多型核粒细胞弹性蛋白酶与肾癌相关性研究
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摘要
肾癌是人类较常见的恶性肿瘤，发病率占所有人类恶性肿瘤的3％，是病死率最高的泌尿系肿瘤。多型核粒细胞弹性蛋白酶是一个强有力的丝氨酸蛋白酶，它能够降解组成细胞外基质的大多数蛋白成分，部份人类肿瘤细胞也可以分泌该酶并且在肿瘤进展的过程中起重要的作用。我们采用分子生物学免疫学和病理学的方法，检测PMNE在肾癌组织中的表达，肾癌细胞对肾血管的侵袭，肾癌组织中PMNE启动子重复序列的测定，将野生型和突变型PMNE启动子插入pGL3-Basic来比较两者对构建载体表达荧光素酶的研究，探讨PMNE在肾癌发生发展过程中的作用。
研究结果如下：
1．PMNE在肾癌组织中高水平表达，与TNM分期关系密切，T3a、T3b期肾癌组织抽提物中PMNE的浓度比T1、T2组明显增高。
2．PMNE在肾癌组织中的表达与癌细胞对微血管的侵袭关系密切。
3．发现1例肾癌患者PMNE启动子第3区-879位、第6区-726位碱基处分别发生单核苷酸置换突变，由原来的A突变为C。
第.军医大母博士李位恰久
4.插入突变PMNE启动子的荧光素酶表达载体转染的K562细胞中荧光素酶表
达强度明显高于野生型P刚E启动子转染的细胞。
结论二P删E在肾癌组织中高表达且与分期关系密切，PMNE启动子第3区一879
位、第6区一716位碱基处分别发生单核昔酸置换突变，由原来的A突变为C，
导致PMNE的表达明显增强，可能参与和促进了肾癌细胞对细胞外基质的侵
袭。我们的实验结果证明PMNE在肾癌发生发展的过程中起了重要的作用。
Renal cell carcinoma (RCC), which accounts for about 3% of all adult malignancy tumors, is the most lethal of the urologic cancers. Although tumor size, tumor grades and nuclear atypia of RCC have been reported as prognostic factors, the biological behavior of this tumor is still unpredictable. Polymorphonuclear leukocyte elastase (PMNE) is a powerful serine protease, since it degrads most protein components of the extracellular matrix, it is suggested to play a crucial role in the processes of some tumor cell invasion and metastasis, including non-small cell lung carcinoma and primary breast cancer. Because there is no published information on the relation between the level of PMNE and prognosis in patients of RCC, we, in this study, explored if PMNE level was involved in the prognosis of RCC patients. Using molecular, immunological and pathological methods, we measured levels of PMNE in
cytoplasmic extracts of 59 renal cell carcinomas and observed microvascular invasion of RCC cells and sequenced PMNE promoter gene of RCC, which showed single nucleic acid mutant whose promoter activity was also compared with wild type PMNE promoter through inserting both promoters into pGL3-Basic to construct luciferase expression vector. Results:
1. The PMNE was over expressed in RCC cell and the level of PMNE in the tissue extract of T3a and T3b RCC was much more higher than those of T1 and T2, So we conclude that the level of PMNE expression in RCC cell is closely related to the TNM staging
2. High level PMNE expression was detected in the specimen of RCC with microvascular invasion, which indicated that the PMNE over expression in RCC might be related to the tumor invasion into microvascular.
3. One important finding of this study was that there were 1 cases of RCC whose PMNE promoter gene sequence had permutation mutant from C to A occurred in the -879th and -716th base of region3 6.
4. Luciferase expressed in K562 cells transfected with mutant PMNE promoter luciferase expression vector was considerablely higher than those transfected with wild type PMNE promoter luciferase expression vector, which suggests that PMNE promoter occurred in RCC enhanced this enzyme activity.
CONCLUSION:
PMNE is over expressed in RCC and the level of its expression is closely related with the stage and the invasion abilities of the tumor. PMNE promoter gene permutation mutant in the region 3 6 may be the cause of higher activity of PMNE enzyme, which promoted the invasion of RCC cell within the matrix. Our data indicated that PMNE may play an important role in the development of RCC.
研究结果如下：
1．PMNE在肾癌组织中高水平表达，与TNM分期关系密切，T3a、T3b期肾癌组织抽提物中PMNE的浓度比T1、T2组明显增高。
2．PMNE在肾癌组织中的表达与癌细胞对微血管的侵袭关系密切。
3．发现1例肾癌患者PMNE启动子第3区-879位、第6区-726位碱基处分别发生单核苷酸置换突变，由原来的A突变为C。
第.军医大母博士李位恰久
4.插入突变PMNE启动子的荧光素酶表达载体转染的K562细胞中荧光素酶表
达强度明显高于野生型P刚E启动子转染的细胞。
结论二P删E在肾癌组织中高表达且与分期关系密切，PMNE启动子第3区一879
位、第6区一716位碱基处分别发生单核昔酸置换突变，由原来的A突变为C，
导致PMNE的表达明显增强，可能参与和促进了肾癌细胞对细胞外基质的侵
袭。我们的实验结果证明PMNE在肾癌发生发展的过程中起了重要的作用。
Renal cell carcinoma (RCC), which accounts for about 3% of all adult malignancy tumors, is the most lethal of the urologic cancers. Although tumor size, tumor grades and nuclear atypia of RCC have been reported as prognostic factors, the biological behavior of this tumor is still unpredictable. Polymorphonuclear leukocyte elastase (PMNE) is a powerful serine protease, since it degrads most protein components of the extracellular matrix, it is suggested to play a crucial role in the processes of some tumor cell invasion and metastasis, including non-small cell lung carcinoma and primary breast cancer. Because there is no published information on the relation between the level of PMNE and prognosis in patients of RCC, we, in this study, explored if PMNE level was involved in the prognosis of RCC patients. Using molecular, immunological and pathological methods, we measured levels of PMNE in
cytoplasmic extracts of 59 renal cell carcinomas and observed microvascular invasion of RCC cells and sequenced PMNE promoter gene of RCC, which showed single nucleic acid mutant whose promoter activity was also compared with wild type PMNE promoter through inserting both promoters into pGL3-Basic to construct luciferase expression vector. Results:
1. The PMNE was over expressed in RCC cell and the level of PMNE in the tissue extract of T3a and T3b RCC was much more higher than those of T1 and T2, So we conclude that the level of PMNE expression in RCC cell is closely related to the TNM staging
2. High level PMNE expression was detected in the specimen of RCC with microvascular invasion, which indicated that the PMNE over expression in RCC might be related to the tumor invasion into microvascular.
