Midkine、Skp2在大肠癌组织中的表达及其临床意义
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摘要
大肠癌是我国最常见的恶性肿瘤之一，其发病率有逐年上升的趋势。尽管近年来以手术为主的综合治疗使大肠癌患者的预后有很大改善，但术后5年生存率仍徘徊在50—60％左右。因此，深入研究控制大肠癌发生、发展过程的关键基因表达变化及其作用将为大肠癌早期诊断、预后判断和抗转移治疗提供理论依据。
目的：本研究旨在通过检测中期因子(Midkine，MK)mRNA、S期激酶相关蛋白2(S-phase kinase-associaced protein 2，Skp2)mRNA和Midkine蛋白、Skp2蛋白、MVD、p27~(kip1)蛋白在大肠不同病变组织的表达情况，探讨Midkine、Skp2在大肠癌中表达的临床意义及其与MVD、p27~(kip1)的关系，明确它们在大肠癌发生、发展中的作用，为临床诊断、治疗提供理论依据。
材料与方法：(1) 组织标本取自南方医科大学珠江医院2000．1-2004．10外科手术切除及结肠镜下活检标本。共选取83例大肠癌、18例大肠腺瘤和20例正常大肠黏膜标本。全部标本经4％多聚甲醛(含0.1％DEPC)固定液固定、常规脱水后石蜡包埋。(2) 应用原位杂交方法检测Midkine mRNA、Skp2 mRNA在大肠癌、大肠腺瘤和正常大肠黏膜组织中的表达。(3) 应用免疫组化SP
Background: Colorectal cancer is one of the commonest malignant tumors in China and its morbidity is still increasing . Although the operation-based comprehensive therapies have greatly improved the prognosis of colorectal cancer patients in recent years, the postoperative 5-year survival rate, unfortunately, is still about 50%. Therefore, further exploring the alterations of key genes related to development and progression of CRC will be considered useful.
Aims: In this study, We sought to investigate the expression of Midkine mRNA, Skp2 mRNA and Midkine protein, Skp2 protein, MVD, p27~(kip1) protein in colorectal cancer, and to identify the clinical significance of Midkine, Skp2 and its relationship with the expression of p27~(kip1) and MVD in colorectal cancer, to provide theoretical basis for early diagnosis and therapy of colorectal cancer.
Materials and Methods: (1) Tissue specimens used for this study were obtained from 101 patients with colorectal cancer or adenoma, which were resected surgically or endoscopically at Hospital from Jan. 2000 to Oct. 2004. All the samples including 20 normal colorectal mucosae, 18 adenomas and 83 cancers were fixed in 4% Polyoxymethylene(0. 1%DEPC) and embedded in paraffin. (2) The expression of Midkine mRNA, Skp2 mRNA was detected by in situ hybridization and the
目的：本研究旨在通过检测中期因子(Midkine，MK)mRNA、S期激酶相关蛋白2(S-phase kinase-associaced protein 2，Skp2)mRNA和Midkine蛋白、Skp2蛋白、MVD、p27~(kip1)蛋白在大肠不同病变组织的表达情况，探讨Midkine、Skp2在大肠癌中表达的临床意义及其与MVD、p27~(kip1)的关系，明确它们在大肠癌发生、发展中的作用，为临床诊断、治疗提供理论依据。
材料与方法：(1) 组织标本取自南方医科大学珠江医院2000．1-2004．10外科手术切除及结肠镜下活检标本。共选取83例大肠癌、18例大肠腺瘤和20例正常大肠黏膜标本。全部标本经4％多聚甲醛(含0.1％DEPC)固定液固定、常规脱水后石蜡包埋。(2) 应用原位杂交方法检测Midkine mRNA、Skp2 mRNA在大肠癌、大肠腺瘤和正常大肠黏膜组织中的表达。(3) 应用免疫组化SP
Background: Colorectal cancer is one of the commonest malignant tumors in China and its morbidity is still increasing . Although the operation-based comprehensive therapies have greatly improved the prognosis of colorectal cancer patients in recent years, the postoperative 5-year survival rate, unfortunately, is still about 50%. Therefore, further exploring the alterations of key genes related to development and progression of CRC will be considered useful.
Aims: In this study, We sought to investigate the expression of Midkine mRNA, Skp2 mRNA and Midkine protein, Skp2 protein, MVD, p27~(kip1) protein in colorectal cancer, and to identify the clinical significance of Midkine, Skp2 and its relationship with the expression of p27~(kip1) and MVD in colorectal cancer, to provide theoretical basis for early diagnosis and therapy of colorectal cancer.
