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研究生:蔡昇達
研究生(外文):Sheng-Ta Tsai
論文名稱:肝、食道、與前列腺癌細胞之蛋白質體學
論文名稱(外文):Proteomics Analysis of Liver, Esophageal, and Prostate Cancer Cells
指導教授:陳仲瑄
指導教授(外文):Chung-Hsuan Chen
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生化暨分子生物研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:英文
論文頁數:84
中文關鍵詞:蛋白質體學
外文關鍵詞:Proteomics
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蛋白質體學為一門跨領域的大規模蛋白質分析學,由於近年來基因體學、質譜分析技術以及生物資訊分析的進步,以質譜為主的技術平台已成為研究癌症蛋白質體學的主力工具之一。癌症的進程、復發以及抗藥性是病人存活率的主要決定因素,利用定量蛋白質體學來研究癌症幹細胞與高侵略性癌細胞的特性,能提供我們對其潛在機制的見解。我們利用幹細胞表面指標CD133來純化肝癌幹細胞,以及利用幹細胞的生長特性,如細胞遷移,侵襲性和細胞球體形成能力來篩選食道癌幹細胞,接著利用蛋白質體學找出具有診斷或治療潛力的目標蛋白質。而在前列腺癌研究中,臨床證據指出高侵略性的前列腺癌細胞會高度表現A型單胺氧化酶,我們利用蛋白質體學以及轉錄體學來分析基因抑制A型單胺氧化酶基因抑制的前列腺癌細胞,發現A型單胺氧化酶可能在前列腺癌進程所扮演的角色。雖然癌症生物學是ㄧ門複雜且具挑戰的難題,但藉由大規模的蛋白質體學分析可以使我們得以更全面的方式瞭解癌症。
Proteomics is a multidisciplinary science of large-scale protein analysis. Because of the notable advancement of genome knowledge, mass spectrometry (MS) technology and bioinformatics, MS-based proteomics has become a powerful tool for cancer research. Cancer progression, relapse and resistance are the key issues affecting the survival rates of its sufferers. Using quantitative proteomics to study the properties of cancer stem cells (CSCs) and high aggressive cancer cells provides insights to underlying mechanisms. Liver CSCs and esophageal CSCs were isolated by stem cell surface CD marker (CD133), and stemness characteristics (migration, invasion and sphere formation ability), respectively. Proteomics of both CSCs found some potential target proteins for cancer therapies. In prostate cancer, the clinical evidence showed that high-grade aggressive prostate cancer exhibit increased expression of monoamine oxidase A (MAOA). Both proteomics and transcriptomics analyses of MAOA-knockdown prostate cancer cells revealed some changes at molecular level, thus showing potential roles of MAOA contributing to prostate cancer progression. Although cancer biology is very complex and challenging, large-scale proteomics could be a useful approach allowing scientists to understand cancer in a more comprehensive way.
Contents
誌謝 i
中文摘要 ii
Abstract iii
Contents iv
List of Figures vii
List of Tables ix
Abbreviations x
1. Introduction 1
1.1 Cancer stem cells 1
1.2 Proteomics 4
1.3 CD133+ liver cancer stem cells 8
1.4 Esophageal cancer stem cells 8
1.5 Prostate cancer 10
2. Material and Methods 12
2.1 Cell line and cell culture 12
2.2 Huh7, CE81T and CE146T cell RNA extraction and reverse transcription polymerase chain reaction (RT-PCR) 12
2.3 RNA extraction and LNCaP cell microarray analysis 14
2.4 Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and in-gel digestion 14
2.5 CE81T and CE146T membrane protein extraction and in-gel digestion 15
2.6 Protein extraction from LNCaP cells and in-solution digestion 15
2.7 Mass spectrometry analysis 16
2.8 Protein identification 17
2.9 Label-free quantitative data analysis 18
2.10 Bioinformatic analysis 19
2.11 Fluorescence-activated cell sorting (FACS) 20
2.12 Sphere-forming assay 20
2.13 Immunofluorescence staining 21
2.14 Western blotting 21
2.15 TopFlash assay 22
2.16 Drug resistance assay 23
2.17 Matrigel invasion and wound healing assay 23
2.18 Tumorigenicity assay in immune deficient mouse model 23
3. Results 25
3.1 Label-free quantitative proteomics of CD133-positive liver cancer stem cells 25
3.1.1 Characterization of the CD133+ subpopulation of the Huh7 hepatoma cells 25
3.1.2 Determination of the proteomes of the CD133+ and CD133- subpopulations of Huh7 cells and normal hepatocytes 29
3.1.3 Identification of the significantly up-regulated and down-regulated proteins in the CD133+ subpopulations of the Huh7 cells 30
3.1.4 Signaling molecules identified in the CD133+ Huh7 cells 34
3.2 ICAM1 is a potential cancer stem cell marker of esophageal squamous cell carcinoma 39
3.2.1 CE146T has more metastatic potential and stemness characteristics than CE81T 39
3.2.2 Identification of CSC markers using a comparative membrane proteomic approach 41
3.2.3 ICAM1 increases metastatic potential of cancer cells 44
3.2.4 ICAM1 increases sphere formation and drug resistance 47
3.2.5 ICAM1 promotes tumorigenesis in immune deficient mice 50
3.2.6 ICAM1 regulates esophageal CSC properties partly through p53-dependent pathway 52
3.2.7 ICAM1 and CD44 could utilize a compensation mechanism to maintain esophageal CSC properties 54
3.3 Proteomics and transcriptomics of MAOA-knockdown LNCaP cells 56
3.3.1 Quantitative Proteomic analysis profiling of MAOA-knockdown LNCaP Cells 56
3.3.2 Transcriptomics analysis profiling of MAOA-knockdown LNCaP Cells 60
4. Discussion 62
4.1 CD133+ Huh7 cells 62
4.2 CE81T and CE146T esophageal squamous cancer cells 65
4.3 MAOA-knockdown LNCaP prostate cancer cells 68
5. Conclusion 70
6. References 71