3. One important finding of this study was that there were 1 cases of RCC whose PMNE promoter gene sequence had permutation mutant from C to A occurred in the -879th and -716th base of region3 6.
4. Luciferase expressed in K562 cells transfected with mutant PMNE promoter luciferase expression vector was considerablely higher than those transfected with wild type PMNE promoter luciferase expression vector, which suggests that PMNE promoter occurred in RCC enhanced this enzyme activity.
CONCLUSION:
PMNE is over expressed in RCC and the level of its expression is closely related with the stage and the invasion abilities of the tumor. PMNE promoter gene permutation mutant in the region 3 6 may be the cause of higher activity of PMNE enzyme, which promoted the invasion of RCC cell within the matrix. Our data indicated that PMNE may play an important role in the development of RCC.
引文
1. Landis SH, Murray T, Bolden S, et al. Cancer Statistics. 1999. CA CancerJ Clin 1999; 49:8-31
2. Chow WH, Devesa SS, Warren JL, et al. Rising incidence of renal cell cancer in the united states. JAMA 1999; 194:629-642
3. Kessler O, Mukamed E, Hadar H, et at. Effect of improved dignosis of renal cell carcinoma on the course of the disease. J Surg Oncol 1994; 57:210
4. Walsh PC, Retik AB, Stamey TA, et al. Campbell's Urology 8th ed 2002.
5. W. B. Saunders Company Muscat JE, Hoffman D, Wynder EL. The epidemiology of renal carcinoma. A second look. Cancer 1995; 75:2552-2557
6. Yuan JM, Gago-Dominguez M, ROSSR K, et al. Hypertension, obesity and their medications in relation to renal cell carcinoma. J Cancer 1998; 77:1508-1513
7. La Vecchia C, Negri E, D' Avanro B, rt al. Smoking and renal cell carcinoma. Cancer Res 1990; 50:5231-5233
8. McLaughlin JK, Lindblad P, Mellemgaard A, et al. International renal cell carcinoma study Ⅰ:Tobacco use. Int J Cancer 1995; 60:194-198
9. Lindblad P, Wolk A, Bergstrom R, et al. Diet and risk of renal cell cancer:A population-based case-control study. Cancer Epidemiol
Biomarkers Preview 1997; 6:215-223
10. Shaoiro JA, Williams MA, WeissNS, et al. Hypertension, antihyperten-si ve medication use, and risk of renal cell carcinoma. Am J Epidemiol
11. Bodmer D, Eleveld MJ, Ligtenberg MJ, et al. An alternative route for mulistep tumorigenesis in a novel case of hereditary renal cell carcinoma and at(2:3)(q35:q21) chromosomal translocation. Am J Hum Genet 1998; 62:1475-1481
12. Gnarra JR, Tory K, Weng Y, et al. Mutational of VHL tumor supressor gene in renal carcinoma. Natl Genet 1994:7:85-90
13. Clifford SC, Czapla K, Richards FM, et al. Hepatocyte growth factor stimulated renal tubular mitogenesis:Effects on expression of c-myc, c-fos, c-met, VEGF and VHL tumor-supressor and related genes. Br J Cancer 1998; 77:1420-1428
14. Oda H, Nakatsuru Y, Ishikawa T, et al. Mutation of p53 gene and p53 protein lecting duct carcinoma of the kidney. J Urol 1997:158:245-266
15. Schullerus D, Herbers Y, Chudek J, et al. Loss of heterozygosity at chromosomes 8p, 9p, 14q is associated with stage and grade of non-papillary renal cell carcinoma. J Urol 1997; 183:151-160
16. Walther MM, Kleiner DE, Lubensky IA, et al. Progelatinase a mRNA expression in renal cell line derived from tumors in patients with
mestastatic renal cell carcinoma correlates inversely with survival. Urology 1997; 50:295-301
17. Schmidt L, Duh FM, Chen FKT, et al. Genmline and somatic mutations in the tyrosine kinase domain of the MET proto oncogene in papillary renal carcinoma. Nati Genet 1997; 16:68-78
18. Jeffers M, Schmidt L, Nakaigawa N, et at. Activating mutations for met tyrosine kinase receptor in human cancer. Proc Natl Acad Sci 1997; 94:11445-11456
19. Kovacs G, Fuzesi L, Emanual A, et al. Cytogenetics of papillary renal cell tumors. Gene Chromosomes cancer 1991; 3:249-255
20. Selli C, Amorosi A, vona G, et al. Retro-spective evaluation of c-erbB-2 oncogene amplification using competitive PCR in collecting duct carcinoma of the kidney. J Urol 1997; 158:245-266
21. Zhuang LY, Zhang ZW, Guo YL, et al. Aberrant expression of growth factor Wnt-5A in six urinary malignant cell lines. Chinese Medical journal 1999; 112:251-25
22. Farrow GM. Diease of the kidney, In murphy WM(ed):Urological pathology 2nd ed. Philadelpha, WB Saundres, 1997, pp 464-470
23. Strkel S, Ebie JN, Adlakha k, et at. Classification of renal cell carcinoma: Workgroup no. 1. union International Cntre Le Cancer (UICC) and American Joint Committee on Cancer(AJCC). Cancer
1997; 80:987-989
24. Theones W, Strkel S, Rumpelt HJ. Histopathology and classification of renal cwll tumors(adenomas, oncocytomas and carcinoma:The basic cytological and histopathological elements and their use of diagnostic. Pathol Res Pract 1986; 181:125-143
25. Fuhrman SA, lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982; 6:655-663
26. Guinan P, Sobin LH, Algaba F, et al. TNM staging of renal cell carcinoma: Workgroup no. 1. union International Cntre Le Cancer (UICC) and American Joint Committee on Cancer(AJCC). Cancer 1997; 80:992-993
27. Schefft P, Novick AC, Straffon RA, et al. Surgery for renal cell carcinoma extending into the inferior vena cava. J Urol 1978; 120: 28-31
28. Ljungberg B, Stenling R, Osterdahl B, et al:Vein invasion in renal cell carcinoma:impact on mestastatic behavior and survival. J Urol 1995; 154:1681-1684
29. Hatcher PA, Anderson EE, Paulson DF, et al. Surgical management and prognosis on renal cell carcinoma invading the vena cava. J Urol 1991; 145:20-24
30. Golimbu M, Joshi P, Sperber A, et al. Renal cell carcinoma:survival and prognosis factors. Urology 1986; 27:291-294
