[75] Baserga R. The insulin-like growth factor I recetor: A key to tumor growth? Cancer Res, 1995, 55(2):249-252.
[76] Baserga R, Sell C, Rorcu P, et al. The role of the IGF-I receptor in the growth and transformation of mammalian cells. Cell Prolif, 1994, 27(1): 63-71.
[1] Bajput B, Degen SF, Reich E, et al. Chromosomal locations of huma tissue plasminogen activator and urokinase genes. Science, 1985, 230 (4726) : 672-674.
[2] Patthy L. Evolution of the proteases of blood coagulation and fibri-nolysis by assembly from modules. Cell, 1985, 41 (3):657-663.
[3] Hart DA, Rehemtulla A. Plasminogen activators and their inhibitors: regulators of extracellular proteolysis and cell function. Comp Biochem Physiol B, 1988, 90(4):691-708.
[4]Celentano DC, Frishman WH. Matrix metalloproteinases and coronary artery disease:a novel therapeutie target. J Clin Pharmacol, 1997, 37(11):991-1000.
[5] Peverali FA, Mandriota SJ, Ciana P, et al. Tumor cells secrete an angiogenic factor that stimulates basic fibroblast growth factor and urokinase expression invascular endothelial cells. J Cell Physiol, 1994, 161(1):1-14.
[6] Ploug M , Ellis V. Structure-function relationships in the receptor for urokinase-type plasminogen activator. Comparison to other members of the Ly-6 family and snake venom alpha-neurotoxins. FEBS Lett, 1994, 349(2):163-168.
[7] Montuori N, Mattiello A, Mancini A,et al. Urokinase-mediated posttranscriptional regulation of urokinase-receptor expression in non small cell lung carcinoma. Int J Cancer, 2003, 105(3):353-360.
[8] Meijers JC, Chung DW. Organization of the genecoding for human protein C inhibitor (plasminogen activator inhibitor-3). Biol Chem, 1991, 266 (23):15028-15034.
[9] Jahkola T, Toivonen T, von Smitten K, et al. Cathe-psin-D, urokinase plasminogen activator and type-1 plasminogen activator inhibitor in early breast cancer: an immunohistochemical study of prognostic value and relations to tenascin-C and other factors. Br J Cancer, 1999, 80(2): 167-174.
[10] Okusa Y, Ichikura T, Mochizuki H. Prognostic impact of stromal cell-derived urokinase-type plasminogen activator in gastric carcinoma. Cancer, 1999, 85(5):1033-1038.
[11] Hoffmann G, PollowK, Weikel W, et al. Urokinase and plasminogen activator-inhibitor (PAI-1) status in primary ovarian carcinomas and ovarian metastases compared to benign ovarian tumors as a function of histopathological parameters. Med, 1999, 37(1):47-53.
[l2]Miyake H, Hara I, Yamanaka K, et al. Elevation of urokinase-type plasminogen activator and its receptor densities as new predictors of disease progression and prognosis in men with prostate cancer. Int J Oncol, 1999, 14(3):535-541.
[13]De Bruin PA,Griffioen G,Verspaget HW,et al.Plasminogen activators and tumor development in the human colon:activity levels in normal mucosa,adenmatous polyps,and adenocarcinomas.Cancer Res,1987,47(17):4654-4657.
[14]刘大林,陈国玉,夏建国,等.尿激酶型纤溶酶原激活物与胃癌侵袭及转移关系的研究.南京医科大学学报,2001,21(5):393-395.
[15]李鹏,高亚,李恭才,等.尿激酶型纤溶酶原激活因子及其受体在神经母细胞瘤中的表达及其意义.中华实验外科杂志,2002,19(2):137-138.
[16]肖继平,张广德,夏文华,等.乳腺癌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.
[17]Odekon LE,Sato Y,Rifkin DB.Urokinase-type plasminogen activator mediates basic fibroblast growth factor-induced bovineen dothelial cell migration independent of its proteolytic activity.J CellPhysiol,1992,150(2):258-263.
[18]Landau B,Kwaan H,Verrusio E,et al.Elevated levels of urokinase-type plasminogen activator and plasminogen activator inhibitor type-1 in malignant human brain tumors.Cancer Res,1994,54(4):1105-1108.
[19]童苗,张启良,倪玉英,等.胃和结肠组织中uPA受体表达的病理意义.上海第二军医大学学报,1994,14(3):217-220.
[20]Bianchi E,Cohen RL,Thor AT,et al.The urokinase receptor is expressed in invasive breast cancer but not in normal breast tissue.Cancer Res,1994,54(4):861-866.
[21]Yang JL,Seetoo D,Wang Y,et al.Urokinase type plasminogen activator and 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.
