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系統識別號 U0026-2401201722551200
論文名稱(中文) 中間絲蛋白vimentin在上皮-間質細胞轉化過程中的角色探討:癌細胞的機械生物學
論文名稱(英文) The role of vimentin in cancer cell mechanics of Epithelial-Mesenchymal Transition
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 105
學期 1
出版年 106
研究生(中文) 劉靜宜
研究生(英文) Ching-Yi Liu
學號 S58991227
學位類別 博士
語文別 英文
論文頁數 96頁
口試委員 指導教授-湯銘哲
召集委員-楊倍昌
口試委員-沈孟儒
口試委員-王仰高
口試委員-陳鴻震
口試委員-沈湯龍
口試委員-郭津岑
中文關鍵字 中間絲蛋白  細胞骨架  細胞機械力  上皮-間質細胞轉型  細胞焦點連結  波型蛋白 
英文關鍵字 intermediate filaments  cytoskeletons  cell mechanics  epithelial-mesenchymal transition  focal adhesions  vimentin 
學科別分類
中文摘要 在細胞內,調節細胞骨架的結構及細胞焦點連結(focal adhesion)的更新常與細胞癌化及上皮-間質細胞轉型(epithelial-mesenchymal transition , EMT)的過程有關。而上皮-間質細胞轉型的過程中常會使細胞喪失上皮標誌及獲得間質細胞的標誌,例如中間絲蛋白vimentin。在臨床資料的分析中,我們發現接受化療後具有較高vimemtin mRNA表現的乳癌病人存活率會較低。因此,我們假設vimentin具有調控細胞骨架組成的能力,並能進而穩定具有上皮-間質細胞轉化型態的癌細胞所具有的機械性質。在我們將MDA-MB231乳癌細胞中的vimentin基因進行剔除之後,發現細胞的生長能力、創傷癒合能力、及細胞的定向爬行能力皆會受到抑制;而在此同時也伴隨著大面積的細胞膜延展。另外,在剔除vimentin基因之後,細胞骨架的結構也會進行重組並降低細胞焦點連結的形成,進而降低細胞的機械性質強度:細胞的硬度及收縮力皆有下降的情形。相反的,我們在MCF7乳癌細胞中過度表現vimentin,則使得細胞的硬度、細胞的移動力及定向爬行能力皆上升,細胞骨架中的微管蛋白也因此重新排列而具有極性(polarity);β1-integrin的增加及細胞連結蛋白E-cadherin的降低亦增加了MCF7上皮-間質細胞轉型的程度。而在上皮-間質細胞轉型過程中扮演重要角色的轉錄蛋白slug,也發現會受到vimentin的調控進而增強了細胞癌化的程度。綜合以上,我們的研究發現了vimentin在上皮-間質細胞轉化型態的癌細胞中的扮演著一個調控者的角色,可以藉由調控細胞骨架的建築結構及細胞內部力量的平衡來維持細胞內的機械性質的恆定。
英文摘要 The modulations of cytoskeletal organization and focal adhesion turnover correlate to tumorigenesis and epithelial-mesenchymal transition (EMT), the latter process accompanied by the loss of epithelial markers and the gain of mesenchymal markers (e.g., vimentin). Clinical microarray results demonstrated that higher levels of vimentin mRNA produced after chemotherapy correlated to a poor survival rate of breast cancer patients. We hypothesized that vimentin mediated the reorganization of cytoskeletons to maintain the mechanical integrity in EMT cancer cells. After we used knockdown strategy, the results showed reduced cell proliferation, impaired wound healing, loss of directional migration, and increased large membrane extension in MDA-MB 231 cells. Vimentin depletion also induced reorganization of cytoskeletons and reduced focal adhesions, which resulted in impaired mechanical strength because of reduced cell stiffness and contractile force. In addition, overexpressing vimentin in MCF7 cells increased cell stiffness, elevated cell motility and directional migration, reoriented microtubule polarity, and increased EMT phenotypes because of the presence of enriched β1-integrin and the loss of junction protein E-cadherin. The EMT-related transcription factor, slug, was also mediated by vimentin to promote cancer malignancy. The current study demonstrated that vimentin serves as a regulator to maintain intracellular mechanical homeostasis by mediating cytoskeleton architecture and the balance of cell force generation in EMT cancer cells.
論文目次 中文摘要 I
Abstract II
誌謝 III
Content V
Figure Content VIII
Chapter 1 Introduction 1
1-1 Tumorigenesis and Epithelial-Mesenchymal transition 1
1-1.1 Genetic instability induced tumorigenesis 1
1-1.2 Epithelial-Mesenchymal transition 3
1-1.2.1 EMT in organ development 3
1-1.2.2 EMT in tissue repairing and fibrosis 4
1-1.2.3 EMT in cancer progression 6
1-2 The biophysical properties of cancer progression 9
1-2.1 Tissue tension homeostasis and cancer progression 9
1-2.2 The mechanical properties of cancer cells 12
1-2.3 The mechanical transduction system in cancer cells 13
1-2.3.1 Mechanosensing from focal adhesions 13
1-2.3.2 Cytoskeleton constructions in cells 15
1-3 Cellular tension generation system and cancer malignancy 18
1-3.1 The mechanobiology of directional migration 18
1-3.2 The cellular tension generation system 21
1-3.3 The biophysical properties of vimentin and cancer progression 22
Chapter 2 Materials and Methods 25
Cell lines and cultures 25
Plasmids, shRNA, siRNA, and antibodies 25
Cell proliferation assay 26
Western blots 27
Wound healing assay 27
Time-lapse tracking 28
Immunofluorescence imaging 28
Invasion assay 29
Cell stiffness measurement and cell surface topology scanning by atomic force microscopy.. 29
Microposts array detector (mPAD) fabrication 30
Statistic 31
Chapter 3 Results 32
The EMT-cancer cells generate higher cell stiffness 32
Vimentin expression contributes to breast cancer development 33
Knockdown of vimentin increases membrane extension but loses focal adhesions 35
Microtubule is reoriented toward the top and bottom of the cell in vimentin knockdown cells 37
Knockdown of vimentin impairs cellular force generation 39
Expressing vimentin in MCF7 cells increases cell stiffness and cell malignancy 41
Vimentin overexpression induced microtubule polarization in MCF7 cells 43
Vimentin mediates slug expression to promote epithelial-mesenchymal transition phenotypes in cancer cells 43
Chapter 4 Discussion 45
Vimentin mediates microtubule polarization to support cell directional migration 47
Vimentin sustains cellular force balancing 48
Signaling networks of vimentin as the vicious cycle of cancer malignancy 50
Chapter 5 Summary and prospect 53
References 56
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