31. Griffiths DE Verghese A, Golash A, et al. Contribution of grade, vascular invasion and age to outcome in clinically localized renal cell carcinoma. BJU Int 2002; 90:26-31
32．高进，章静波癌的侵袭与转移基础与临床科学出版社2003．第一版 第一章
33. Woodhouse EC, Chuaqui RF, Liotta LA:General mechanisms of mesastasis. Cancer 1997; 80(suppl):1529-1537
34. Rovenskey YA. 1998 Celluar and molecular mechanisms of tumor invasion. Biochemistry Mosc, 63(9):1029-1043
35. Cockett MI, Murphy G, Birch ML, et al. Matrix meyalloproteinases andmestastasic cancer. Biochem Soc Symp, 63:295-313
36. Matrisian L:Metalloproteinases and their inhibitor in matix remodeling. Trend 1990; 6:121-125
37. Sun Y, Wenger L, rutter JC, et al. p53 down regulates human matix metalloproteinase-1 gene expression. J Bio Chem 1999; 274: 11535-11540
38. Ricca A, Biroccio A, Del BD, et al. bc1-2 over-expression enhances NF-kappaB activity and induces matrix metalloproteinase-9 transcription in human MCFT(ADR) breast cancer cells. Int J Cancer
2000; 86:188-196
39. Ornstein DL, Macnab J, Cohn KH, et al. Evidence for tumor-host cooperation in regulating matix metalloproteinase-2 expression inhuman colon cancer. Clin Exp Mestastasis 1999; 17:205-212
40．高庆，吴秉铨．基质金属蛋白酶与肿瘤侵袭与转移．中华病理学杂志1998；27(2)：155-156
41. Kugler A, HemmerleinB, Thelen P, et al. Expression of matix metalloproteinase 2 and 9 and their inhibitors in renal cell carcinoma. J Urol 1998; 160:1914-1918
42. Lein M, Jung K, Lanbe C, et al. Matix metalloproteinase and their inhibitors in plasma and tumor tissues of patients with renal cell carcinoma. Int J Cancer 2000; 85:801-804
43. Walther MM, Keiner DE, Lubensky IA, et al. Progelatinse A mRNA expression in cell lines derived from tumor in patients with mestastatic renal cell carcinoma correlates inversely with survival. Urology 1997; 50:295-301
44．张饶，吴小侯，曹贵华等．基质金属蛋白酶-9的表达与肾细胞癌血管生成的关系．癌症2004；23(3)：326-329
45. Watson SA, Morris TM, Parsons SL, et al. Therapeutic effect of matix metalloproteinase inhibitor batimastat in a human colorectal cancer ascite model. B J Cancer 1996; 74:1354-1358
46. Schoenemark MP, Mitchell TI, Rutter JL, et al. Retinoid-mediated suppression of tumor invasion and matix metalloproteinase synthesis. Ann NY Acad Sci 1999; 878:466-486
47．高进，张静波．癌的侵袭与转移基础与临床科学出版社2003．第一版 第六章
48. Rabbani SA, Xing-RH. Role of urokinase(uPA) and its receptor (uPAR) in invasion and mestastasis of hormone-dependentmalignancies. Int J Oncol 1998; 12(4):911-920
49. Hofmann R, Lehmer A, Buresch M, et al. Clinical relevance of urokinase plasminogen activator, its receptor, and its inhibitor in patients with renal cell carcinoma. Cancer. 1996 Aug 1; 78(3):487-492.
50. Swiercz R, Wolfe JD, Zaher A, Jankun J. Expression of the plasminogen activation system in kidney cancer correlates with its aggressive phenotype. Clin Cancer Res. 1998 Apr; 4(4):869-877.
51. Gohji K, Nakajima M, Boyd D, et al. Organ-site dependence for the production of urokinase-type plasminogen activator and metastasis by human renal cell carcinoma cells. Am J Pathol. 1997 Dec; 151(6):1655-1661.
52. Xu Y, Hagege J, Doublet JD. er al Endothelial and macrophage upregulation of urokinase receptor expression in human renal cell
carcinoma. Hum Pathol. 1997 Feb; 28(2):206-213.
53. Sinha S, Watorek W, Karr S. Giles J. Primary structure of human neutrophil elastase. Proc Natl Acad Sci 1987; 84:2228-2232
54. Yamaguchi K, Patturajan M, Trink B, Usadel H, et al. Circulating antibodies to p40(AIS) in the sera of respiratory tract cancer patients. Int J Cancer. 2000 Nov 20; 89(6):524-8.
55. Bieth JG. In vivo significance of kinectic constants of proteinase inhibitors. Biochem Med 1984; 32(3):387-397
56. Janoff A, Sloan 8, Weinbaum G, et al. Experimental emphysema induced with purified human neutrophil elastase:tissue localization of the instilled protease. Am Rev Respir Dis 1977 Mar; 115(3):461-478
57. Bode W, Wei AZ, Huber R, et al. X-ray crystal structure of the complex of human leukocyte elastase(PMNelastase) and the third domain of the turkey ovomucoid inhibitor. EMBO J 1986 oct; 5(10):2453-2458
58. Takahashi H, Nukiwa T, Satoh K, et al. Characterization of the gene and protein of the alfa 1-antitrypsin deficiency allele mprocida. J Biol Chem 1988 Oct 25; 263(30):15528-15534
59. Zimmer M, medcalf RL, Fink TM, et al. Three human elastase-like gene coordinately expressed in the myelomonocyte lineage are organized as a single genetic locuson 19pter. Proc Natl Acad Sci USA 1992; 89:8215
60. Kraut J. Serine proteases: structure and mechanism of catalysis. Annu Rev Biochem 1977; 46:331-358
61. Neurath H. Evolution of proteolytic enzymes. Science 1984 Apr 27; 224(4647):350-357
62. Craik CS, Rutter WJ, Fletterick R. Splice junction: association with variation in protein structure. Science 1983 Jun 10; 220(4602):1125-1129
63. Rogers J. Exonshuffling and intron insertion in serine protease gene. Nature 1985 Jun 6-2; 315(6019):458-459
64. Asakai R, Davie EW, Chung DW. Organization of the gene for human factor Ⅺ. Biochemistry 1987; 26(23):7221-7228.
65. Falloon J, Gallin JI. Neutrophil granules in health and diease. J Allergy Clin. Immunol 1986; 77(5):653-662.
66. von Heijne G. Patterns of amino acids near signal-sequence cleavage sites. Eur J Biochem 1983; 133(1): 17-21.
67. Watson M. E. Compilation of published signal sequences. Nucleic Acids Res 1984; 12(13):5145-5164.
68. Perlman D, Halvorson HO. A putative signal peptides recognition site and sequence in eukaryotic and prokaryotic signal peptides. J Mol Biol 1983; 167(2):391-409.
69. Eskridge E M, Shields D. The NH2 terminus of preproinsulin directs
the translocation and glycosylation of bacterial cytoplasmic protein by mammalian microsomal membranes. J Cell Biol. 1986; 103:2263-2272.