[22]Ganesh S,SierC F,Griffioen G,et al.Prognostic relevance of plasminogen activators and their inhibitors in colorecral cancer.Cancer Res,1994,54(15):4065-4071.
[23]Pedersen H,Brunner N,Francis D,et al.Prognostic impact of urokinase,urokinase receptor,and type Ⅰ plasminogen activator inhibitor in squamous and large cell lung cancer tissue.Cancer Res,1994,54(17):4671-4675.
[24]Foekens J A,Schmitt M,van Putten WI,et al.Prognostic value of urokinase-type plasminogen activator in 671 primary breast cancer patients.Cancer Res,1992,52(21):6101-6105.
[25]Schmalfeldt B,Kuhn W,Reuning U,et al.Primarytumor and metastasis in ovarian cancer differ in their content of urokinase-type plasminogen activator,its receptor,and inhibitors types Ⅰ and Ⅱ.Cancer Res,1995,55(21):3958-3963.
[26]Borgfeldt C,Hansson SR,Gustavsson B,et al.Dedifferentiation of serous ovarian cancer from cystic to solid tumors is associated with increased expression of mRNA for urokinase plasminogen activator,its receptor and its inhibitor.Int J Cancer, 2001,92(4):497-502.
[27]陈杰,王晶,侯淑风.卵巢癌发生、进展及预后与纤溶酶原激活系统表达的关系.中国临床康复,2004,8(35):8009-8011.
[28]程红,陈惠祯.尿激酶1型纤溶酶原激活剂及其受体、抑制剂在卵巢腺癌中的表达及临床意义.华中医学杂志,2001,25(4):195-196.
[29]毛敬,辛晓燕,刘玉,等.卵巢癌UPA及HPA的表达与肿瘤转移的相关性的研究.现代肿瘤医学,2006,14(3):329-331.
[30]Astedt B,Holmberg L.Immunological identity of urokinase and ovarian carcinoma plasminogen activator released in tissue culture.Nature,1976,261(5561):595-597.
[31]Dano K,Andreasen PA,Grondahl-hansen J,et al.Plasminogen activators,tissue degradation,and cancer.Adv Cancer Res,1985,44:139-266.
[32]Schmitt M,Harbeck N,Thom ssen C,et al.Clinical impact of the plasminogen activation and target for therapy.Thromb Haemost,1997,78(1):285-296.
[33]Conese M,Blasi F.Urokinase/urokinase receptor system:internalization/degradation of urokinase-serpin complexes:mechanism and regulation.Biol Chem Hoppe Seyler,1995,376(3):143-155.
[34]Cajot J F,Bamat J,Bergonzelli G E,et al.Plasm inogen-activator inhibitor type Ⅰ is a potent natural inhibitor of extracellular matrix degradation by fibrosarcoma and colon carcinoma cells.Proc Natl Acad Sci USA,1990,87(18):6939-6943.
[35]Durko M,Brodt P.Suppression of type Ⅰ collagenase expression by antisense RNA in melanoma cells results in reduced synthesis of the urokinase-type plasmindgen activator receptor.Biochem Biophys Res Commun,1998,247(2):342-348.
[36]Yu HR,Schultz RM.Relationship between secreted urokinase plasminase activator activity and metastatic potential in marine B16 cells transfected with human urokinase sense and antisensegenes.Cancer Res,1990,50(23):7623-7633.
[37]王伊洵,Chambers SK.卵巢癌细胞浸润性的研究.现代妇产科进展,1996,5(4):306-308.
[38]Festuccia C,Dolo V,Guerra F,et al.Plasminogen activator system modulates invasive capacity and proliferation in prostatic tumor cells.Clin Exp Metastasis,1998,16(6):513-528.
[39]Chun M,Hoffmann MK.Plasmin-depletion therapy.A new approach to overcoming tumor cell drug resistance.Ann N Y Acad Sci,1999,886(3):240-242.
[40]陈淑勤,黄培生,李一伟,等.尿激酶型纤溶原激活物在鼻咽癌的表达及临床意义.福建医科大学学报,2002,36(1):36-38.
[41]Fisher JL,Mackie PS,Howard ML,et al.The expression of the urokinase plasminogen activator system in metastatic murine osteosarcoma:an in vivo mouse.Olin Cancer Res,2001,7(6):1654-1660.
[42]潘国庆,姚运红,陆元志,等.uPA、uPAR、PAI-1在具有不同转移率的鼻咽癌细胞系中的表达.中国癌症杂志,2002,12(4):310-313.
[43]赵恩民,韩德民,于振坤,等.尿激酶型纤溶酶原激活剂及其抑制剂在喉癌患者预后中的价值.临床耳鼻咽喉科杂志,2002,16(11):599-602.