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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 周綠蘋(Lu-Ping Chow) | |
dc.contributor.author | Chih-Ta Chen | en |
dc.contributor.author | 陳治達 | zh_TW |
dc.date.accessioned | 2021-06-16T17:13:44Z | - |
dc.date.available | 2025-08-27 | |
dc.date.copyright | 2020-08-27 | |
dc.date.issued | 2020 | |
dc.date.submitted | 2020-04-16 | |
dc.identifier.citation | 1 Ahmed, I. & Lobo, D. N. Malignant tumours of the liver. Surgery (Oxford) 27, 30-37, doi:https://doi.org/10.1016/j.mpsur.2008.12.005 (2009).
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/63539 | - |
dc.description.abstract | 肝癌病患由於缺乏有效的早期診斷方法,大多確診的皆為中後期患者,也因此能採取的治療方法也相當有限。目前唯一現行臨床用標靶藥物蕾莎瓦(sorafenib, Nexavar®),卻常常出現抗藥性的問題。考量現行的狀況,若能深入的了解造成癌細胞抗藥性的機制,則對未來發展更有效的治療方法應會有相當大的助益。為了達成此目的,我們利用定量磷酸蛋白體學之方式,來分析抗藥性肝癌細胞株(HuH-7R)與母株(HuH-7)間蛋白質磷酸化的差異表現,藉以闡明促進產生抗藥性相關之訊息傳遞變化。在本篇研究中,我們總共鑑定並定量到約1500個差異表現磷酸化蛋白,其中有533個是在抗藥性細胞株中明顯上升。更進一步,透過生物資訊學工具的協助下,我們針對功能性,訊息路徑,以及交互作用連結,進行不同分類分析。其中,我們發現在抗藥性細胞株中,關於細胞貼附及移動相關功能,細胞生長以及存活相關功能路徑有顯著的異常改變,並於其中發現到一個新的潛在治療標的EphA2 。接下來的細胞實驗中,我們觀察到透過抑制EphA2之功能,可以抑制抗藥性細胞之生長,移動等相關功能。更重要的是,也可以破壞抗藥性細胞對於蕾莎瓦之抗性。近一步地探究發現,透過調控抑制EphA2之功能可以抑制下游之Akt蛋白之活性。另一方面,透過結合分析以及電腦模擬之方式,我們也找到了一個配體類似的前驅化合物,並且具有減弱EphA2無配體活化致癌性功能之活性。最後,在活體模式動物的實驗中,也證實了於蕾莎瓦處理時,合併抑制EphA2之功能可對抗抗藥性; 並且相對於控制組,可以延長帶有抗藥性肝癌細胞腫瘤組織小鼠之整體存活時間。總結,我們的研究發現了一個新的潛在對抗抗藥性之治療標的EphA2,並提供了一個可能作為未來治療中後期肝癌病人的新的思考方向。 | zh_TW |
dc.description.abstract | Limited therapeutic options are available for advanced-stage hepatocellular carcinoma owing to its poor diagnosis. Drug resistance to sorafenib, the only available targeted agent, is commonly reported. The comprehensive elucidation of the mechanisms underlying sorafenib resistance may thus aid in the development of more efficacious therapeutic agents. To clarify the signaling changes contributing to resistance, we applied quantitative phosphoproteomics to analyze the differential phosphorylation changes between parental and sorafenib-resistant HuH-7 cells. Consequently, an average of ~1500 differential phosphoproteins were identified and quantified, among which 533 were significantly upregulated in resistant cells. Further bioinformatic integration via functional categorization annotation, pathway enrichment and interaction linkage analysis led to the discovery of alterations in pathways associated with cell adhesion and motility, cell survival and cell growth and the identification of a novel target, EphA2, in resistant HuH-7R cells. In vitro functional analysis indicated that the suppression of EphA2 function impairs cell proliferation and motility and, most importantly, overcomes sorafenib resistance. The attenuation of sorafenib resistance may be achieved prior to its development through the modulation of EphA2 and the subsequent inhibition of Akt activity. Binding analyses and in silico modeling revealed a ligand mimic lead compound, prazosin, that could abate the ligand-independent oncogenic activity of EphA2. Finally, data obtained from in vivo animal models verified that the simultaneous inhibition of EphA2 with sorafenib treatment can effectively overcome sorafenib resistance and extend the projected survival of resistant tumor-bearing mice. Thus, our findings regarding the targeting of EphA2 may provide an effective approach for overcoming sorafenib resistance and may contribute to the management of advanced hepatocellular carcinoma. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T17:13:44Z (GMT). No. of bitstreams: 1 ntu-109-D02442004-1.pdf: 13129487 bytes, checksum: 9a8c013402a136b35d7bc867e3c2b2bb (MD5) Previous issue date: 2020 | en |
dc.description.tableofcontents | Table of contents
口試委員會審定書 i 謝誌 ii 中文摘要 iv Abstract v Abbreviations vii List of Tables 1 List of Figures 1 List of Appendix 3 List of Supplements 3 Chapter I-Overview and Rationale 4 1.1 Liver cancer 5 1.2 HCC staging and treatment 6 1.3 Sorafenib 9 1.4 Sorafenib and tumor progression 9 1.5 Specific aims 10 Chapter II- SILAC-Based Quantitative Phosphoproteomic Analysis Identifies the Potential Therapeutic Target EphA2 for Overcoming Sorafenib Resistance in Hepatocellular Carcinoma Cells 11 2.1 Introduction 12 2.2 Material and methods 15 2.3 Results 27 2.4 Discussion 39 Chapter III- Conclusion and Perspectives 47 Tables and Figures 51 References 91 Appendix and Supplement 99 Published reference 115 | |
dc.language.iso | en | |
dc.title | 利用定量磷酸蛋白體學分析找尋與蕾莎瓦抗藥性肝細胞癌相關之潛在治療標的 | zh_TW |
dc.title | Using quantitative phosphoproteomic analysis to identify potential therapeutic target in sorafenib resistant hepatocellular carcinoma | en |
dc.type | Thesis | |
dc.date.schoolyear | 108-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 黃麗華(Lih-Hwa Hwang),游佳融(Chia-Jung Yu),蔡孟勳(Mon-Hsun Tsai),潘思樺(Szu-Hua Pan) | |
dc.subject.keyword | 肝細胞癌,抗藥性,雷莎瓦,治療標的,EphA2,磷酸蛋白體,傅立葉轉換電場軌道阱混合式質譜儀,動物模式, | zh_TW |
dc.subject.keyword | hepatocellular carcinoma,drug resistance,sorafenib,therapeutic target,EphA2,phosphoproteomic,LTQ-Orbitrap Velos,animal model, | en |
dc.relation.page | 115 | |
dc.identifier.doi | 10.6342/NTU202000711 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2020-04-16 | |
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 |
文件中的檔案:
檔案 | 大小 | 格式 | |
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ntu-109-1.pdf 目前未授權公開取用 | 12.82 MB | Adobe PDF |
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