70. Morishita K, Tsuchiya M, Asano S, et al. Chrosomal gene structure of human myeloperoxides and regulation of its expression by granulocyte colony-stimulating factor. J Biol Chem. 1987; 262:15208-15213.
71. Segundo BS, Martinez MC, Vilanova M, et al. The severed activation segment of porcine pancreatic procarboxypeptidase A is powerful inhibitor of the active enzyme. Isolation and characterization of the activation peptide. Biochim Biophys Acta. 1982; 707:74-80.
72. Siebenlist U, Hennighausen L, Battey J, et al. Chromatin structure and protein binding in the putative regulatory region of the c-myc gene in Burkitt Lyphoma. Cell 1984; 37:381-391
73. Faust PL, Kornfeld S, Chirgwin J M, et al. Cloning and sequence analysis of cDNA for human cathephin D. Proc. Natl. Acad. Sci. U. S. A. 1985; 82:4910-4914.
74. Oshima A, Kyle JW, Miller RD, et al. Cloning, sequencing, and expression of cDNA for human beta-glucuronidase. Proc. Natl. Acad. Sci. U. S. A. 1987; 84:685-689.
75. Yoshimura K, Chu CS, Crystal RG. Enhancer function of a 53-bp
repetitive element in the 5' flanking region of the human neutrophil elastase gene. Biochem Biophys Res Commun 1994 204:38-42.
76. Ancliff PJ, Gale RE, Watts MJ, et al. Paternal mosaicism proves the pathogenic nature of mutations in neutrophil elastase in severe congenital neutropenia. Blood 2002; 100:707-709
77. Dale DC, Person RE, BolyardAA, et al. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood 2000; 96:2317-2322.
78. Yamashita J, Tashiro K, Yoneda S, et al. Local increase in polymorphonuclear leukocyte elastase is associated with tumor invasiveness in non-small cell lung cancer. Chest, 1996, 109: 1328-1334.
79. Achilles K, Bednarski PJ. Quantification of elastase-like activity in 13 human cancer cell lines and in an immortalized human epithelial cell line by RP-HPLC. Biol Chem. 2003 May; 384(5):817-824.
80. Inada, M., Yamashita, J., and Ogawa, M. Neutrophil elastase inhibitor (ONO-5046-Na) inhibits the growth of human lung cancer cell lines transplanted into severe combined immunodefficiency (SCID) mice, Res. Commun. Mol. Path. Pharmacol., 1997;
97:229.
81. Matsumura F., Yamaguchi Y., and Ogawa M. Adhesion molecule expression in vascular endothelial cells incubated with cancer cell line supernatant are inhibited by neutrophil elastase inhibitor (ONO-5046Na). Res. Commun. Mol. Path. Pharmacol. 1997; 98: 109.
82. Fumiaki N, Masahiko H, Akihiro O, et al. Elastase Activity Enhances the Adhesion of Neutrophil and Cancer Cells to Vascular Endothelial Cells. J Surg Res 2000; 94:153-158
83. Starcher B, O'Neal P, Granstein RD., et al. Inhibition of neutrophil elastase suppresses the development of skin tumors in hairless mice. J Invest Dermatol 1996; 107: 159-163.
84. Troll W, Meyn MS, Rossman TG. Mechanisms of protease action in carcinogenesis. Carcinogenesis 1977; 2:301-312.
85. Inada M, Yamashita J, Nakano S. Complete inhibition of spontaneous pulmonary metastasis of human lung carcinoma cell line EBC-1 by a neutrophil elastase inhibitor (ONO-5046. Na). Anticancer Res 1998; 18: 885-890.
86. Doi K, Horiuchi T, Uchinami M. et al. Neutrophil elastase inhibitor reduces hepatic metastases induced by ischaemia-reperfusion in rats. Eur J Surg 2002:168:507-510
87. Foeken JA, Christain R, Maxime P, et al. The prognostic of polymorphonuclear leukocyte elastase in patients with primary breast cancer. Cancer Res 2003; 15(63):337-341
88. Yamashita J, Ogawa M, Ikei S, et al. Production of immunoreactive polymorphonuclear leucocyte elastase in human breast cancer cells: possible role of polymorphonuclear leucocyte elastase in the progression of human breast cancer. Br J Cancer 1994; 69:72-76.
89. Yamashita J, Ogawa M, Shirakusa T. Free-form neutrophil elastase is an independent marker predicting recurrence in primary breast cancer. J Leukoc Biol 1995; 57: 375-378
90. Yamashita J, Ogawa M, Abe M, et al. Tumor neutrophil elastase is closely associated with the direct extension of non-small cell lung cancer into the aorta. Chest 1997; 111: 885-890.
91. Yamashita J, Tashiro K, Yoneda S, et al. Local increase in polymorphonuclear leukocyte elastase is associated with tumor invasiveness in non-small cell lung cancer. Chest 1996; 109: 1328-1334.
92. Taniguchi K, Yang P, Jett J, et al. Polymorphisms in the promoter region of the neutrophil elastase gene are associated with lung cancer development. Olin Cancer Res 2002; 8: 1115-1120
93. Tanaka E, Yamashita J, Hayashi N, Kato S, et al. A pulmonary
metastatic model of human non-small cell lung carcinoma cells that produce a neutrophil elastase-like molecule in severe combined immunodeficiency mice. Chest. 2003 Apr; 123(4):1248-53.
94. Zhifu Sun and Ping Yang. Role of imbalance between neutrophil elastase and α1-antitrypsin in cancer development and progression. Oncnlogy 2004; 5(3):182-190
95. Yamaguchi K, Shimada S, Tashima S, et al. A potentially novel peptidase, resembling but distinct from neutrophil elastase, produced by carcinoma cells. Oncol Rep 2000; 7:1017-1021.
96. Shamamian P, Schwartz JD, Pocock BJ, et al. Activation of progelatinase A (MMP-2) by neutrophil elastase, cathepsin G, and Proteinase-3: a role for inflammatory cells in tumor invasion and angiogensis. J Cell Physiol 2001; 189:197-206
97. Okada Y, Nakanishi I. Activation of matrix metalloproteinase-3 (stromelysin) and matrix metalloproteinase-2 (gelatinase). by human neturophil elastase and cathespin G. FEBS Letters 1989; 249:353-356.
98. Chen G, Goeddel DV. TNF-R1 signaling: a beautiful pathway. Science 2002; 296:1634-1635
99. Szabo E, Riffe ME, Steinberg SM, et al. Altered cJUN expression: an early event in human lung carcinogenesis. Cancer Res 1996; 56:
305-315.