Materials and Methods: (1) Tissue specimens used for this study were obtained from 101 patients with colorectal cancer or adenoma, which were resected surgically or endoscopically at Hospital from Jan. 2000 to Oct. 2004. All the samples including 20 normal colorectal mucosae, 18 adenomas and 83 cancers were fixed in 4% Polyoxymethylene(0. 1%DEPC) and embedded in paraffin. (2) The expression of Midkine mRNA, Skp2 mRNA was detected by in situ hybridization and the
引文
1．汪建平，杨祖立，王磊．结直肠癌临床病理特征与预后的多因素回归分析 中华肿瘤杂志，2003，25(1)：59-61．
2. Graeven U, Andre N, Schmiegel W. Colorectal cancer: current treatment options Z Gastroenterol. 2004, 42(12):1399-407.
3. Nakanishi T, Kadomatsu K, Okamoto T, et al. Expression of midkine and pleiotropin in ovarian tumors. Obstet Gynecol, 1997, 90(2):285-290.
4. Choudhuri R, Zhang HT, Donnini S, et al. An angiogenic role for the neurokines midkine and p leiotrophin in tumorigenesis. Cancer Res, 1997(2), 57:1814-1819.
5. Qi M, Ikematsu S, Ichihara-Tanaka K, et al. Midkine rescues Wilms' tumor cells from cisplatin-induced apoptosis: regulation of Bcl-2 expression by midkine. J Biochem, 2000, 127 (2):269-277.
6. Sato W, Kadomatsu K, Yuzawa Y, Yet al. Midkine is involved in neutrophil infiltration into the tubulointerstitium in ischemic renal injury. J immuol, 2001, 167(6):3463-3469.
7. Ikematsu S, Okamoto K, Yoshida Y, et al. High levels of urinary midkine in various cancer patients. Biochem Biophys Res Commun, 2003, 306 (2):329-332.
8. Kadomatsu K, Muramatsu T. Midkine and pleiotrophin in neural development and cancer. CancerLett, 2004, 204(2):127-143.
9. Ikematsu S, Yano A, Aridime K, et al. Serum midkine levels are increased in patients with various types of carcinomas. Br J Cancer, 2000, 83(6):701～706.
10．罗杰，王长谦，黄定九．CD34基因与血管内皮细胞．国外医学-生理、病理 科学与临床分册, 2000, 20 (6): 442-444.
11. Acenero MJ, Gonzalez JF, Gallego MG, et al. Vascular enumeration as a significant prognosticator for invasive breast carcinoma . J Clinical Oncology. 1998, 16 (5): 1684-1688.
12. Kudo Y, Kitajima S, Ogawa I. Down-regulation of Cdk inhibitor p27 in oral squamous cell carcinoma. Oral Oncol, 2005, 41 (2): 105-116.
13. Nitti D, Belluco C, Mammano E, et al. Low leavel of p27 (kipl) protein expression in gastric adenocarcinoma a is associated with disease progression and poor outcome. J Surg Oncol, 2002, 81 (4): 167-175.
14. Ohtani M, Isozaki H, Fujii K, et al. Impact of the expression of cyclin-dependent kinase inhibitor p27kipl and apoptosis in tumor cells on the over all survival of patients with non-early stage gastriccarcinoma. Cancer, 1999,85(8): 1711-1717.
15. Kossatz U, Dietrich N, Zender L, et al. Skp2-dependent degradation of p27kipl is essential for cell cycle progression. Genes Dev, 2004, 18(21): 2602-2607.
16. Tsvetkov LM, Yeh KH, Lee SJ, et al. p27 ( Kipl) ubiquitination and degradation is regulated by the SCF ( Skp2 ) complext hrough phosphorylated Thr187 in p27. Curr Biol, 1999, 9 (12) : 6612664.
17. Ishii T, MatsuseT, MasudaM, et al. The effects of S-phase kinase-associated protein 2 (SKP2) on cell cycle status, viability, and chemoresistance in A549 lung adenocarcinoma cells. Exp Lung Res, 2004, 30 (8): 687-703.
18. Ben-Izhak O, Lahav-Baratz S, Meretyk S, et al. Inverse relationship between Skp2 ubiquitin ligase and the cyclin dependent kinase inhibitor p27Kipl in prostate cancer. JUrol, 2003, 170 (1): 241-245.
19. WeidnerN, FolkmanJ, Pozza F, et al. Tumor angiogenesis: a new significant and independent prognostic indicator in early- stage breast carcinoma. Natl Cancer Inst, 1992, 84 (24): 1875-1887.
20. Kadomatsu K, Tomomura M, Muramatsu T, et al. cDNA cloning and sequencing of a new gene intensely expressed in early diferentiation stages of embryonal carcinoma cells and in mid-gestation period of mouse embryogenesis. Biochem Biophys Res Commun, 1988, 151 (3): 1312-1318.
