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博碩士論文 etd-0813113-071807 詳細資訊
Title page for etd-0813113-071807
論文名稱
Title
活化型STAT3的表現在台灣子宮頸癌上所扮演的角色
The Role of Activated STAT3 (p-tyr705 and p-ser727-STAT3) in Taiwanese Cervical Cancer
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
49
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2013-07-31
繳交日期
Date of Submission
2013-09-13
關鍵字
Keywords
細胞訊息傳遞、STAT3酪氨酸705位置磷酸化、癌症、子宮頸癌、STAT3絲氨酸727位置磷酸化
cancer, Cervical cancer, phosphorylated serine residue 727 (p-ser727-STAT3), phosphorylated tyrosine residue 705 (p-tyr705-STAT3), signal transducer and activator
統計
Statistics
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中文摘要
子宮頸癌是全世界女性腫瘤中造成許多患者死亡的癌症之一。雖然子宮頸抹片檢查已經發展成為有效的偵測子宮頸癌癌症初期的篩選方式。但是我們對於病毒與造成人類癌症之發展機轉仍然未明。活化細胞訊息傳遞路徑JAK/STAT中的signal transducer and activator of transcription 3 (STAT3)已經被並證實與許多癌症形成有關。然而在STAT3之酪氨酸705位置磷酸化(p-tyr705-STAT3)和STAT3絲氨酸727位置磷酸化(p-ser727-STAT3)在子宮頸癌的形成機轉中的功能及影響仍未明朗。我們研究主要的目的是為了要了解活化STAT3之酪氨酸705位置磷酸化與絲氨酸727位置磷酸化分別在子宮頸癌的形成所扮演的角色。研究結果顯示臨床上當病患有較高p-tyr705-STAT3、p-ser727-STAT3與Ki67(細胞增生標記)的表現量時,這些病患預後較差。
Abstract
Cervical cancer is one of the most important female deaths caused by cancer in the world. Although the Pap smear has become an effective screening method for early detection of cervical cancer.The cause of human cancer by virus and mechanisms of cancer development are still unclear.Activation of signal transducer and activator of transcription 3 (STAT3) in JAK/STAT signaling pathway has been observed during the development of cancer formation.
However,the roles play by the phosphorylated tyrosine residue 705 (p-tyr705-STAT3) and phosphorylated serine residue 727 (p-ser727-STAT3) of STAT3 in cervical carcinogenesis of human clinical specimens are not clear.
Our research aimed to understand the role of phosphorylation of signal transducer and activator of transcription 3 (STAT3) at the tyrosine residue 705 and the serine residue 727 respectively.The results indicated that patients with higher expression of both activated residues,p-tyr705 and p-ser727,and Ki67,a cell proliferation marker,showed poor prognosis significantly.
目次 Table of Contents
論文審定書 i
中文摘要 ii
英文摘要 iii
目錄 iv
圖次 vi
表次 vii
第一章 背景介紹 1
1.1 子宮頸癌 1
1.2 STATs 蛋白質 2
1.3 STATs 蛋白質簡介 3
1.4 STATs蛋白質的結構 4
1.5 STATs蛋白質的活化機制 4
1.6 STATs蛋白質與腫瘤形成的相關性 5
1.7 STAT3蛋白質 6
1.8 STAT3蛋白質與腫瘤發生之關係 6
1.9 Ki67蛋白質 7
第二章 實驗目的 8
第三章 實驗材料和方法 9
3.1檢體收集與保存 9
3.2 化學免疫組織染色法 9
3.2.1石蠟包埋組織切片 9
3.2.2 化學免疫組織染色(Immunohistochemistry,IHC)試劑 9
3.2.3化學免疫組織染色法步驟 10
3.2.4化學免疫組織染色結果評估 11
3.3統計分析 11
第四章 實驗結果 12
第五章 討論 14
參考文獻 15
圖表 22
附錄圖表 34
參考文獻 References
中華民國行政院衛生福利部國民健康署癌症防治網於2013年5月6日公告癌症統計資料(Http://www.hpa.gov.tw)
行政院衛生署國民健康局.中華民國100 年子宮頸癌篩檢登記報告資料(Http://www.hpa.gov.tw)
Akira, S: Roles of STAT3 defined by tissue-specific gene targeting. Oncogene 2000, 19:2607-2611.
Arany I, Grattendick KG, Tyring SK: Interleukin-10 induces transcription of the early promoter of human papillomavirus type 16 (HPV16) through the 5'-segment of the upstream regulatory region (URR). Antiviral Res 2002, 55: 331-9.
Aggarwal BB, Kunnumakkara AB, Harikumar KB, et al.: Signal transducer and activator of transcription-3, inflammation, and cancer: how intimate is the relationship? Ann N Y Acad Sci 2009, 1171: 59-76.