100. Smith LM, Wise SC, Hendricks DT, et al. c-Jun overexpression in MCF-7 breast cancer cells produces a tumorigenic, invasive and hormone resistant pheaotype. Oncogene 1999; 18: 6063-6070
101. Troll W, Meyn MS, Rossman TG. Mechanisms of protease action in carcinogenesis. Carcinogenesis 1977; 2:301-312.
102. Iwatsuki K, Kumara E, Yoshimine T, et al. Elastase expression by infiltrating neutrophils in gliomas. Neurol Res 2000; 22: 465-468.
103. Wang DG, Fan JB, Siao CJ, et al. Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science, 1998, 280:1077-1082.
104. Li W, SadlerLA. Low nucleotide diversity in man. Genetics, 1991, 129: 513-523.
105. Nickerson DA, Taylor SL, Weiss KM, et al. DNA sequence diversity in a 9. 7 kb region of the human lipoprotein lipase gene. Nature Genetics, 1998, 19: 233-240.
106. Broder S, Venter J C. Annu Rev Pharmacol Toxicol, 2000, 491 97; Sachidanandam R, et al. Nature, 2001, 409: 928.
107. Kruglyak L. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nature Genetics, 1999, 22:139-144.
108. Collins A, Loniou C, Morton NE. Genetic epidemiology of single-nucleotid polyphisms. Proc Natl Acad Sci U S A, 1999, 96(26):15173-7. /
109. Laan M, Paabo S. Demographic history and linkage disequilibrium in human populations, et al. Nat Genet, 1997, 17(4):435-8. /
110. Lonjou C, Collins A, Morton NE. Allelic association between marker loci. Proc Natl Acad Sci U S A, 1999, 96(4):1621-6. /
111. Nickerson DATaylor SL, Weiss KM, et al. DNA sequence diversity in a 9. 7-kb region of the human lipoprotein lipase gene. Nat Genet, 1998, 19(3):233-40. /
112. Halushka MK, Fan JB, Hsie L, et al. Patterns of single-nucleotide polymorphisms in candidate genes for blood pressure homeostasis. Nat Genet, 1999, 22(3):239-47. /
113. Rieder MJ, Taylor SL, Clark AG, et al. Sequence variation in the human angiotensin converting enzyme. Nat Genet, 1999, 22(1):59-62. /
114. Cambien F, Poirier O, Nicaud V, et al Sequence diversity in 36 candidate genes for cardiovascular disorders. Am J Hum Genet, 1999, 65(1):183-91. /
115. Cargill M, Altshuler D, Ireland J, et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes.
Nat Genet, 1999, 22(3):231-8. /
116. Ohnishi Y, Tanaka T yamada R, et al. Identification of 187 single nucleotide polymorphisms among 41 candidate genes for ischemic heart diease in the japanese population. Hum Genet, 2000, 106(3):288-92. /
117. Yamada R, Tanaka T. Identification of 142 single nucleotide polymorphisms in 41 candidate genes for rheumatoid arthritis in the japanese population. Hum Genet, 2000, 106(3):293-7. /
118．贾瑞鹏，程继义，马庆铮，等．局限性肾癌微血管侵犯的临床意义．中华泌尿外科杂志2003；24卷8期：512-513．
119. Osika E, Cavaillon J-M, Chadelat K, et al. Distinct sputum cytokine profiles in cystic fibrosis and other chronic inflammatory airway disease. Eur Respir J, 1999; 14:339.
120. Miami M, Llewellyn-Jones CH, Bayley D, et al. The chemotactic activity of sputum from patients with bronchiectasis. Am J Respir Crit Care Med, 1998; 157:723.
121. Yamashita J, Horiuchi S, Kimura M, et al. Plasminogen activator as afunctional marker for estrogen dependence in human breast cancer cells. Jpn J Cancer Res 1986; 77:177-181
2. Chow WH, Devesa SS, Warren JL, et al. Rising incidence of renal cell cancer in the united states. JAMA 1999; 194:629-642
3. Kessler O, Mukamed E, Hadar H, et at. Effect of improved dignosis of renal cell carcinoma on the course of the disease. J Surg Oncol 1994; 57:210
4. Walsh PC, Retik AB, Stamey TA, et al. Campbell's Urology 8th ed 2002.
5. W. B. Saunders Company Muscat JE, Hoffman D, Wynder EL. The epidemiology of renal carcinoma. A second look. Cancer 1995; 75:2552-2557
6. Yuan JM, Gago-Dominguez M, ROSSR K, et al. Hypertension, obesity and their medications in relation to renal cell carcinoma. J Cancer 1998; 77:1508-1513
7. La Vecchia C, Negri E, D' Avanro B, rt al. Smoking and renal cell carcinoma. Cancer Res 1990; 50:5231-5233
8. McLaughlin JK, Lindblad P, Mellemgaard A, et al. International renal cell carcinoma study Ⅰ:Tobacco use. Int J Cancer 1995; 60:194-198
9. Lindblad P, Wolk A, Bergstrom R, et al. Diet and risk of renal cell cancer:A population-based case-control study. Cancer Epidemiol
Biomarkers Preview 1997; 6:215-223
10. Shaoiro JA, Williams MA, WeissNS, et al. Hypertension, antihyperten-si ve medication use, and risk of renal cell carcinoma. Am J Epidemiol
11. Bodmer D, Eleveld MJ, Ligtenberg MJ, et al. An alternative route for mulistep tumorigenesis in a novel case of hereditary renal cell carcinoma and at(2:3)(q35:q21) chromosomal translocation. Am J Hum Genet 1998; 62:1475-1481
12. Gnarra JR, Tory K, Weng Y, et al. Mutational of VHL tumor supressor gene in renal carcinoma. Natl Genet 1994:7:85-90
13. Clifford SC, Czapla K, Richards FM, et al. Hepatocyte growth factor stimulated renal tubular mitogenesis:Effects on expression of c-myc, c-fos, c-met, VEGF and VHL tumor-supressor and related genes. Br J Cancer 1998; 77:1420-1428
14. Oda H, Nakatsuru Y, Ishikawa T, et al. Mutation of p53 gene and p53 protein lecting duct carcinoma of the kidney. J Urol 1997:158:245-266
15. Schullerus D, Herbers Y, Chudek J, et al. Loss of heterozygosity at chromosomes 8p, 9p, 14q is associated with stage and grade of non-papillary renal cell carcinoma. J Urol 1997; 183:151-160
16. Walther MM, Kleiner DE, Lubensky IA, et al. Progelatinase a mRNA expression in renal cell line derived from tumors in patients with
mestastatic renal cell carcinoma correlates inversely with survival. Urology 1997; 50:295-301