21. Tomomura M, Kadomatsu K, Matsubara S, et al. A retinoic acid-responsive gene, MK, found in the teratocarcinoma system. Heterogeneity of the transcript and the nature of the translation product. J Biol Chem, 1990, 265 (18): 10765-10770.
22. Obama H, Matsubara S, Guenet J et al. The midkine (MK) family of growth/differentiation factors : structure of a MK-related sequence in a pseudogene and evolutionary relationship among members of the MK family. J Biochem, 1994, 115: 516-522.
23. Satyamoorthy K, Oka M, Herlyn, M. An antisense strategy for inhibition of human melanoma growth targets the growth factor pleiotrophin. Pigment Cell Res. 2000, 13 (Supple 8): 87-93.
24. Muramatsu H, Inui T, Kimura T, et al. Localization of heparin-binding, neuritis outgrowth and antigenic regions in midkine molecule. Biochem Biophys Res Commun. 1994, 203 (2): 1131-1139
25. Jun-ichiro T, Kazuyoshi U, Kenji K, et al. A new family of heparinbinding factors: strong conservation of midkine(MK) sequences between the human and the mouse. Biochem Biophys Res Commun 1991, 176(2): 792-797.
26. Uehara K, Matsubara S, Kadomatsu K, et al. Genomic structure of human midkine (MK), a retinoic acid-responsive growth/differentiation factor. J Biochem, 1992, 111 (5): 563-567.
27. Fairhurst JL, Kretschmer PJ, Kovacs E, et al. Structure of the gene coding for the human retinoic acid-inducible factor, MK. DNA and cell Biol, 1993, 12 (2): 139-147.
28. Pedraza C, Matsubara S, Muramatsu T. A retinoic acid-responsive element in human midkine gene. J Biochem. 1995, 117: 845-849.
29. Kadomatsu K, HagiharaM, Akhter S, et al. Midkine induces the transformation of NIH3T3 cells. BrJ Cancer, 1997, 75 (3): 354-359
30. Soichi K, Tatsuyal, Terutshi K, et al. Sythetic peptides derived from Midkine enhance plasminogen activator activity in bovine aortic endothelial cells. Biochem Biophys Res Commun, 1995, 206 (2): 468-473.
31. Konishi N, Nakamura M, Nakaoka S, et al, Immunohistochemical analysis of midkine expression in human prostate carcinoma. Oncology, 1999, 57 (3): 253-257.
32. Ratoviski EA, Burrow CR. Midkine stimulates wilm's tumor cell proliferation via its signaling receptor. CellMolBiol, 1997, 43 (3): 425-431.
33. Miyauchi M, Shimada H, Kadomatsu K, et al. Frequent expression of midkine gene in esophageal cancer suggests a potential usage of its promoter for suicide gene therapy. Jpn J Cancer Res, 1999, 90 (4): 469-475.
34. Aridome K, Takao S, Kaname T, et al. Truncated midkine as a marker of diagnosis and detection of nodal metastases in gastrointestinal carcinomas. Br J Cancer, 1998, 78 (4): 472-477.
35. Miyashirol, Kaname T, Nakayama T et al. Expression of truncated midkine in human colorectal cancers. Cancer Lett. 1996, 106 (2): 287-291.
36. Martin L, Holcombe C, Renshow C, et al. Standandising the counting technique of neo-vascularisation in invasive breast cancer. Breast Cancer Res Treat, 1996, 37 (Supple 1): 34-39.
37. Yokoi S, Yasui K, Saito-Ohara F et al. A novel target gene, SKP2, within the 5p13 amplicon that is frequently detected in small cell lung cancers. Am J Pathol. 2002, 161 (1): 207-216.
38. Schulman BA, Carrano AC, Jeffrey PD, et al. Insights into SCF ubiquit2in ligases from the structure of the SKP1-SKP2 complex. Nature, 2000, 408 (6810) : 381-386.
39. Jordan R, Bradley G, Slinyerland J. Reduced levels of the cell2cycleinhibitor p27 Kip1 in epithelial dysplasia and carcinoma of the oralcavity. Am J Pathol, 1998, 142 (2): 585-590.
40. Osoegawa A, Yoshino I, Tanaka S, et al. Regulation of p27 by S-phase kinase2associated protein 2 is associated with aggressiveness in non2small2cell lung cancer. JClin Oncol, 2004, 22 (20): 4165-4173.
41. Dong Y, SuiL, Watanabe Y, et al. S-phase kinase-associated p rotein 2 expression in laryngeal squamous cell carcinomas and its prognostic implications 1 Oncol Rep, 2003, 10 (2): 321-325.