Aggarwal BB, Sethi G, Ahn KS, et al.:Targeting signal-transducer-and-activator-of-transcription-3 for prevention and therapy of cancer: modern target but ancient solution. Ann N Y Acad Sci. 2006 , 1091: 151-69.
Bromberg, JF, Horvath, CM, Wen, Z, Schreiber, RD, Darnell JE Jr :Transcriptionally active Stat1 is required for the antiproliferative effects of both IFN-α and IFN-γ. Proc Natl Acad Sci USA 1996, 93: 7673-7678.
Bromberg, JF, Fan, Z, Brown, C, Mendelsohn, J, Darnell JE Jr: Epidermal growth factor-induced growth inhibition requires Stat1 activation. Cell Growth Differ 1998, 9: 505-512.
Bromberg J,Horvath CM, Besser D,Lathem WW,Darnell JE Jr. Stat3 activation is required for cellular transformation by v-src.Mol Cell Biol 1998, 18: 2553-8.
Bromberg, J, Darnell JE Jr: The role of STATs in transcriptional control and their impact on cellular function. Oncogene 2000, 19: 2468-2473.
Bromberg J.Stat proteins and oncogenesis.J Clin Invest.2002.109:1139-42
Buettner R, Mora LB, Jove R. Activated STAT signaling in humain tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res 2002, 8: 945-54.
Bromberg JF, Wrzeszczynska MH, Devgan G,et al: Stat3 as an oncogene. Cell 1999, 98: 295-303.
Bao YP, Li N, Smith JS, Qiao YL: Human papillomavirus type distribution in women from Asia: a meta-analysis. Int J Gynecol Cancer 2008, 18: 71-9.
Bharti AC, Donato N, Singh S, Aggarwal BB: Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and IkappaBalpha kinase in human multiple myeloma cells, leading to uppression of proliferation and induction of apoptosis. Blood 2003, 101: 1053-62.
Bharti AC, Donato N, Aggarwal BB: Curcumin (diferuloylmethane) inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cells. J Immunol 2003, 171: 3863-71.
Bharti AC, Shukla S, Mahata S, Hedau S, Das BC:Anti-human papillomavirus therapeutics: facts & future. Indian J Med Res. 2009 , 130 : 296-310.
Caldenhoven E, van Dijk TB,Solari R,Armstrong J, Raaijmakers JA,Lammers JW,Koenderman L,de Groot RP.STAT3beta,a splice variant of transcription factor STAT3,is a domainant negative regulator of transcription.J Biol Chem 1996, 271: 13221-7.
Calò V, Migliavacca M, Bazan V ,et al:STAT proteins from normal control of cellular events to tumorigenesis. J Cell Physiol. 2003, 197: 157-68.
Catlett-Falcone R,Dalton WS,Jove R.STAT proteins as novel targets for cancer therapy.Signal transducer an activator of transcription.Curr Opin Oncol 1999, 11: 490-6.
Chen CL, Hsieh FC, Lieblein JC, et al.: Stat3 activation in human endometrial and cervical cancers. Br J Cancer 2007, 96: 591-9.
Clifford GM, Gallus S, Herrero R, et al.: Worldwide distribution of human papillomavirus types in cytologically normal women in the International Agency for Research on Cancer HPV prevalence surveys: a pooled analysis. Lancet. 2005, 366: 991-8.
Candotti, F., Notarangelo, L., Visconti, R., and O’Shea, J. Molecular aspects of primary immunodeficiencies: lessons from cytokine and other signaling pathways. J. Clin. Invest. In press. J Clin Invest. 2002, 109: 1261-9.
Chin, YE, et al. Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/CIP1 mediated by STAT1. Science 1996, 272: 719-722.
Chapman RS,Lourenco PC,Tonner E,Flint DJ,Selbert S,Takeda K,Akira S,Clarke AR,Watson CJ.Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3.Genes Dev 1999, 13: 2604-16.
Chatley A, Jaiswal AK, Jain M, Behari S .Congenital irreducible atlantoaxial dislocation associated with cervical intramedullary astrocytoma causing progressive spastic quadriparesis. Neurol India 2008, 56: 477-9.
Decker, T., Stockinger, S., Karaghiosoff, M., Müller, M., and Kovarik, P. Interferons and Stats in innate immunity to microorganisms. J. Clin. Invest. In press. J Clin Invest. 2002, 109: 1271-7.
Darnell JE Jr,. STATs and gene regulation. Science 1997, 277: 1630-1635.
Darnell JE .Reflections on STAT3,STAT5,andSTAT6 as fat STATs. Proc Natl Acad Sci 1996, 93: 6221-4.
