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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/70115完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 李明學 | |
| dc.contributor.author | Shang-Ru Wu | en |
| dc.contributor.author | 吳尚儒 | zh_TW |
| dc.date.accessioned | 2021-06-17T03:44:18Z | - |
| dc.date.available | 2028-02-01 | |
| dc.date.copyright | 2018-02-22 | |
| dc.date.issued | 2017 | |
| dc.date.submitted | 2018-02-02 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/70115 | - |
| dc.description.abstract | 在腫瘤侵襲和癌症惡化過程中，細胞表面蛋白降解系統的失調經常扮演重要角色。過去已報導第二型肝細胞生長因子活化抑制者HAI-2 (Hepatocyte growth factor activator inhibitor-2)在人類攝護腺癌細胞中，當其表現降低時會導致間質蛋白酶Matriptase活化，進而促使攝護腺癌細胞的侵襲與腫瘤生長。此研究中，我進一步探討HAI-2是如何抑制Matriptase，細究HAI-2是利用那個蛋白結構區域(domain)來影響Matritpase的活化以及細胞侵襲能力。結果顯示過度表達HAI-2能夠抑制Matriptase活化，且造成攝護腺癌細胞侵襲能力降低。進一步研究顯示HAI-2是利用第一個結構域(KD1)來抑制Matriptase的活化與攝護腺癌細胞的移動力，儘管酵素實驗與蛋白動力分析顯示HAI-2的第二個結構域(KD2)與其第一個結構域(KD1)對Matriptase也有同樣的抑制與結合效果。這些結果綜合指出HAI-2是Matriptase同源的抑制者，而且是透過其第一個結構域(KD1)來抑制細胞Mtriptase的活化以及人類攝護腺癌細胞的侵襲力。另一方面，HAI-2同樣也在人類肺腺癌細胞的侵襲力與轉移扮演重要角色。由於在肺腺癌細胞株中，只存在極少量的Matriptase，因此我鑑尋在肺腺癌中HAI-2的抑制標的蛋白。結果顯示HAI-2能夠抑制一個血中大量存在的重要蛋白酶，纖溶酶(plasmin)，進而抑制肺癌細胞的侵襲力。此外，當HAI-2表現量下降時，亦會導致肺腺癌細胞發生上皮間葉細胞轉化 (epithelial-mesenchymal transition; EMT)的現象，進而增進細胞移動能力。進一步研究發現，HAI-2是透過調控plasmin抑制兩種生長因子的活化，pro-HGF (pro-form hepatocyte growth factor) 和pro-TGF-β1 (pro-form transforming growth factor-β1)，來控制EMT的發生。重要的是，這些發現都能在動物實驗上觀察到。結果清楚指出在HAI-2表現下降的肺腺癌細胞中，其細胞表面plasmin的蛋白活性、EMT現象、與轉移能力都大幅提升。同時研究證實純化的重組HAI-2蛋白能有效抑制Matriptase和plasmin的活性，並且降低人類攝護腺癌細胞及肺腺癌細胞的侵襲能力。綜合以上結果，顯示HAI-2不論在未來臨床診斷以及癌症治療的研究與發展上，皆有極大的重要性。 | zh_TW |
| dc.description.abstract | Dysregulation of pericellular proteolysis is often required for tumor invasion and cancer progression. It has been shown that down-regulation of hepatocyte growth factor activator inhibitor-2 (HAI-2) results in activation of matriptase (a membrane-anchored serine protease), human prostate cancer cell motility and tumor growth. This study investigated the role of HAI-2 in two common human cancers, prostate cancer and lung adenocarcinoma. In prostate cancer, it is further characterized if HAI-2 was a cognate inhibitor for matriptase and identified which Kunitz domain of HAI-2 was required for inhibiting matriptase and human prostate cancer cell motility. The results showed that HAI-2 overexpression suppressed matriptase-induced prostate cancer cell motility. The data further demonstrate that HAI-2 interacts with matriptase on cell surface and inhibits matriptase proteolytic activity. Moreover, cellular HAI-2 harnesses its Kunitz domain 1 (KD1) to inhibit matriptase activation and prostate cancer cell motility although recombinant KD1 and KD2 of HAI-2 both show an inhibitory activity and interaction with matriptase protease domain. The results together indicate that HAI-2 is a cognate inhibitor of matriptase, and KD1 of HAI-2 plays a major role in the inhibition of cellular matritptase activation and cell invasion in human prostate cancer. On the other hand, HAI-2 also plays an important role in the cell motility, progression and tumor invasion of lung adenocarcinoma. Since there is none or little matriptase in lung adenocarcinoma cells, I then sought and identified a serum-derived serine protease plasmin to be an alternative target of HAI-2 in lung adenocarcinoma. The results revealed that HAI-2 repressed cell-surface plasmin activity and lung cancer cell motility. Down-regulation of HAI-2 promoted the epithelial-mesenchymal transition (EMT) of lung cancer cells which contributed to an increase of the cell motility. Moreover, the data showed that HAI-2 could suppress plasmin-mediated