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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 李明學(Ming-Shyue Lee) | |
| dc.contributor.author | Ting-Wei Hsu | en |
| dc.contributor.author | 許庭瑋 | zh_TW |
| dc.date.accessioned | 2021-06-08T01:50:49Z | - |
| dc.date.copyright | 2016-08-26 | |
| dc.date.issued | 2016 | |
| dc.date.submitted | 2016-07-27 | |
| dc.identifier.citation | [1] Chen YW, Lee MS, Lucht A, Chou FP, Huang W, Havighurst TC, Kim K, Wang JK, Antalis TM, Johnson MD, Lin CY: TMPRSS2, a serine protease expressed in the prostate on the apical surface of luminal epithelial cells and released into semen in prostasomes, is misregulated in prostate cancer cells. Am J Pathol 2010, 176:2986-96.
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[37] Jin X, Yagi M, Akiyama N, Hirosaki T, Higashi S, Lin CY, Dickson RB, Kitamura H, Miyazaki K: Matriptase activates stromelysin (MMP-3) and promotes tumor growth and angiogenesis. Cancer Sci 2006, 97:1327-34. [38] Takeuchi T, Harris JL, Huang W, Yan KW, Coughlin SR, Craik CS: Cellular localization of membrane-type serine protease 1 and identification of protease-activated receptor-2 and single-chain urokinase-type plasminogen activator as substrates. J Biol Chem 2000, 275:26333-42. [39] Netzel-Arnett S, Currie BM, Szabo R, Lin CY, Chen LM, Chai KX, Antalis TM, Bugge TH, List K: Evidence for a matriptase-prostasin proteolytic cascade regulating terminal epidermal differentiation. J Biol Chem 2006, 281:32941-5. [40] Andreasen PA, Egelund R, Petersen HH: The plasminogen activation system in tumor growth, invasion, and metastasis. Cell Mol Life Sci 2000, 57:25-40. [41] Chen M, Chen LM, Lin CY, Chai KX: The epidermal growth factor receptor (EGFR) is proteolytically modified by the Matriptase-Prostasin serine protease cascade in cultured epithelial cells. Biochim Biophys Acta 2008, 1783:896-903. [42] Benaud C, Oberst M, Hobson JP, Spiegel S, Dickson RB, Lin CY: Sphingosine 1-phosphate, present in serum-derived lipoproteins, activates matriptase. J Biol Chem 2002, 277:10539-46. [43] Hung RJ, Hsu Ia W, Dreiling JL, Lee MJ, Williams CA, Oberst MD, Dickson RB, Lin CY: Assembly of adherens junctions is required for sphingosine 1-phosphate-induced matriptase accumulation and activation at mammary epithelial cell-cell contacts. Am J Physiol Cell Physiol 2004, 286:C1159-69. [44] Benaud C, Dickson RB, Lin CY: Regulation of the activity of matriptase on epithelial cell surfaces by a blood-derived factor. Eur J Biochem 2001, 268:1439-47. 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[63] Tsai CH, Teng CH, Tu YT, Cheng TS, Wu SR, Ko CJ, Shyu HY, Lan SW, Huang HP, Tzeng SF, Johnson MD, Lin CY, Hsiao PW, Lee MS: HAI-2 suppresses the invasive growth and metastasis of prostate cancer through regulation of matriptase. Oncogene 2014, 33:4643-52. [64] Fukai K, Yokosuka O, Chiba T, Hirasawa Y, Tada M, Imazeki F, Kataoka H, Saisho H: Hepatocyte growth factor activator inhibitor 2/placental bikunin (HAI-2/PB) gene is frequently hypermethylated in human hepatocellular carcinoma. Cancer Res 2003, 63:8674-9. [65] Betsunoh H, Mukai S, Akiyama Y, Fukushima T, Minamiguchi N, Hasui Y, Osada Y, Kataoka H: Clinical relevance of hepsin and hepatocyte growth factor activator inhibitor type 2 expression in renal cell carcinoma. Cancer Sci 2007, 98:491-8. [66] Bergum C, List K: Loss of the matriptase inhibitor HAI-2 during prostate cancer progression. Prostate 2010, 70:1422-8. 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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/19255 | - |
| dc.description.abstract | 攝護腺癌的惡化進程是一個多步驟且複雜的過程。一旦攝護腺癌發生轉移，治癒癌症將變得很困難。癌轉移機制目前尚未完全清楚，但轉移的過程中，細胞周圍蛋白酶水解作用扮演相當重要的角色。最新研究指出第二型嵌膜絲胺酸蛋白酶II (TMPRSS2) 參與攝護腺癌細胞侵襲及轉移;其機制經由活化受質間質蛋白酶 (matriptase)及細胞間質的降解，造成攝護腺癌細胞侵襲力增加、腫瘤生長及轉移。因生理上蛋白酶均會受到蛋白酶抑制蛋白的調控，本篇研究將進一步鑑尋TMPRSS2抑制蛋白。利用免疫沉澱及質譜分析的方式，其結果發現許多可與第二型嵌膜絲胺酸蛋白酶II作用的候選蛋白質，其中具有Kunitz domain的第一型和第二型肝細胞生長因子活化抑制者(HAI-1&HAI-2)最引起我們的研究興趣。經由生化分析重組的第二型肝細胞生長因子活化抑制者(HAI-2)蛋白質相較於第一型肝細胞生長因子活化抑制者(HAI-1)，對TMPRSS2有較顯著的活性抑制效果。進一步發現第二型肝細胞生長因子活化抑制者的Kunitz domain 2是與TMPRSS2交互作用的重要區塊。再者，在攝護腺癌細胞中表達第二型肝細胞生長因子活化抑制者，可以降低由第二型嵌膜絲胺酸蛋白酶II所引發的腫瘤細胞侵襲能力，證實第二型嵌膜絲胺酸蛋白酶II確實可受到第二型肝細胞生長因子活化抑制者的抑制調控。這些研究提供未來攝護腺癌治療的新策略方向，可利用調節第二型嵌膜絲胺酸蛋白酶 II 及第二型肝細胞生長因子活化抑制者兩者間的平衡，達到抑制攝護腺腫瘤生長與轉移的目的。 | zh_TW |
