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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳青周(Ching-Chow Chen) | |
| dc.contributor.author | Wen-Shu Chen | en |
| dc.contributor.author | 陳雯淑 | zh_TW |
| dc.date.accessioned | 2021-06-15T13:09:16Z | - |
| dc.date.available | 2016-08-26 | |
| dc.date.copyright | 2016-08-26 | |
| dc.date.issued | 2016 | |
| dc.date.submitted | 2016-06-29 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/50962 | - |
| dc.description.abstract | Maspin 透過促進細胞貼附和細胞凋亡，以及抑制細胞移動能力而抑制腫瘤進展。然而maspin在肝癌(hepatocellular carcinoma, HCC)中的角色尚未釐清。因此，本篇研究主要探討maspin蛋白在肝癌中的調控機制，以及其表現與HCC病人的預後之間的關聯性。本研究發現，Hepatitis B virus (HBV)感染誘發的肝癌中maspin蛋白之表現量降低，並與肝癌病人的預後較差有高度相關性。我們進一步發現，HBV主要透過X蛋白(HBx)增加microRNA-7/107/21的表現，直接結合maspin mRNA而抑制maspin蛋白表現，進而促進肝癌細胞的移動能力以及增加細胞對anoikis和化療的抗性。在臨床檢體中也發現，高度表現這些microRNA的HCC病人其maspin表現量較低並有較差的存活率。此外，在HBV感染的HCC病人檢體中nuclear inhibitor-kB kinase-α (IKKα)的表現量和maspin表現量呈高度負相關。我們也發現maspin mRNA 和蛋白的表現量會受到nuclear IKKα抑制，但卻不受IKKβ影響。抑制IKKα 可以有效回復HBx造成的maspin表現抑制和化療抗性。更進一步證實，HBx過度表現會促使nuclear IKKα直接結合到microRNA-7、microRNA -103、microRNA -107和microRNA-21的promoter上，誘發這些microRNA的轉錄，進而抑制maspin的表現。
此研究不僅證實了HBV感染降低maspin表現的分子機制，更指出nuclear IKKα是造成HBx誘發HCC腫瘤侵略性和化療抗性的主要調控因子。因此，IKKα可望成為治療標靶以提升臨床上HCC病人的療效。 | zh_TW |
| dc.description.abstract | Maspin suppresses tumor progression by promoting cell adhesion and apoptosis and by inhibiting cell motility. However, its role in tumorigenesis of hepatocellular carcinoma (HCC) remains unclear. The gene regulation of maspin and its relationship with HCC patient prognosis were investigated in this study. Maspin expression was specifically reduced in HBV-associated patients and correlated with their poor prognosis. Maspin downregulation in HCC cells was induced by HBV X protein (HBx) to promote their motility and resistance to anoikis and chemotherapy. HBx-dependent induction of microRNA-7, -107, and -21 was further demonstrated to directly target maspin mRNA, leading to its protein downregulation. Higher expressions of these microRNAs were also correlated with maspin downregulation in HBV-associated HCC patients, and were associated with their poor overall survival. Our data further revealed that nuclear inhibitor-kB kinase-α (IKKα) expression was inversely correlated with maspin expression in HBV-associated patients. Nuclear IKKα but not IKKβ reduced maspin protein and mRNA expression, and inhibition of IKKα reverses HBx-mediated maspin downregulation and chemoresistance. In response to HBx overexpression, nuclear IKKα was further demonstrated to induce the gene expressions of microRNA-7, -103, -107, and -21 by directly targeting their promoters, thereby leading to maspin downregulation. These data not only provided new insights into the molecular mechanisms of maspin deficiency by HBx, but also indicated nuclear IKKα as a critical regulator for HBx-mediated aggressiveness and chemoresistance in HCC, and suggested IKKα as a promising target to improve the therapeutic outcome of HCC patients. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T13:09:16Z (GMT). No. of bitstreams: 1 ntu-105-D00443003-1.pdf: 5186377 bytes, checksum: e583dc49b6f7a8811754f35e56a4323c (MD5) Previous issue date: 2016 | en |
| dc.description.tableofcontents | Abbreviations………………………………………………………….…..…i
Chinese Abstract………………..…………………………………………...iv English Abstract….…….……………………………………………..…….vi Chapter 1- Introduction….…………………………………………………………….1 1-1. Hepatocellular carcinoma…………………………………………………2 1-2. Hepatitis virus infection and HCC development………………………...3 1-3. Role of HBx in HCC progression and drug resistance…………….…….5 1-4. Tumor suppressor gene Maspin……………………………………….….6 1-5. NF-κB signaling pathway……………………………………………….....8 1-6. Role of IKK in maspin regulation……………...………………………10 1-7. Motivation…………………………………………..…………………….10 Chapter 2- Materials and Methods…………………………………………………..12 Chapter 3- Results……………………………………………………………………..24 3-1. Downregulation of maspin by HBx correlates inversely with disease-free survival of HBV-associated HCC patients..................................................25 3-2. HBx-mediated suppression of maspin contributes to metastasis, anoikis resistance, and chemoresistance…………………………………….……26 3-3. HBx induces microRNA-7, -103, -107, and -21 to suppress maspin expression………………………………………………………………….28 3-4. Nuclear IKK significantly correlates with low levels of maspin expression in HBV-associated HCC patients…………………………….30 3-5. Nuclear IKK but not IKK mediated HBx-dependent maspin suppression and chemoresistance in HCC cells………………………….31 3-6. Nuclear IKKα downregulats maspin expression through disrupting its mRNA stability…………………………………………………………….32 3-7. Nuclear IKKα induces miR-7, -103, -107, and -21 to mediate HBx- dependent maspin suppression……………………………………………33 3-8. Nuclear IKK coordinates the transcriptional activity of NF-B to mediate microRNA-7/21/103/107 expressions in HBx-expressing HCC cells………………………………………………………………………...34 Chapter 4- Discussion…………………………………………………………………71 Chapter 5- Conclusion……………………...…………………………………………79 Chapter 6- Perspective…………………….………………………………………….81 References………………………………...……………………………………………83 Appendix……………………………………………………………………………….96 Publication list……………………………..…………………………………………101 | |
| dc.language.iso | en | |
| dc.title | HBx經由IKKα/microRNA路徑抑制maspin表現促進肝癌惡化 | zh_TW |
| dc.title | Suppression of Maspin by IKKα-dependent MicroRNAs Confers HBx-mediated Hepatocellular Cancer Progression | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.coadvisor | 黃偉謙(Wei-Chien Huang) | |
| dc.contributor.oralexamcommittee | 吳明賢(Ming-Shiang Wu),楊春茂(Chuen-Mao Yang),王紹椿(Shao-Chun Wang),謝嘉玲(Chia-Ling Hsieh) | |
| dc.subject.keyword | HBx,maspin,IKKα,NFkB,microRNA,轉移,化療抗性, | zh_TW |
| dc.subject.keyword | HBx,maspin,IKKα,NFkB,microRNA,metastasis,chemoresistance, | en |
| dc.relation.page | 105 | |
| dc.identifier.doi | 10.6342/NTU201600556 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2016-06-29 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥理學研究所 | zh_TW |
| 顯示於系所單位： | 藥理學科所 | |
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