activations of pro-HGF (pro-form hepatocyte growth factor) and pro-TGF-β1 (pro-form transforming growth factor-β1), and then decrease the plasmin-induced EMT of lung adenocarcinoma cells. Most importantly, those findings were further proven in a xenografted animal model, indicating that down-regulation of HAI-2 can increase the EMT, plasmin activity, and lung metastatic ability of lung cancer cells. In addition, recombinant HAI-2 proteins exhibited a potent inhibition against matriptase, plasmin and cell invasion of human prostate cancer and lung adenocarcinoma. These results together indicate a suppression role of HAI-2 in the progression of human prostate and lung cancer and may exhibit a potential to develop a therapeutic strategy against human cancer. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T03:44:18Z (GMT). No. of bitstreams: 1 ntu-106-D99442005-1.pdf: 9547536 bytes, checksum: 19036b58a4bf6197b66351a732c71aa2 (MD5) Previous issue date: 2017 | en |
| dc.description.tableofcontents | Introduction 1
Prostate cancer 1 Non-small cell lung cancer 2 Metastasis and cancer-related proteases 3 Matriptase 4 Protease inhibitors 5 Hepatocyte growth factor activator inhibitor 1 (HAI-1) 7 Hepatocyte growth factor activator inhibitor-2 (HAI-2) 8 Plasminogen activation system 9 Epithelial-mesenchymal transition 11 Materials and Methods 13 Cell culture- 13 Transfection 14 Genetic knockdown by shRNA with lentiviral particles- 14 Western blot- 15 Transwell migration/invasion assay 17 Immunofluorescence and confocal microscopy 18 Immunoprecipitation 19 Purification of recombinant matriptase protease domain (Trx-MTX PD) 19 Purification of GST fusion proteins- 21 Matriptase activity assay- 22 Baculovirus expression system and recombinant HAI-2 (rHAI-2) protein purification- 22 SPR-based BIAcore assay- 24 Computation of protein-protein docking- 25 Immunohistochemistry (IHC) of tissue array and statistical analysis- 25 GST-pulldown assay and LC/MS/MS- 26 Protease activity assay- 27 Zymography- 28 Real-time PCR 28 Lung metastatic assay- 29 In situ zymography of plasmin activity- 29 Statistical analysis- 30 Results I: The role of HAI-2 in human prostate cancer 31 Down-regulation of HAI-2 in metastatic prostate cancer of the xenografted model 31 HAI-2 represses matriptase activation through direct interaction and proteolytic inhibition 32 Recombinant HAI-2 proteins reduce matriptase activation and prostate cancer cell invasion 33 Inhibitory effects of recombinant HAI-2 KD1 and KD2 proteins on the in vitro proteolytic activity of matriptase 34 Dynamic bindings and computational docking models of HAI-2’s KD1 and KD2 with matriptase protease domain 35 Kunitz domain 1 of HAI-2 responsible for its inhibitory effect on cell migration and invasion 37 Recombinant HAI-2 proteins containing Kunitz domain 1 repressed matriptase activation and prostate cancer cell invasion 38 Results II: The role of HAI-2 in lung adenocarcinoma 39 Inverse correlation of HAI-2 expression with lung cancer progression and poor prognosis 39 HAI-2 played an inhibitory role in lung cancer cell migration and invasion 41 Identification of plasminogen as a HAI-2 target protease in lung cancer cells 41 HAI-2 repressed plasmin activity, plasmin-induced lung cancer cell motility, uPA activation and MMP2/9 activities 43 Recombinant HAI-2 proteins repressed cell surface plasmin activities, lung cancer cell migration and invasion 45 HAI-2 inhibited an EMT-like transition of lung cancer cells through suppression of plasmin/uPA, HGF and TGF-β1 signaling 46 Knockdown of HAI-2 promoted lung cancer metastasis and EMT in a xenografted mouse model 51 Discussion 52 Figures 65 Figure 1 Roles of matriptase and HAI-2 in prostate cancer progression model. 