| dc.description.abstract | Dysregulation of pericellular serine proteases has been proposed as an important effector for tumor progression, because of their roles in the degradation of extracellular matrix and alteration of microenvironment for invasive tumor growth. Among them, TMPRSS2, a type II serine protease acts as an important mediator in androgen-induced prostate cancer cell invasion, tumor growth and metastasis, via a proteolytic activation of matriptase and degradation of extracellular matrix. For a proteolytic system, there is a general phenomenon that proteases are usually accompanied with their cognate protease inhibitors via non-covalent interaction. To further identify whether there is a serine protease inhibitor to modulate the activity of TMPRSS2, in this study, we used co-immunoprecipitation assay and LC/MS/MS analysis to isolate TMPRSS2-interacting proteins, and isolated the candidates of hepatocyte growth factor activator inhibitors (HAIs) as an inhibitor for TMPRSS2. The recombinant HAI-2 proteins exhibited a better inhibitory effect on TMPRSS2 proteolytic activity than HAI-1. Moreover, the results from co-immunoprecipitation showed that HAI-2 could form a complex with TMPRSS2. HAI-2 overexpression could suppress TMPRSS2-induced prostate cancer cell invasion. In summary, the results indicate that HAI-2 can function as a cognate inhibitor for TMPRSS2 in prostate cancer cells. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T01:50:49Z (GMT). No. of bitstreams: 1 ntu-105-R03442001-1.pdf: 7248465 bytes, checksum: 1339e6b257f77fed27db74c41d6bf333 (MD5) Previous issue date: 2016 | en |
| dc.description.tableofcontents | Contents
致謝…………………………………………………………………………………….i 中文摘要………………………………………………………………………………ii ABSTRACT……………………………………………………………………..........iii Chapter 1 Introduction ………………………………………………………………1 1.1 Prostate cancer ……………………………………………………………….2 1.2 Metastasis…………………………………...………………………………..3 1.3 Pericellular proteolysis……………………………………………………….3 1.4 Type II transmembrane serine proteases……………………………………..5 1.5 Type II transmembrane protease, serine 2 (TMPRSS2)…………...................6 1.6 Matriptase…………………………………………………………………….8 1.7 Kunitz-type serine protease inhibitor……………………………………….11 1.8 Hepatocyte Growth Factor Activator Inhibitor-1 (HAI-1)………………….12 1.9 Hepatocyte Growth Factor Activator Inhibitor-2 (HAI-2)………….………13 1.10 The purpose for this study…………………………………………………15 Chapter 2 Materials & Methods……………………………………………………...16 Chapter 3 Results…………………………………………………………………….28 3.1 Identification of TMPRSS2 interacting protein(s) in PCa cells…………….29 3.2 Gene expression profiles and protein levels of HAI-1 and HAI-2 in PCa cells.......................................................................................................................30 3.3 Co-localization of HAI-2 and TMPRSS2 in PCa cells……………………..31 3.4 HAI-2 is a potent inhibitor of TMPRSS2…………………………………...31 3.5 HAI-2 can form complexes with TMPRSS2 in cell plasma membrane…….31 3.6 Kinetic analysis of HAI-2 inhibition effects on TMPRSS2………………...32 3.7 Identification of the functional domain of HAI-2 to inhibit TMPRSS2 proteolytic activity………………………………………………………………33 3.8 TMPRSS2 promoted prostate cancer cell invasion…………………………34 3.9 HAI-2 inhibits TMPRSS2-induced PCa invasion………….……………….36 3.10 Co-overexpression of HAI-2 and TMPRSS2 modified the activation of matriptase……………………………………………………………………….36 Chapter 4 Discussion…………………………………………………………………37 Chapter 6 Figures…………………………………………………………………….45 Chapter 7 References…………………………………………………………………73 | |
| dc.language.iso | en | |
| dc.title | 鑑選抑制第二型絲胺酸蛋白酶所誘發攝護腺癌細胞侵襲的調控蛋白 | zh_TW |
| dc.title | Identification of a protease inhibitor for TMPRSS2-induced cancer cell invasion | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 林敬哲(Jing-Jer Lin),蕭培文(Pei-Wen Hsiao),游佳融(Chia-Jung Yu),張震東(Geen-Dong Chang) | |
| dc.subject.keyword | 第二型嵌膜絲胺酸蛋白? II,第一型肝細胞生長因子活化抑制者,第二型肝細胞生長因子活化抑制者,間質蛋白?,攝護腺癌,轉移, | zh_TW |
| dc.subject.keyword | TMPRSS2,HAI-1,HAI-2,matriptase,prostate cancer,metastasis, | en |
| dc.relation.page | 80 | |
| dc.identifier.doi | 10.6342/NTU201601489 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2016-07-27 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
| 顯示於系所單位： | 生物化學暨分子生物學科研究所 | |
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