17. Schmidt L, Duh FM, Chen FKT, et al. Genmline and somatic mutations in the tyrosine kinase domain of the MET proto oncogene in papillary renal carcinoma. Nati Genet 1997; 16:68-78
18. Jeffers M, Schmidt L, Nakaigawa N, et at. Activating mutations for met tyrosine kinase receptor in human cancer. Proc Natl Acad Sci 1997; 94:11445-11456
19. Kovacs G, Fuzesi L, Emanual A, et al. Cytogenetics of papillary renal cell tumors. Gene Chromosomes cancer 1991; 3:249-255
20. Selli C, Amorosi A, vona G, et al. Retro-spective evaluation of c-erbB-2 oncogene amplification using competitive PCR in collecting duct carcinoma of the kidney. J Urol 1997; 158:245-266
21. Zhuang LY, Zhang ZW, Guo YL, et al. Aberrant expression of growth factor Wnt-5A in six urinary malignant cell lines. Chinese Medical journal 1999; 112:251-25
22. Farrow GM. Diease of the kidney, In murphy WM(ed):Urological pathology 2nd ed. Philadelpha, WB Saundres, 1997, pp 464-470
23. Strkel S, Ebie JN, Adlakha k, et at. Classification of renal cell carcinoma: Workgroup no. 1. union International Cntre Le Cancer (UICC) and American Joint Committee on Cancer(AJCC). Cancer
1997; 80:987-989
24. Theones W, Strkel S, Rumpelt HJ. Histopathology and classification of renal cwll tumors(adenomas, oncocytomas and carcinoma:The basic cytological and histopathological elements and their use of diagnostic. Pathol Res Pract 1986; 181:125-143
25. Fuhrman SA, lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982; 6:655-663
26. Guinan P, Sobin LH, Algaba F, et al. TNM staging of renal cell carcinoma: Workgroup no. 1. union International Cntre Le Cancer (UICC) and American Joint Committee on Cancer(AJCC). Cancer 1997; 80:992-993
27. Schefft P, Novick AC, Straffon RA, et al. Surgery for renal cell carcinoma extending into the inferior vena cava. J Urol 1978; 120: 28-31
28. Ljungberg B, Stenling R, Osterdahl B, et al:Vein invasion in renal cell carcinoma:impact on mestastatic behavior and survival. J Urol 1995; 154:1681-1684
29. Hatcher PA, Anderson EE, Paulson DF, et al. Surgical management and prognosis on renal cell carcinoma invading the vena cava. J Urol 1991; 145:20-24
30. Golimbu M, Joshi P, Sperber A, et al. Renal cell carcinoma:survival and prognosis factors. Urology 1986; 27:291-294
31. Griffiths DE Verghese A, Golash A, et al. Contribution of grade, vascular invasion and age to outcome in clinically localized renal cell carcinoma. BJU Int 2002; 90:26-31
32．高进，章静波癌的侵袭与转移基础与临床科学出版社2003．第一版 第一章
33. Woodhouse EC, Chuaqui RF, Liotta LA:General mechanisms of mesastasis. Cancer 1997; 80(suppl):1529-1537
34. Rovenskey YA. 1998 Celluar and molecular mechanisms of tumor invasion. Biochemistry Mosc, 63(9):1029-1043
35. Cockett MI, Murphy G, Birch ML, et al. Matrix meyalloproteinases andmestastasic cancer. Biochem Soc Symp, 63:295-313
36. Matrisian L:Metalloproteinases and their inhibitor in matix remodeling. Trend 1990; 6:121-125
37. Sun Y, Wenger L, rutter JC, et al. p53 down regulates human matix metalloproteinase-1 gene expression. J Bio Chem 1999; 274: 11535-11540
38. Ricca A, Biroccio A, Del BD, et al. bc1-2 over-expression enhances NF-kappaB activity and induces matrix metalloproteinase-9 transcription in human MCFT(ADR) breast cancer cells. Int J Cancer
2000; 86:188-196
39. Ornstein DL, Macnab J, Cohn KH, et al. Evidence for tumor-host cooperation in regulating matix metalloproteinase-2 expression inhuman colon cancer. Clin Exp Mestastasis 1999; 17:205-212
40．高庆，吴秉铨．基质金属蛋白酶与肿瘤侵袭与转移．中华病理学杂志1998；27(2)：155-156
41. Kugler A, HemmerleinB, Thelen P, et al. Expression of matix metalloproteinase 2 and 9 and their inhibitors in renal cell carcinoma. J Urol 1998; 160:1914-1918
42. Lein M, Jung K, Lanbe C, et al. Matix metalloproteinase and their inhibitors in plasma and tumor tissues of patients with renal cell carcinoma. Int J Cancer 2000; 85:801-804
43. Walther MM, Keiner DE, Lubensky IA, et al. Progelatinse A mRNA expression in cell lines derived from tumor in patients with mestastatic renal cell carcinoma correlates inversely with survival. Urology 1997; 50:295-301
44．张饶，吴小侯，曹贵华等．基质金属蛋白酶-9的表达与肾细胞癌血管生成的关系．癌症2004；23(3)：326-329
45. Watson SA, Morris TM, Parsons SL, et al. Therapeutic effect of matix metalloproteinase inhibitor batimastat in a human colorectal cancer ascite model. B J Cancer 1996; 74:1354-1358
46. Schoenemark MP, Mitchell TI, Rutter JL, et al. Retinoid-mediated suppression of tumor invasion and matix metalloproteinase synthesis. Ann NY Acad Sci 1999; 878:466-486
47．高进，张静波．癌的侵袭与转移基础与临床科学出版社2003．第一版 第六章
48. Rabbani SA, Xing-RH. Role of urokinase(uPA) and its receptor (uPAR) in invasion and mestastasis of hormone-dependentmalignancies. Int J Oncol 1998; 12(4):911-920
49. Hofmann R, Lehmer A, Buresch M, et al. Clinical relevance of urokinase plasminogen activator, its receptor, and its inhibitor in patients with renal cell carcinoma. Cancer. 1996 Aug 1; 78(3):487-492.
50. Swiercz R, Wolfe JD, Zaher A, Jankun J. Expression of the plasminogen activation system in kidney cancer correlates with its aggressive phenotype. Clin Cancer Res. 1998 Apr; 4(4):869-877.
51. Gohji K, Nakajima M, Boyd D, et al. Organ-site dependence for the production of urokinase-type plasminogen activator and metastasis by human renal cell carcinoma cells. Am J Pathol. 1997 Dec; 151(6):1655-1661.
52. Xu Y, Hagege J, Doublet JD. er al Endothelial and macrophage upregulation of urokinase receptor expression in human renal cell
carcinoma. Hum Pathol. 1997 Feb; 28(2):206-213.