42. MasudaTA, InoueH, SonodaH, et al. Clinical and biological significance of S-phase kinase-associated protein 2 ( Skp2 ) gene expression in gastric carcinoma. Cancer Res, 2002, 62 (13) : 3819-3825.
43. Oliveira AM, Okuno SH, Nascimento AG, et al. Skp2 protein expression in soft tissue sarcomas. JClin Oncol. 2003 Feb 15, 21 (4): 722-727.
1. Yokoi S, Yasui K, Saito-Ohara F et al. A novel target gene, SKP2, within the 5p13 amplicon that is frequently detected in small cell lung cancers. Am J Pathol. 2002, 161 (1):207-216.
2. Schulman BA, Carrano AC, Jeffrey PD, et al. Insights into SCF ubiquit2in ligases from the structure of the SKP1-SKP2 complex. Nature, 2000, 408 (6810):381-386.
3. Jordan R, Bradley G, Slinyerland J. Reduced levels of the cell2cycleinhibitor p27 Kipl in epithelial dysplasia and carcinoma of the oralcavity. Am J Pathol, 1998, 142(2):585-590.
4. Garrano AC, Eytan E, Hershko A, et al. SKP2 is required for ubiquitin2mediated degradation of the CDK inhibitor p27. Nat Cell Biol,1999, 1(4):193-199.
5. Tsvetkov LM, Yeh KH, Lee SJ, et al. p27 ( Kip1) ubiquitination and degradation is regulated by the SCF ( Skp2 ) complext hrough phosphorylated Thr187 in p27. Curr Biol, 1999, 9 (12) : 661-664.
6. Bornstein G, Bloom J, Sitry-Shevah D, et al. Role of the SCFSkp2 ubiquitin ligase in the degradation of p21Cip1 in S phase. J Biol Chem. 2003, 278(28): 25752-25757.
7. Tedesco D, Lukas J, Reed SI. The pRb2related protein p130 is regulated by phosphorylation2dependent proteolysis via the protein2ubiquitin ligase SCF ( Skp2). Genes Dev, 2002, 16 (22) : 2946-2957.
8. Liang M, Liang YY, Wrighton K, et al. Ubiquitination and proteolysis of cancer-derived Smad4 mutants by SCFSkp2. Mol Cell Biol, 2004, 24 (17): 7524-7537.
9. Farhana L , Dswson M, Rishi AK, et al. CyclinB and E2F21 expression in prostate carcinoma cells treated with the novel retinoid CD437 are regulated by the ubiquitin-mediated pathway. Cancer Res, 2002, 62 (13): 3842-3849.
10. Vonder Lehr N, Johansson S, Larsson LG. Imp lication of the ubiquitin system in Myc-regulated transcription. Cell Cycle, 2003, 2 (5): 403-407.
11. Imaki H, Nakayama K, Delehouzee S, et al. Cell cycle dependent regulation of Skp2 promoter by GA2binding protein. Cancer Res, 2003, 63 (15): 4607-4613.
12. Wang W, Ungermannova D, Jin J P, et al. Negative regulation of SCF-Skp2 ubiquitin ligase by TGF-beta signaling. J Cell Bio, 2005, 168 (1): 55-66.
13. Stewart SA, Kothapalli D, Yung Y, Antimitogenesis linked to regulation of Skp2 gene expression. J Biol Chem. 2004, 279 (28): 29109-29113.
14. Yang G, Ayala G, Marzo AD, et a. Elevated Skp2 protein expression in human prostate cancer: association wit h loss of the cyclin2dependent kinase inhibitior p27 and PTEN and with reduced recurrence2free survival. Clin Cancer Res, 2002, 8 (11): 3419-3426.
15. Zhang YW, Nakayama K, Nakayama KI, et al. A novel route for connexin 43 to inhibit cell proliferation: negative regulation of s-phase kinase2associated protein ( Skp2) . Cancer Res, 2003, 63 (7): 1623-1630.
16. Osoegawa A, Yoshino I, Tanaka S, et al. Regulation of p27 by S-phase kinase2associated protein 2 is associated with aggressiveness in non2small2cell lung cancer. JClin Oncol, 2004, 22 (20): 4165-4173.
17. Dong Y, SuiL, Watanabe Y, et al. S-phase kinase-associated p rotein 2 expression in laryngeal squamous cell carcinomas and its prognostic implications 1 Oncol Rep, 2003, 10 (2): 321-325.