List of Figures
Figure 1. Experimental scheme for the label-free quantitation analysis of human hepatocytes, CD133+ Huh7 cells, and CD133- Huh7 cells 27
Figure 2. Characterization of CD133+ Huh7 and CD133- Huh7 cells 28
Figure 3. Comparison of proteomes and distribution of ratios. 30
Figure 4. Validation of significantly up-regulated proteins in CD133+ Huh7 and CD133- Huh7 cells 34
Figure 5. Pathway analysis by KEGG database 36
Figure 6. String database mapping reveals the interaction groups of the significantly regulated proteins. 38
Figure 7. CE146T has more metastatic potential and stemness characteristics than CE81T 40
Figure 8. Validation of the proteomics data 43
Figure 9. ICAM1 increases metastatic potential of cancer cells 45
Figure 10. ICAM1 increases sphere formation and drug resistance of CE146T 48
Figure 11. ICAM1 increases tumorigenesis of CE146T 51
Figure 12. ICAM1 affects the expression levels of p53 and p53-related proteins 54
Figure 13. ICAM1 and CD44 compensate their expression in CE146T 55
Figure 14. Experimental scheme for the proteomics and transcriptomics of MAOA-knockdown LNCaP cells 56
Figure 15. The proteomics analysis of MAOA-knockdown LNCaP cells 57
Figure 16. String database mapping reveals the interaction groups of the significantly regulated proteins in MAOA-knockdown LNCaP cells 61

List of Tables
Table 1. List of primers used for RT-PCR 13
Table 2. List of antibodies used for western blot and immunocytochemistry analysis 22
Table 3. Significantly up-regulated proteins in the CD133+ Huh7 cells 33
Table 4. Up-expressed membrane proteins in CE146T compared with CE81T 42
Table 5. Down-expressed and p53-related proteins in ICAM1 knockdown CE146T 53
Table 6. Significantly regulated proteins in the MAOA-knockdown LNCaP cells 59

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