Durbin, JE, Hackenmiller, R, Simon, MC, Levy, DE. Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell 1996, 84: 443-450.
Dupuis S, Dargemont C, Fieschi C, et al Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation. Science 2001, 13,293: 300-3.
Fuaka T,Hibi M,Yamanaka Y,Takahashi-Tezuka M,Fujitani Y,Yamaguchi T,Nadajima K,Hirano T.Two signals are necessary for cell proliferation induces by a cytokine receptor gp130:involvement of STAT3 in anti-apoptosis Immunity 1996, 5: 449-60.
Germain D, Frank DA: Targeting the cytoplasmic and nuclear functions of signal transducers and activators of transcription 3 for cancer therapy. Clin Cancer Res. 2007, 13: 5665-9.
Garcia R,Bowman TL,Niu G,Tu H,Minton S,Muro-Cacho CA,Cox CE,Falcone R,Fairclough R,Parsons S,Laudano A,Gazit A,Levitzki A,Kraker A,Jove R.Constitutive activation of Stat3 by the Src and JAK tyrosin kinases participates in growth regulation of human breast carcinoma cells.Oncogene 2001, 20: 2499-513.
Johansen C, Mellemkjaer L, Frisch M, Kjaer SK, Gridley G, Olsen JH.Acta:Risk for anogenital cancer and other cancer among women hospitalized with gonorrhea. Acta Obstet Gynecol Scand. 2001, 80: 757-61.
Kaplan, DH, et al. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci USA 1998, 95: 7556-7561.
Kumar, A, Commane, M, Flickinger, TW, Horvath, CM, Stark, GR.DefectiveTNF-alpha-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science 1997, 278: 1630-1632.
Kim DJ, Chan KS, Sano S, Digiovanni J: Signal transducer and activator of transcription 3 (Stat3) in epithelial carcinogenesis. Mol Carcinog 2007, 46: 725-31.
Levy, DE. Physiological significance of STAT proteins: investigations through gene disruption in vivo. Cell Mol Life Sci 1999, 55: 1559-1567.
Levy, DE, Lee, C. What does Stat3 do? J Clin Invest 2002, 109: 1143-1148.
Lee, CK, Smith, E, Gimeno, R, Gertner, R, Levy, DE. STAT1 affects lymphocyte survival and proliferation partially independent of its role downstream of IFN-gamma. J Immunol 2000, 164: 1286-1292.
Levy DE, Darnell JE Jr: Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 2002, 3: 651-62.
Meraz, MA, et al. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 1996, 84: 431-442.
Ouchi, T, Lee, SW, Ouchi, M, Aaronson, SA, Horvath, CM. Collaboration of signal transducer and activator of transcription 1 (STAT1) and BRCA1 in differential regulation of IFN-gamma target genes. Proc Natl Acad Sci USA 2000, 97: 5208-5213.
Prusty BK, Das BC: Constitutive activation of transcription factor AP-1 in cervical cancer and suppression of human papillomavirus (HPV) transcription and AP-1 activity in HeLa cells by curcumin. Int J Cancer. 2005, 113: 951-60.
Prusty BK, Husain SA, Das BC: Constitutive activation of nuclear factor-kB: preferntial homodimerization of p50 subunits in cervical carcinoma. Front Biosci 2005, 10: 1510-9.
Sexl, V, et al. Stat5a/b contribute to interleukin 7-induced B-cell precursor expansion, but abl- and bcr/abl-induced transformation are independent of stat5. Blood 2000, 96: 2277-2283.
Schwaller J, Parganas E, Wang D, et al. Stat5 is essential for the myelo- and lymphoproliferative disease induced by TEL/JAK2. Mol Cell 2000, 6: 693-704.
Sankaranarayanan R: Overview of cervical cancer in the developing world. FIGO 6th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet 2006, 95 Suppl 1: S205-10.
Thierry F: Transcriptional regulation of the papillomavirus oncogenes by cellular and viral transcription factors in cervical carcinoma. Virology 2009, 384: 375-9.
Wen Z, Zhong Z, Darnell JE Jr: Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 1995, 82: 241-50.
Wang R, Cherukuri P, Luo J: Activation of Stat3 sequence-specific DNA binding and transcription by p300/CREB-binding protein-mediated acetylation. J Biol Chem 2005, 280: 11528-34.
Woodman CB, Collins SI, Young LS.The natural history of cervical HPV infection: unresolved issues.Nature Review Cancer 2007,7: 11-22.
Yuan ZL, Guan YJ, Chatterjee D, Chin YE: Stat3 dimerization regulated by reversible acetylation of a single lysine residue.Science 2005 , 307: 269-73.
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