18. BaratzLS, lzhak BO, SaboE, etal. Decreased level of the cell cycle regulator p27 and increased level of its ubiquitin ligase Skp2 in endometrial carcinoma but not in normal secretory or in hyperstimulated endometrium. Mol Hum Reprod, 2004, 10 (8): 567-572.
19. Langner C, Wasielewski R, RatschekM, et al. Exp ression of p27 and its ubiquitin ligase subunit skp2 in upper urinary tract transitional cell carcinoma. Urology, 2004, 64 (3): 611-616.
20. Knight JS , Sharma N, Robertson ES. SCF-Skp2 complex targeted by Epstein-Barr virus essential nuclear antigen. Mol Cell Biol. 2005, 25 (5): 1749-1763.
21. Masuda TA, Inoue H, Sonoda H, et al. Clinical and biological significance of S-phase kinase-associated protein 2 ( Skp2) gene expression in gastric carcinoma. Cancer Res, 2002, 62 (13) : 3819-3825.
22. Oliveira AM, Okuno SH, Nascimento AG, et al. Skp2 protein expression in soft tissue sarcomas. J Clin Oncol. 2003, 21 (4): 722-727.
23. Dowen SE, Scott A, Mukherjee G, et al, Overexp ression of Skp2 in carcinoma of the cervix does not correlate inversely with p27 expression. Int J Cancer, 2003, 105 (3): 326-330.
24. Signoretti S, Di Marcotullio L, Richardson A, et al. Oncogenic role of the ubiquitin ligase subunit Skp2 in human breast cancer. J Clin Invest. 2002, 110 (5): 633-641.
25. Hu YQ, Liu YJ. Expression of Cx43 and Skp2 in epithelial ovarian tumor and their clinical significances. Aizheg, 2005, 24 (1): 104-109.
26. Lim MS, Adamson A, Lin Z, et al. Expression of Skp2, a p27 (Kip1) ubiquitin ligase, in malignant lymphoma: correlation with p27 (Kip1 ) and proliferation index. Blood. 2002, 100 (8): 2950-2956.
27. Yokoi S, Yasui K, LizasaT, et al. Down-regulation of skp2 induces apoptosis in lung-cancer cells. Cancer Sci, 2003, 94 (4): 344-349.
28. Kodo Y, Kitajima S, Shimizu A, et al. Small interfering RNA targeting of S-phase kinase-interacting protein 2 inhibits cell growth of oral cancer cells by inhibiting p27 degradation. Mol Cancer Ther, 2005, 4 (3): 471-476.
29. Sumimoto H, Yamagata S, Shimizu A, et al. Gene therapy for human small-cell lung carcinoma by inactivation of Skp-2 with virally mediated RNA interference. Gene Ther, 2005, 12 (1): 95-100.
2. Graeven U, Andre N, Schmiegel W. Colorectal cancer: current treatment options Z Gastroenterol. 2004, 42(12):1399-407.
3. Nakanishi T, Kadomatsu K, Okamoto T, et al. Expression of midkine and pleiotropin in ovarian tumors. Obstet Gynecol, 1997, 90(2):285-290.
4. Choudhuri R, Zhang HT, Donnini S, et al. An angiogenic role for the neurokines midkine and p leiotrophin in tumorigenesis. Cancer Res, 1997(2), 57:1814-1819.
5. Qi M, Ikematsu S, Ichihara-Tanaka K, et al. Midkine rescues Wilms' tumor cells from cisplatin-induced apoptosis: regulation of Bcl-2 expression by midkine. J Biochem, 2000, 127 (2):269-277.
6. Sato W, Kadomatsu K, Yuzawa Y, Yet al. Midkine is involved in neutrophil infiltration into the tubulointerstitium in ischemic renal injury. J immuol, 2001, 167(6):3463-3469.
7. Ikematsu S, Okamoto K, Yoshida Y, et al. High levels of urinary midkine in various cancer patients. Biochem Biophys Res Commun, 2003, 306 (2):329-332.
8. Kadomatsu K, Muramatsu T. Midkine and pleiotrophin in neural development and cancer. CancerLett, 2004, 204(2):127-143.
9. Ikematsu S, Yano A, Aridime K, et al. Serum midkine levels are increased in patients with various types of carcinomas. Br J Cancer, 2000, 83(6):701～706.
10．罗杰，王长谦，黄定九．CD34基因与血管内皮细胞．国外医学-生理、病理 科学与临床分册, 2000, 20 (6): 442-444.
11. Acenero MJ, Gonzalez JF, Gallego MG, et al. Vascular enumeration as a significant prognosticator for invasive breast carcinoma . J Clinical Oncology. 1998, 16 (5): 1684-1688.
12. Kudo Y, Kitajima S, Ogawa I. Down-regulation of Cdk inhibitor p27 in oral squamous cell carcinoma. Oral Oncol, 2005, 41 (2): 105-116.