53. Sinha S, Watorek W, Karr S. Giles J. Primary structure of human neutrophil elastase. Proc Natl Acad Sci 1987; 84:2228-2232
54. Yamaguchi K, Patturajan M, Trink B, Usadel H, et al. Circulating antibodies to p40(AIS) in the sera of respiratory tract cancer patients. Int J Cancer. 2000 Nov 20; 89(6):524-8.
55. Bieth JG. In vivo significance of kinectic constants of proteinase inhibitors. Biochem Med 1984; 32(3):387-397
56. Janoff A, Sloan 8, Weinbaum G, et al. Experimental emphysema induced with purified human neutrophil elastase:tissue localization of the instilled protease. Am Rev Respir Dis 1977 Mar; 115(3):461-478
57. Bode W, Wei AZ, Huber R, et al. X-ray crystal structure of the complex of human leukocyte elastase(PMNelastase) and the third domain of the turkey ovomucoid inhibitor. EMBO J 1986 oct; 5(10):2453-2458
58. Takahashi H, Nukiwa T, Satoh K, et al. Characterization of the gene and protein of the alfa 1-antitrypsin deficiency allele mprocida. J Biol Chem 1988 Oct 25; 263(30):15528-15534
59. Zimmer M, medcalf RL, Fink TM, et al. Three human elastase-like gene coordinately expressed in the myelomonocyte lineage are organized as a single genetic locuson 19pter. Proc Natl Acad Sci USA 1992; 89:8215
60. Kraut J. Serine proteases: structure and mechanism of catalysis. Annu Rev Biochem 1977; 46:331-358
61. Neurath H. Evolution of proteolytic enzymes. Science 1984 Apr 27; 224(4647):350-357
62. Craik CS, Rutter WJ, Fletterick R. Splice junction: association with variation in protein structure. Science 1983 Jun 10; 220(4602):1125-1129
63. Rogers J. Exonshuffling and intron insertion in serine protease gene. Nature 1985 Jun 6-2; 315(6019):458-459
64. Asakai R, Davie EW, Chung DW. Organization of the gene for human factor Ⅺ. Biochemistry 1987; 26(23):7221-7228.
65. Falloon J, Gallin JI. Neutrophil granules in health and diease. J Allergy Clin. Immunol 1986; 77(5):653-662.
66. von Heijne G. Patterns of amino acids near signal-sequence cleavage sites. Eur J Biochem 1983; 133(1): 17-21.
67. Watson M. E. Compilation of published signal sequences. Nucleic Acids Res 1984; 12(13):5145-5164.
68. Perlman D, Halvorson HO. A putative signal peptides recognition site and sequence in eukaryotic and prokaryotic signal peptides. J Mol Biol 1983; 167(2):391-409.
69. Eskridge E M, Shields D. The NH2 terminus of preproinsulin directs
the translocation and glycosylation of bacterial cytoplasmic protein by mammalian microsomal membranes. J Cell Biol. 1986; 103:2263-2272.
70. Morishita K, Tsuchiya M, Asano S, et al. Chrosomal gene structure of human myeloperoxides and regulation of its expression by granulocyte colony-stimulating factor. J Biol Chem. 1987; 262:15208-15213.
71. Segundo BS, Martinez MC, Vilanova M, et al. The severed activation segment of porcine pancreatic procarboxypeptidase A is powerful inhibitor of the active enzyme. Isolation and characterization of the activation peptide. Biochim Biophys Acta. 1982; 707:74-80.
72. Siebenlist U, Hennighausen L, Battey J, et al. Chromatin structure and protein binding in the putative regulatory region of the c-myc gene in Burkitt Lyphoma. Cell 1984; 37:381-391
73. Faust PL, Kornfeld S, Chirgwin J M, et al. Cloning and sequence analysis of cDNA for human cathephin D. Proc. Natl. Acad. Sci. U. S. A. 1985; 82:4910-4914.
74. Oshima A, Kyle JW, Miller RD, et al. Cloning, sequencing, and expression of cDNA for human beta-glucuronidase. Proc. Natl. Acad. Sci. U. S. A. 1987; 84:685-689.
75. Yoshimura K, Chu CS, Crystal RG. Enhancer function of a 53-bp
repetitive element in the 5' flanking region of the human neutrophil elastase gene. Biochem Biophys Res Commun 1994 204:38-42.
76. Ancliff PJ, Gale RE, Watts MJ, et al. Paternal mosaicism proves the pathogenic nature of mutations in neutrophil elastase in severe congenital neutropenia. Blood 2002; 100:707-709
77. Dale DC, Person RE, BolyardAA, et al. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood 2000; 96:2317-2322.
78. Yamashita J, Tashiro K, Yoneda S, et al. Local increase in polymorphonuclear leukocyte elastase is associated with tumor invasiveness in non-small cell lung cancer. Chest, 1996, 109: 1328-1334.
79. Achilles K, Bednarski PJ. Quantification of elastase-like activity in 13 human cancer cell lines and in an immortalized human epithelial cell line by RP-HPLC. Biol Chem. 2003 May; 384(5):817-824.
80. Inada, M., Yamashita, J., and Ogawa, M. Neutrophil elastase inhibitor (ONO-5046-Na) inhibits the growth of human lung cancer cell lines transplanted into severe combined immunodefficiency (SCID) mice, Res. Commun. Mol. Path. Pharmacol., 1997;
97:229.
81. Matsumura F., Yamaguchi Y., and Ogawa M. Adhesion molecule expression in vascular endothelial cells incubated with cancer cell line supernatant are inhibited by neutrophil elastase inhibitor (ONO-5046Na). Res. Commun. Mol. Path. Pharmacol. 1997; 98: 109.
82. Fumiaki N, Masahiko H, Akihiro O, et al. Elastase Activity Enhances the Adhesion of Neutrophil and Cancer Cells to Vascular Endothelial Cells. J Surg Res 2000; 94:153-158
83. Starcher B, O'Neal P, Granstein RD., et al. Inhibition of neutrophil elastase suppresses the development of skin tumors in hairless mice. J Invest Dermatol 1996; 107: 159-163.
84. Troll W, Meyn MS, Rossman TG. Mechanisms of protease action in carcinogenesis. Carcinogenesis 1977; 2:301-312.
85. Inada M, Yamashita J, Nakano S. Complete inhibition of spontaneous pulmonary metastasis of human lung carcinoma cell line EBC-1 by a neutrophil elastase inhibitor (ONO-5046. Na). Anticancer Res 1998; 18: 885-890.
