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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 曾宇鳳(Yufeng Jane Tseng) | |
| dc.contributor.author | Ming-Tsung Hsu | en |
| dc.contributor.author | 徐銘聰 | zh_TW |
| dc.date.accessioned | 2021-07-10T22:07:49Z | - |
| dc.date.available | 2021-07-10T22:07:49Z | - |
| dc.date.copyright | 2018-08-21 | |
| dc.date.issued | 2018 | |
| dc.date.submitted | 2018-08-10 | |
| dc.identifier.citation | 1. Torre, L.A., et al., Global cancer statistics, 2012. CA Cancer J Clin, 2015. 65(2): p. 87-108.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77542 | - |
| dc.description.abstract | 胞外體為重要的細胞外囊泡，參與細胞間的訊號交流，以脂質雙層膜包裹各種分子組成（例如：蛋白質、信使核醣核酸、小分子核醣核酸），將來源細胞的訊息傳送至鄰近細胞和遠端細胞。先前的研究指出，癌症幹細胞釋放出之胞外體可當作生物標誌物，以進行癌症的診斷與預後。然而，針對癌症幹細胞胞外體全面性的分子鑑定和特徵描述仍屬缺乏。本研究利用液相層析質譜儀，鑑定老鼠肺癌幹細胞胞外體之蛋白質和脂質，並針對基因本體、生物途徑和疾病進行功能性富集分析，探索在細胞間胞外體從事訊號傳遞功能的重要分子。結果顯示，老鼠肺癌幹細胞胞外體總計帶有198個蛋白質，其中主要的蛋白質包含有：胞外體的標誌蛋白（Cd9、Alix、Tsg101）；參與內吞作用的網格蛋白、胞內體分選運輸蛋白複合體、Rab蛋白家族；參與細胞骨架調控的肌動蛋白、絲切蛋白、前纖維蛋白；參與細胞外基質與受體交互作用的整聯蛋白、層黏蛋白。此外，老鼠肺癌幹細胞胞外體存在47個特有專屬蛋白，反映出肺癌幹細胞進行訊號傳遞的獨特性和重要性。蛋白質分類系統將胞外體蛋白質分成25大類，前三大類分別為：核酸結合蛋白、酵素調節蛋白、水解酶。分析老鼠肺癌幹細胞胞外體蛋白質的人類同源蛋白基因，顯示許多同源基因與癌症、癌瘤、腫瘤轉移、細胞增生疾病有關。透過整合癌幹細胞胞外體蛋白質、相關疾病及已知藥物三者的連結關係，找到一個具有發展潛力的癌幹細胞治療藥物，並已藉由細胞存活分析，證實了該藥物對癌幹細胞的抑制效果。另外，分析脂質在老鼠肺癌幹細胞胞外體的分佈情形，顯示其含有高含量的甘油磷脂（PC aa C34:1、PC aa C34:2、PC aa C36:2、PC aa C36:3、PC aa C36:4）、鞘脂（SM C16:0、SM C24:0、SM C24:1）和肉鹼。亦從脂質本體的重新組織整理，得知脂質扮演的生物功能和參與的生化途徑。總結來說，本研究為全方位分析肺癌幹細胞胞外體分子組成的首要研究，從胞外體分子群中找出重要的關鍵分子，將能更進一步地瞭解胞外體如何調控腫瘤進展，本研究提供了肺癌幹細胞胞外體之分子圖譜，並建立了分析胞外體的策略和平台，為未來的胞外體研究奠定了良好的研究發展基礎。 | zh_TW |
| dc.description.abstract | Exosome is an important extracellular vesicle (EV) which participates in cell-cell communication by transferring molecular components, such as protein, mRNA and miRNA encapsulated in the lipid bilayer membrane of the exosome, from donor cells to proximal and distal cells. Previous studies showed that exosomes released from cancer stem cells (CSCs) can serve as biomarkers for cancer diagnosis and prognosis. However, a comprehensive molecular characterization of molecular components of CSC-derived exosomes remains unclear. In this study, we characterized proteins and lipids of exosomes derived from mouse lung CSCs. LC-MS/MS was used for identification and quantification of proteins and lipids. Functional enrichment analyses on gene ontology, pathway and disease were performed to investigate key components for exosome-mediated communication between cells. In total, 198 reliable proteins were identified. Major proteins include exosomal markers (Cd9, Alix, Tsg101); clathrin, ESCRT protein complex and Rab family proteins involved in endocytosis; actin, cofilin and profilin involved in regulation of actin cytoskeleton; integrins and laminins involved in ECM-receptor interaction. In addition, 47 specific proteins were recognized in mouse lung CSC-derived exosomes, which reflects the uniqueness and value of exploring lung CSC-induced signaling. Protein classification system classified exosomal proteins into 25 protein classes with nucleic acid binding, enzyme modulator and hydrolase being the top 3 abundant protein classes. Disease enrichment of human homologs indicated that many homologous genes associate with cancer, carcinoma, neoplasm metastasis, and disease of cellular proliferation. By integrating the relations among CSC-derived exosomal proteins, associated diseases and known drugs, a potential CSC-targeting therapeutic drug was found on the basis of the relation networks, and its inhibitory effect was already confirmed via cell viability assay. For the lipid composition, high abundance of glycerophospholipids (PC aa C34:1, PC aa C34:2, PC aa C36:2, PC aa C36:3, PC aa C36:4), sphingolipids (SM C16:0, SM C24:0, SM C24:1) and carnitine were observed. Lipid ontology was curated and reorganized to show their biological functions and involved processes. In summary, this is the first study to identify molecular components of exosomes from lung CSCs. Finding key components of exosomes could unmask the mystery of exosome-mediated regulation in tumor progression. This study provides a great exosomal landscape of lung CSCs, and an excellent analytical strategy and platform for future study of exosomes. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-10T22:07:49Z (GMT). No. of bitstreams: 1 ntu-107-D00B48004-1.pdf: 16819445 bytes, checksum: 4c13a85d16c1aa0c7456c9ab06c32fc5 (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 口試委員會審定書 #
誌謝 i 摘要 iv Abstract vi Table of Contents viii List of Figures xii List of Tables xiv Chapter 1. Introduction 1 1.1 Lung cancer 1 1.2 Tumor microenvironment 2 1.3 Exosomes 3 1.3.1 Extracellular vesicles 3 1.3.2 Biogenesis, secretion and uptake of exosomes 4 1.3.3 Functions of exosomes 7 1.3.4 Composition of exosomes 8 1.3.5 Applications of exosomes 12 1.4 Aim of this study 13 Chapter 2. Materials and Methods 16 2.1 Lung cancer stem cells 16 2.1.1 Origin of cells 16 2.1.2 Cell culture 16 2.2 Exosomes 17 2.2.1 Exosome isolation 17 2.2.2 Transmission electron microscopy (TEM) 18 2.2.3 Size distribution of exosomes 19 2.2.4 Western blot 19 2.3 Proteomics 20 2.3.1 Sample pre-processing 20 2.3.2 In-solution digestion 20 2.3.3 LC-MS/MS 21 2.3.4 Protein identification 22 2.3.5 Data analysis 22 2.3.6 Cell viability assay 24 2.4 Lipidomics 25 2.4.1 Targeted metabolic phenotyping 25 2.4.2 Functional annotation of metabolites and lipids 25 Chapter 3. Results 26 3.1 Lung cancer stem cells and exosomes 26 3.1.1 Characterization of lung CSC-derived exosomes 26 3.2 Proteomics 27 3.2.1 Proteomic profiling and protein composition of lung CSC-derived exosomes 27 3.2.2 Common and specific proteins between lung CSC-derived exosomes and other cell types-derived exosomes 29 3.2.3 Functional classification and indication of lung CSC-derived exosomal proteins 30 3.2.4 Functional enrichment analysis 38 3.2.5 Protein-protein interactions 41 3.2.6 Disease-protein-drug relations 42 3.2.7 Cell viability assay 43 3.3 Lipidomics 44 3.3.1 Lipidomic profiling and lipid composition of lung CSC-derived exosomes 44 Chapter 4. Discussion 48 4.1 Exosome extraction 48 4.2 Data completeness 48 4.3 Database 49 4.4 Strength and weakness 50 Chapter 5. Conclusion 52 Bibliography 178 | |
| dc.language.iso | en | |
| dc.subject | 生物資訊學 | zh_TW |
| dc.subject | 胞外體 | zh_TW |
| dc.subject | 癌幹細胞 | zh_TW |
| dc.subject | 肺癌 | zh_TW |
| dc.subject | 分子特徵 | zh_TW |
| dc.subject | 蛋白質體學 | zh_TW |
| dc.subject | 脂質體學 | zh_TW |
| dc.subject | Exosome | en |
| dc.subject | Bioinformatics | en |
| dc.subject | Lipidomics | en |
| dc.subject | Proteomics | en |
| dc.subject | Molecular characterization | en |
| dc.subject | Lung cancer | en |
| dc.subject | Cancer stem cell | en |
| dc.title | 肺癌幹細胞胞外體之分子鑑定 | zh_TW |
| dc.title | Molecular Identification of Lung Cancer Stem Cell-Derived Exosomes | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 106-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 周綠蘋(Lu-Ping Chow),張瑛芝(Ying-Chih Chang),閻雲(Yun Yen),黃彥華(Yen-Hua Huang),郭柏齡(Po-Ling Kuo) | |
| dc.subject.keyword | 胞外體,癌幹細胞,肺癌,分子特徵,蛋白質體學,脂質體學,生物資訊學, | zh_TW |
| dc.subject.keyword | Exosome,Cancer stem cell,Lung cancer,Molecular characterization,Proteomics,Lipidomics,Bioinformatics, | en |
| dc.relation.page | 196 | |
| dc.identifier.doi | 10.6342/NTU201802910 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2018-08-13 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 基因體與系統生物學學位學程 | zh_TW |
| 顯示於系所單位： | 基因體與系統生物學學位學程 | |
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