13. Nitti D, Belluco C, Mammano E, et al. Low leavel of p27 (kipl) protein expression in gastric adenocarcinoma a is associated with disease progression and poor outcome. J Surg Oncol, 2002, 81 (4): 167-175.
14. Ohtani M, Isozaki H, Fujii K, et al. Impact of the expression of cyclin-dependent kinase inhibitor p27kipl and apoptosis in tumor cells on the over all survival of patients with non-early stage gastriccarcinoma. Cancer, 1999,85(8): 1711-1717.
15. Kossatz U, Dietrich N, Zender L, et al. Skp2-dependent degradation of p27kipl is essential for cell cycle progression. Genes Dev, 2004, 18(21): 2602-2607.
16. Tsvetkov LM, Yeh KH, Lee SJ, et al. p27 ( Kipl) ubiquitination and degradation is regulated by the SCF ( Skp2 ) complext hrough phosphorylated Thr187 in p27. Curr Biol, 1999, 9 (12) : 6612664.
17. Ishii T, MatsuseT, MasudaM, et al. The effects of S-phase kinase-associated protein 2 (SKP2) on cell cycle status, viability, and chemoresistance in A549 lung adenocarcinoma cells. Exp Lung Res, 2004, 30 (8): 687-703.
18. Ben-Izhak O, Lahav-Baratz S, Meretyk S, et al. Inverse relationship between Skp2 ubiquitin ligase and the cyclin dependent kinase inhibitor p27Kipl in prostate cancer. JUrol, 2003, 170 (1): 241-245.
19. WeidnerN, FolkmanJ, Pozza F, et al. Tumor angiogenesis: a new significant and independent prognostic indicator in early- stage breast carcinoma. Natl Cancer Inst, 1992, 84 (24): 1875-1887.
20. Kadomatsu K, Tomomura M, Muramatsu T, et al. cDNA cloning and sequencing of a new gene intensely expressed in early diferentiation stages of embryonal carcinoma cells and in mid-gestation period of mouse embryogenesis. Biochem Biophys Res Commun, 1988, 151 (3): 1312-1318.
21. Tomomura M, Kadomatsu K, Matsubara S, et al. A retinoic acid-responsive gene, MK, found in the teratocarcinoma system. Heterogeneity of the transcript and the nature of the translation product. J Biol Chem, 1990, 265 (18): 10765-10770.
22. Obama H, Matsubara S, Guenet J et al. The midkine (MK) family of growth/differentiation factors : structure of a MK-related sequence in a pseudogene and evolutionary relationship among members of the MK family. J Biochem, 1994, 115: 516-522.
23. Satyamoorthy K, Oka M, Herlyn, M. An antisense strategy for inhibition of human melanoma growth targets the growth factor pleiotrophin. Pigment Cell Res. 2000, 13 (Supple 8): 87-93.
24. Muramatsu H, Inui T, Kimura T, et al. Localization of heparin-binding, neuritis outgrowth and antigenic regions in midkine molecule. Biochem Biophys Res Commun. 1994, 203 (2): 1131-1139
25. Jun-ichiro T, Kazuyoshi U, Kenji K, et al. A new family of heparinbinding factors: strong conservation of midkine(MK) sequences between the human and the mouse. Biochem Biophys Res Commun 1991, 176(2): 792-797.
26. Uehara K, Matsubara S, Kadomatsu K, et al. Genomic structure of human midkine (MK), a retinoic acid-responsive growth/differentiation factor. J Biochem, 1992, 111 (5): 563-567.
27. Fairhurst JL, Kretschmer PJ, Kovacs E, et al. Structure of the gene coding for the human retinoic acid-inducible factor, MK. DNA and cell Biol, 1993, 12 (2): 139-147.
28. Pedraza C, Matsubara S, Muramatsu T. A retinoic acid-responsive element in human midkine gene. J Biochem. 1995, 117: 845-849.
29. Kadomatsu K, HagiharaM, Akhter S, et al. Midkine induces the transformation of NIH3T3 cells. BrJ Cancer, 1997, 75 (3): 354-359
30. Soichi K, Tatsuyal, Terutshi K, et al. Sythetic peptides derived from Midkine enhance plasminogen activator activity in bovine aortic endothelial cells. Biochem Biophys Res Commun, 1995, 206 (2): 468-473.
31. Konishi N, Nakamura M, Nakaoka S, et al, Immunohistochemical analysis of midkine expression in human prostate carcinoma. Oncology, 1999, 57 (3): 253-257.