86. Doi K, Horiuchi T, Uchinami M. et al. Neutrophil elastase inhibitor reduces hepatic metastases induced by ischaemia-reperfusion in rats. Eur J Surg 2002:168:507-510
87. Foeken JA, Christain R, Maxime P, et al. The prognostic of polymorphonuclear leukocyte elastase in patients with primary breast cancer. Cancer Res 2003; 15(63):337-341
88. Yamashita J, Ogawa M, Ikei S, et al. Production of immunoreactive polymorphonuclear leucocyte elastase in human breast cancer cells: possible role of polymorphonuclear leucocyte elastase in the progression of human breast cancer. Br J Cancer 1994; 69:72-76.
89. Yamashita J, Ogawa M, Shirakusa T. Free-form neutrophil elastase is an independent marker predicting recurrence in primary breast cancer. J Leukoc Biol 1995; 57: 375-378
90. Yamashita J, Ogawa M, Abe M, et al. Tumor neutrophil elastase is closely associated with the direct extension of non-small cell lung cancer into the aorta. Chest 1997; 111: 885-890.
91. Yamashita J, Tashiro K, Yoneda S, et al. Local increase in polymorphonuclear leukocyte elastase is associated with tumor invasiveness in non-small cell lung cancer. Chest 1996; 109: 1328-1334.
92. Taniguchi K, Yang P, Jett J, et al. Polymorphisms in the promoter region of the neutrophil elastase gene are associated with lung cancer development. Olin Cancer Res 2002; 8: 1115-1120
93. Tanaka E, Yamashita J, Hayashi N, Kato S, et al. A pulmonary
metastatic model of human non-small cell lung carcinoma cells that produce a neutrophil elastase-like molecule in severe combined immunodeficiency mice. Chest. 2003 Apr; 123(4):1248-53.
94. Zhifu Sun and Ping Yang. Role of imbalance between neutrophil elastase and α1-antitrypsin in cancer development and progression. Oncnlogy 2004; 5(3):182-190
95. Yamaguchi K, Shimada S, Tashima S, et al. A potentially novel peptidase, resembling but distinct from neutrophil elastase, produced by carcinoma cells. Oncol Rep 2000; 7:1017-1021.
96. Shamamian P, Schwartz JD, Pocock BJ, et al. Activation of progelatinase A (MMP-2) by neutrophil elastase, cathepsin G, and Proteinase-3: a role for inflammatory cells in tumor invasion and angiogensis. J Cell Physiol 2001; 189:197-206
97. Okada Y, Nakanishi I. Activation of matrix metalloproteinase-3 (stromelysin) and matrix metalloproteinase-2 (gelatinase). by human neturophil elastase and cathespin G. FEBS Letters 1989; 249:353-356.
98. Chen G, Goeddel DV. TNF-R1 signaling: a beautiful pathway. Science 2002; 296:1634-1635
99. Szabo E, Riffe ME, Steinberg SM, et al. Altered cJUN expression: an early event in human lung carcinogenesis. Cancer Res 1996; 56:
305-315.
100. Smith LM, Wise SC, Hendricks DT, et al. c-Jun overexpression in MCF-7 breast cancer cells produces a tumorigenic, invasive and hormone resistant pheaotype. Oncogene 1999; 18: 6063-6070
101. Troll W, Meyn MS, Rossman TG. Mechanisms of protease action in carcinogenesis. Carcinogenesis 1977; 2:301-312.
102. Iwatsuki K, Kumara E, Yoshimine T, et al. Elastase expression by infiltrating neutrophils in gliomas. Neurol Res 2000; 22: 465-468.
103. Wang DG, Fan JB, Siao CJ, et al. Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science, 1998, 280:1077-1082.
104. Li W, SadlerLA. Low nucleotide diversity in man. Genetics, 1991, 129: 513-523.
105. Nickerson DA, Taylor SL, Weiss KM, et al. DNA sequence diversity in a 9. 7 kb region of the human lipoprotein lipase gene. Nature Genetics, 1998, 19: 233-240.
106. Broder S, Venter J C. Annu Rev Pharmacol Toxicol, 2000, 491 97; Sachidanandam R, et al. Nature, 2001, 409: 928.
107. Kruglyak L. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nature Genetics, 1999, 22:139-144.
108. Collins A, Loniou C, Morton NE. Genetic epidemiology of single-nucleotid polyphisms. Proc Natl Acad Sci U S A, 1999, 96(26):15173-7. /
109. Laan M, Paabo S. Demographic history and linkage disequilibrium in human populations, et al. Nat Genet, 1997, 17(4):435-8. /
110. Lonjou C, Collins A, Morton NE. Allelic association between marker loci. Proc Natl Acad Sci U S A, 1999, 96(4):1621-6. /
111. Nickerson DATaylor SL, Weiss KM, et al. DNA sequence diversity in a 9. 7-kb region of the human lipoprotein lipase gene. Nat Genet, 1998, 19(3):233-40. /
112. Halushka MK, Fan JB, Hsie L, et al. Patterns of single-nucleotide polymorphisms in candidate genes for blood pressure homeostasis. Nat Genet, 1999, 22(3):239-47. /
113. Rieder MJ, Taylor SL, Clark AG, et al. Sequence variation in the human angiotensin converting enzyme. Nat Genet, 1999, 22(1):59-62. /
114. Cambien F, Poirier O, Nicaud V, et al Sequence diversity in 36 candidate genes for cardiovascular disorders. Am J Hum Genet, 1999, 65(1):183-91. /
115. Cargill M, Altshuler D, Ireland J, et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes.
Nat Genet, 1999, 22(3):231-8. /
116. Ohnishi Y, Tanaka T yamada R, et al. Identification of 187 single nucleotide polymorphisms among 41 candidate genes for ischemic heart diease in the japanese population. Hum Genet, 2000, 106(3):288-92. /
117. Yamada R, Tanaka T. Identification of 142 single nucleotide polymorphisms in 41 candidate genes for rheumatoid arthritis in the japanese population. Hum Genet, 2000, 106(3):293-7. /
118．贾瑞鹏，程继义，马庆铮，等．局限性肾癌微血管侵犯的临床意义．中华泌尿外科杂志2003；24卷8期：512-513．
119. Osika E, Cavaillon J-M, Chadelat K, et al. Distinct sputum cytokine profiles in cystic fibrosis and other chronic inflammatory airway disease. Eur Respir J, 1999; 14:339.
120. Miami M, Llewellyn-Jones CH, Bayley D, et al. The chemotactic activity of sputum from patients with bronchiectasis. Am J Respir Crit Care Med, 1998; 157:723.
121. Yamashita J, Horiuchi S, Kimura M, et al. Plasminogen activator as afunctional marker for estrogen dependence in human breast cancer cells. Jpn J Cancer Res 1986; 77:177-181