65 Figure 2 HAI-2 represses matriptase activation through the interactions with matriptase and the inhibition of matriptase activity. 67 Figure 3 Purified recombinant HAI-2 proteins repressed cellular matriptase activation and prostate cancer cell motility. 69 Figure 4 Inhibitory effects of HAI-2’s KD1 and KD2 on the in vitro proteolytic activity of matriptase. 70 Figure 5 Dynamic bindings and computational molecular docking between HAI-2’s KDs and matriptase’s protease domain. 72 Figure 6 Characterization of HAI-2’s KDs in inhibiting matriptase activation. 74 Figure 7 Recombinant HAI-2 proteins containing KD1 inhibited matriptase activation and prostate cancer cell invasion. 75 Figure 8 Down-regulation of HAI-2 is related to cell invasion, survival rate and progression of NSCLCs. 77 Figure 9 Role of HAI-2 in cancer cell motility of lung adenocarcinoma. 79 Figure 10 Identification of HAI-2’s associated proteins in lung adenocarcinoma. 81 Figure 11 HAI-2 represses plasmin activities and decreases cell migration, cell invasion, as well as the activation of uPA and MMPs. 83 Figure 12 Recombinant HAI-2 (rHAI-2) repressed cell-surface plasmin activity, uPA activation, cell migration and invasion. 87 Figure 13 Screening the transcription factors that is involved in EMT of CL1-0 to CL1-5, and A549 cells with HAI-2 knockdown. 88 Figure 14 HAI-2 mediates partial MET through repressing plasmin activity, HGF/c-MET signaling and pro-TGF-β1 activation. 89 Figure 15 Down-regulation of HAI-2 increases lung metastatic ability of A549 cells as well as promoting the tissue plasmin activity and EMT. 91 Figure 16 HAI-2 complexes with matriptase and reduces the matriptase-HAI-1 complex in the presence of HAI-1. 93 Figure 17 Cell-surface biotinylation and pulldown reveal the presence of HAI-2 on the cell surface of N2 prostate cancer cells. 94 Figure 18 The enzyme-inhibitor kinetics of HAI-2, PAI-1, and α-2-antiplasmin. 95 Figure 19 HAI-2 is physically associated and co-localized with CK8/18 in A549 cells. 96 Figure 20 Plasmin and HAI-2 did not affect EGFR signaling. 98 Figure 21 Domain functions of HAI-2 on inhibiting plasmin and cell invasion. 99 Figure 22 Matriptase expression of lung adenocarcinoma cell lines. 101 References 102 | |
| dc.language.iso | en | |
| dc.subject | 纖溶? | zh_TW |
| dc.subject | 第二型肝細胞生長因子活化抑制者 | zh_TW |
| dc.subject | 轉移 | zh_TW |
| dc.subject | 細胞侵襲 | zh_TW |
| dc.subject | 間質蛋白? | zh_TW |
| dc.subject | 人類攝護腺癌細胞 | zh_TW |
| dc.subject | 人類肺腺癌細胞 | zh_TW |
| dc.subject | cell invasion | en |
| dc.subject | HAI-2 | en |
| dc.subject | human prostate cancer | en |
| dc.subject | human lung adenocarcinoma | en |
| dc.subject | matriptase | en |
| dc.subject | plasmin | en |
| dc.subject | metastasis | en |
| dc.title | 探討第二型肝細胞生長因子活化抑制者在抑制人類攝護腺癌細胞與肺腺癌細胞侵襲的作用機制與差異性 | zh_TW |
| dc.title | Differential Mechanisms of Hepatocyte Growth Factor Activator Inhibitor-2 in Repressing Cell Invasion of Human Prostate Cancer and Lung Adenocarcinoma | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 106-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 蕭培文,陳惠文,林敬哲,黃祥博,潘思樺 | |
| dc.subject.keyword | 第二型肝細胞生長因子活化抑制者,間質蛋白?,人類攝護腺癌細胞,人類肺腺癌細胞,纖溶?,細胞侵襲,轉移, | zh_TW |
| dc.subject.keyword | HAI-2,human prostate cancer,human lung adenocarcinoma,matriptase,plasmin,cell invasion,metastasis, | en |
| dc.relation.page | 124 | |
| dc.identifier.doi | 10.6342/NTU201800283 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2018-02-02 | |
| 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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