32. Ratoviski EA, Burrow CR. Midkine stimulates wilm's tumor cell proliferation via its signaling receptor. CellMolBiol, 1997, 43 (3): 425-431.
33. Miyauchi M, Shimada H, Kadomatsu K, et al. Frequent expression of midkine gene in esophageal cancer suggests a potential usage of its promoter for suicide gene therapy. Jpn J Cancer Res, 1999, 90 (4): 469-475.
34. Aridome K, Takao S, Kaname T, et al. Truncated midkine as a marker of diagnosis and detection of nodal metastases in gastrointestinal carcinomas. Br J Cancer, 1998, 78 (4): 472-477.
35. Miyashirol, Kaname T, Nakayama T et al. Expression of truncated midkine in human colorectal cancers. Cancer Lett. 1996, 106 (2): 287-291.
36. Martin L, Holcombe C, Renshow C, et al. Standandising the counting technique of neo-vascularisation in invasive breast cancer. Breast Cancer Res Treat, 1996, 37 (Supple 1): 34-39.
37. Yokoi S, Yasui K, Saito-Ohara F et al. A novel target gene, SKP2, within the 5p13 amplicon that is frequently detected in small cell lung cancers. Am J Pathol. 2002, 161 (1): 207-216.
38. Schulman BA, Carrano AC, Jeffrey PD, et al. Insights into SCF ubiquit2in ligases from the structure of the SKP1-SKP2 complex. Nature, 2000, 408 (6810) : 381-386.
39. Jordan R, Bradley G, Slinyerland J. Reduced levels of the cell2cycleinhibitor p27 Kip1 in epithelial dysplasia and carcinoma of the oralcavity. Am J Pathol, 1998, 142 (2): 585-590.
40. Osoegawa A, Yoshino I, Tanaka S, et al. Regulation of p27 by S-phase kinase2associated protein 2 is associated with aggressiveness in non2small2cell lung cancer. JClin Oncol, 2004, 22 (20): 4165-4173.
41. Dong Y, SuiL, Watanabe Y, et al. S-phase kinase-associated p rotein 2 expression in laryngeal squamous cell carcinomas and its prognostic implications 1 Oncol Rep, 2003, 10 (2): 321-325.
42. MasudaTA, InoueH, SonodaH, et al. Clinical and biological significance of S-phase kinase-associated protein 2 ( Skp2 ) gene expression in gastric carcinoma. Cancer Res, 2002, 62 (13) : 3819-3825.
43. Oliveira AM, Okuno SH, Nascimento AG, et al. Skp2 protein expression in soft tissue sarcomas. JClin Oncol. 2003 Feb 15, 21 (4): 722-727.
1. Yokoi S, Yasui K, Saito-Ohara F et al. A novel target gene, SKP2, within the 5p13 amplicon that is frequently detected in small cell lung cancers. Am J Pathol. 2002, 161 (1):207-216.
2. Schulman BA, Carrano AC, Jeffrey PD, et al. Insights into SCF ubiquit2in ligases from the structure of the SKP1-SKP2 complex. Nature, 2000, 408 (6810):381-386.
3. Jordan R, Bradley G, Slinyerland J. Reduced levels of the cell2cycleinhibitor p27 Kipl in epithelial dysplasia and carcinoma of the oralcavity. Am J Pathol, 1998, 142(2):585-590.
4. Garrano AC, Eytan E, Hershko A, et al. SKP2 is required for ubiquitin2mediated degradation of the CDK inhibitor p27. Nat Cell Biol,1999, 1(4):193-199.
5. Tsvetkov LM, Yeh KH, Lee SJ, et al. p27 ( Kip1) ubiquitination and degradation is regulated by the SCF ( Skp2 ) complext hrough phosphorylated Thr187 in p27. Curr Biol, 1999, 9 (12) : 661-664.
6. Bornstein G, Bloom J, Sitry-Shevah D, et al. Role of the SCFSkp2 ubiquitin ligase in the degradation of p21Cip1 in S phase. J Biol Chem. 2003, 278(28): 25752-25757.
7. Tedesco D, Lukas J, Reed SI. The pRb2related protein p130 is regulated by phosphorylation2dependent proteolysis via the protein2ubiquitin ligase SCF ( Skp2). Genes Dev, 2002, 16 (22) : 2946-2957.
8. Liang M, Liang YY, Wrighton K, et al. Ubiquitination and proteolysis of cancer-derived Smad4 mutants by SCFSkp2. Mol Cell Biol, 2004, 24 (17): 7524-7537.
9. Farhana L , Dswson M, Rishi AK, et al. CyclinB and E2F21 expression in prostate carcinoma cells treated with the novel retinoid CD437 are regulated by the ubiquitin-mediated pathway. Cancer Res, 2002, 62 (13): 3842-3849.
