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系統識別號 U0026-1709201017595100
論文名稱(中文) 人類凝血酶調節素於上皮-間質轉化及腫瘤發生之研究
論文名稱(英文) Study of Thrombomodulin in Epithelial-Mesenchymal Transition and Tumorigenesis
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 99
學期 1
出版年 99
研究生(中文) 高遠忠
研究生(英文) Yuan-Chung Kao
學號 s5893106
學位類別 博士
語文別 英文
論文頁數 97頁
口試委員 指導教授-施桂月
召集委員-葉才明
口試委員-吳華林
口試委員-張文粲
口試委員-林尊湄
口試委員-林淑華
中文關鍵字 上皮-間質轉化  人類凝血酶調節素  腫瘤發生 
英文關鍵字 epithelial-mesenchymal transition  thrombomodulin  tumorigenesis 
學科別分類
中文摘要 凝血酶調節素 (Thrombomodulin, TM)是一種鈣離子依賴性的黏著分子,在不同類型的癌症都已發現有表現量下降的情形。然而,凝血酶調節素在腫瘤發生過程低表現量的機制及對細胞作用尚未明確。本實驗中我們觀察到,凝血酶調節素與上皮細胞間質轉化轉錄因子Snail,在許多不同種類的癌症細胞株都呈現負相關的表現模式。另在HaCaT及A431細胞為研究對象,施以轉化生長因子 (transforming growth factor) 以及表皮生長因子(epidermal growth factor) 誘導上皮-間質轉化(epithelial-mesenchymal transition, EMT)的細胞模式中亦確認此一情形。我們證明Snail會與凝血酶調節素啟動子片段距離轉錄起始點之前-828至-823鹼基的特定序列 (CACCTG) 專一性的結合以抑制凝血酶調節素的表現。同時,我們以小髮夾RNA抑制凝血酶調節素的表現並建立凝血酶調節素表現量降低的穩定細胞株。在鈣離子轉換試驗中,凝血酶調節素表現量降低的穩定細胞株,其鈣黏著素E (E-cadherin) 與細胞間質beta索烴素 (beta-catenin) 的結合力降低,並且鈣黏著素E會堆積在細胞質當中。因此,降低凝血酶調節素表現量會影響鈣黏著素E的動態平衡。另一方面,傷口癒合以及腫瘤侵襲的細胞體外試驗結果顯示,凝血酶調節素表現量降低的穩定細胞株具有較強的細胞活動力。將此穩定細胞株以皮下注射的方式植入免疫缺陷的老鼠會誘發腫瘤的產生。我們更將小鼠的凝血酶調節素基因轉殖在凝血酶調節素表現量降低的穩定細胞株中,使得此細胞恢復類似上皮細胞的型態,同時增加鈣黏著素E與細胞間質beta索烴素的結合力。到目前為止,我們證明凝血酶調節素,為Snail調控的下游分子,在上皮-間質轉化過程中扮演維持上皮細胞型態並有抑制腫瘤發生之功能。
英文摘要 The expression of thrombomodulin (TM), a calcium-dependent adhesion molecule, is frequently down-regulated in various cancer types. However, the mechanism responsible for the low expression level of TM in tumorigenesis is unknown. Here, an inverse expression of TM and Snail was detected in different cancer cell lines. We further confirmed this inverse relation using epithelial-mesenchymal transition cell model in HaCaT and A431 cells. We demonstrated that Snail suppressed TM expression by binding to E-box (CACCTG) in TM promoter. Moreover, TM knockdown by short hairpin RNA disrupted E-cadherin-mediated cell junctions and contributed to tumorigenesis. In calcium switch assay, E-cadherin lost the ability to associate with beta-catenin and accumulated in cytoplasm in TM knockdown cells. Meanwhile, wound healing and invasive assays showed that TM knockdown promoted cell motility. A subcutaneous injection of TM knockdown transfectants into immunocompromised mice induced squamous cell carcinoma-like tumors. Besides, forced expression of murine TM in TM knockdown cells made the cells re-assume epithelial-like morphology and increased calcium-dependent association of E-cadherin and beta-catenin. In conclusion, TM, a novel downstream target of Snail in epithelial-mesenchymal transition, is required for maintaining epithelial morphology and functions as a tumor suppressor.
論文目次 I Abstract 1
II Chinese Abstract 2
III Acknowledgments 3
IV Content Table 4
V Abbreviations 9
VI Introduction 11
VI-1 Structure of Thrombomodulin 11
VI-2 Other Roles of TM beyond Anti-coagulation 13
VI-3 Regulatory Expression of TM 16
VI-4 Epithelial-Mesenchymal Transition 17
VI-5 The Association of TM with EMT 20
VII Materials and Methods 22
VII-1 Cell Cultures 22
VII-2 Constrcuts and Transfections 23
VII-3 SDS-PAGE (Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis) 24
VII-4 Western Blotting 25
VII-5 Immuno-fluorescent Staining 27
VII-6 EMSA 28
VII-7 Reporter Gene Assay 30
VII-8 ChIP Assay 32
VII-9 Wound Healing Assay and Individual Cell Tracking 32
VII-10 Invasion Assay 33
VII-11 Co-immunoprecipitation Assay 34
VII-12 Cell Fractionation 34
VII-13 Tumorigenesis of TM Knockdown Transfectants in NOD-SCID Mice 35
VII-14 Immuno-histochemistry Staining 35
VII-15 Statistical Analysis 36
VIII Results 37
VIII-1 Inverse expression of TM and Snail 37
VIII-2 Snail directly suppresses TM and E-cadherin expression 38
VIII-3 Binding of Snail to TM promoter suppresses TM expression 38
VIII-4 TM knockdown induces E-cadherin and beta-catenin dissociation from cell membrane 39
VIII-5 TM knockdown abolishes E-cadherin-mediated cell-cell contact formation 40
VIII-6 TM knockdown promotes cell motility 41
VIII-7 TM knockdown induces SCC-like tumors 42
VIII-8 Forced mTM expression suppresses TM knockdown-induced morphology alteration and mesenchymal marker expression 43
VIII-9 TM directly interacts with actinin-4 43
IX Discussion 45
X References 51
XI Figures and Legends 60
Fig. 1 Down-regulation of TM in tumor cells associates with EMT 60
Fig. 2 Snail directly suppresses TM and E-cadherin expression 63
Fig. 3 Snail specifically binds to TM promoter 65
Fig. 4 TM is necessary for E-cadherin and beta-catenin to localize to cell membrane 67
Fig. 5 TM knockdown abolishes E-cadherin-mediated cell junction rebuilding 69
Fig. 6 TM knockdown increases cell motility and invasion 72
Fig. 7 TM knockdown induces SCC-like tumor 75
Fig. 8 Forced TM expression suppresses TM knockdown induced morphology alteration and mesenchymal markers expression 77
Fig. 9 Proposed role of TM in EMT process 81
Supplementary Fig. 1 TM knockdown enhanced cell permeability 83
Supplementary Fig. 2 TM directly interacted with actinin-4 84
Supplementary Fig. 3 Forced expression of mTM reverted TGF-beta1 and EGF induced cell morphology change 86
XII Tables 87
1 Short hairpin sequences specific to TM 87
2 Probe sequences of TM in EMSA 87
3 Primer sequences of ChIP assay 88
4 Cell lines phenotype 88
XIII Reagents, Drugs, and Chemicals 89
XIV Instruments 94
XV Resume 97
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