10. Vonder Lehr N, Johansson S, Larsson LG. Imp lication of the ubiquitin system in Myc-regulated transcription. Cell Cycle, 2003, 2 (5): 403-407.
11. Imaki H, Nakayama K, Delehouzee S, et al. Cell cycle dependent regulation of Skp2 promoter by GA2binding protein. Cancer Res, 2003, 63 (15): 4607-4613.
12. Wang W, Ungermannova D, Jin J P, et al. Negative regulation of SCF-Skp2 ubiquitin ligase by TGF-beta signaling. J Cell Bio, 2005, 168 (1): 55-66.
13. Stewart SA, Kothapalli D, Yung Y, Antimitogenesis linked to regulation of Skp2 gene expression. J Biol Chem. 2004, 279 (28): 29109-29113.
14. Yang G, Ayala G, Marzo AD, et a. Elevated Skp2 protein expression in human prostate cancer: association wit h loss of the cyclin2dependent kinase inhibitior p27 and PTEN and with reduced recurrence2free survival. Clin Cancer Res, 2002, 8 (11): 3419-3426.
15. Zhang YW, Nakayama K, Nakayama KI, et al. A novel route for connexin 43 to inhibit cell proliferation: negative regulation of s-phase kinase2associated protein ( Skp2) . Cancer Res, 2003, 63 (7): 1623-1630.
16. Osoegawa A, Yoshino I, Tanaka S, et al. Regulation of p27 by S-phase kinase2associated protein 2 is associated with aggressiveness in non2small2cell lung cancer. JClin Oncol, 2004, 22 (20): 4165-4173.
17. Dong Y, SuiL, Watanabe Y, et al. S-phase kinase-associated p rotein 2 expression in laryngeal squamous cell carcinomas and its prognostic implications 1 Oncol Rep, 2003, 10 (2): 321-325.
18. BaratzLS, lzhak BO, SaboE, etal. Decreased level of the cell cycle regulator p27 and increased level of its ubiquitin ligase Skp2 in endometrial carcinoma but not in normal secretory or in hyperstimulated endometrium. Mol Hum Reprod, 2004, 10 (8): 567-572.
19. Langner C, Wasielewski R, RatschekM, et al. Exp ression of p27 and its ubiquitin ligase subunit skp2 in upper urinary tract transitional cell carcinoma. Urology, 2004, 64 (3): 611-616.
20. Knight JS , Sharma N, Robertson ES. SCF-Skp2 complex targeted by Epstein-Barr virus essential nuclear antigen. Mol Cell Biol. 2005, 25 (5): 1749-1763.
21. Masuda TA, Inoue H, Sonoda H, et al. Clinical and biological significance of S-phase kinase-associated protein 2 ( Skp2) gene expression in gastric carcinoma. Cancer Res, 2002, 62 (13) : 3819-3825.
22. Oliveira AM, Okuno SH, Nascimento AG, et al. Skp2 protein expression in soft tissue sarcomas. J Clin Oncol. 2003, 21 (4): 722-727.
23. Dowen SE, Scott A, Mukherjee G, et al, Overexp ression of Skp2 in carcinoma of the cervix does not correlate inversely with p27 expression. Int J Cancer, 2003, 105 (3): 326-330.
24. Signoretti S, Di Marcotullio L, Richardson A, et al. Oncogenic role of the ubiquitin ligase subunit Skp2 in human breast cancer. J Clin Invest. 2002, 110 (5): 633-641.
25. Hu YQ, Liu YJ. Expression of Cx43 and Skp2 in epithelial ovarian tumor and their clinical significances. Aizheg, 2005, 24 (1): 104-109.
26. Lim MS, Adamson A, Lin Z, et al. Expression of Skp2, a p27 (Kip1) ubiquitin ligase, in malignant lymphoma: correlation with p27 (Kip1 ) and proliferation index. Blood. 2002, 100 (8): 2950-2956.
27. Yokoi S, Yasui K, LizasaT, et al. Down-regulation of skp2 induces apoptosis in lung-cancer cells. Cancer Sci, 2003, 94 (4): 344-349.
28. Kodo Y, Kitajima S, Shimizu A, et al. Small interfering RNA targeting of S-phase kinase-interacting protein 2 inhibits cell growth of oral cancer cells by inhibiting p27 degradation. Mol Cancer Ther, 2005, 4 (3): 471-476.
29. Sumimoto H, Yamagata S, Shimizu A, et al. Gene therapy for human small-cell lung carcinoma by inactivation of Skp-2 with virally mediated RNA interference. Gene Ther, 2005, 12 (1): 95-100.