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系統識別號 U0026-2205201318235400
論文名稱(中文) 整合蛋白 β1在子宮肌瘤細胞之伸展及增生所扮演的角色
論文名稱(英文) The Role of Integrin-β1 in Leiomyomal Cell Spreading and Proliferation
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 101
學期 2
出版年 102
研究生(中文) 陳秀梅
研究生(英文) Hsiu-Mei Chen
學號 s58931251
學位類別 博士
語文別 英文
論文頁數 87頁
口試委員 指導教授-陳麗玉
召集委員-蔡少正
口試委員-洪文俊
口試委員-林以行
口試委員-周振陽
口試委員-黃娟娟
中文關鍵字 子宮肌瘤  整合蛋白  細胞伸展  細胞黏著  細胞增生 
英文關鍵字 leiomyoma  integrin  cell spreading  cell adhesion  proliferation 
學科別分類
中文摘要 子宮肌瘤是一種由子宮平滑肌層所衍生的良性腫瘤,好發於生殖年齡的女性,是最常見的婦女疾病之一。子宮肌瘤患者會有腹腔壓迫,不正常子宮出血以及不孕等症狀。由於子宮肌瘤常常被過多的纖維狀細胞外基質(extracellular matrix)所包附著,因此它又被稱為纖維瘤(fibroid)。細胞外基質除了使子宮肌瘤體積大量增加,它也有可能在其他方面影響子宮肌瘤的進程。整合蛋白(Integrins)是細胞表面上主要的細胞外基質接受體(receptor)。整合蛋白與細胞外基質的交互作用可幫助細胞黏著,並且活化下游訊息以調控細胞伸展(spreading),移行(migration),生長(proliferation)以及分化(differentiation)。但是,整合蛋白與細胞外基質之間的作用如何影響子宮肌瘤的發生及進程,則尚不清楚。因此,本研究主要的目的便是探討整合蛋白—尤其是整合蛋白β1—在子宮肌瘤病理上所扮演的角色。我的研究結果發現,子宮肌瘤細胞明顯比正常的子宮肌細胞表現更多量的整合蛋白β1。體外細胞培養的實驗結果顯示,雖然抑制子宮肌瘤細胞之整合蛋白β1,並不影響細胞在纖維連接蛋白(fibronectin),層黏蛋白(laminin)以及膠原蛋白(collagen)上的附著,但是卻會抑制細胞伸展及應力纖維(stress fiber)的形成而造成細胞形狀的改變,進而影響局部黏著斑(focal adhesion)的形成以及減弱細胞的收縮力(contraction force)。更進一步的研究顯示,抑制整合蛋白β1表現會透過抑制子宮肌瘤細胞之黏著斑激酶(focal adhesion kinase)以及細胞外訊息調控激酶(extracellular signal-regulated kinase)的磷酸化程度,進而減少細胞週期蛋白D1及A表現量而達到抑制細胞增生的效果。此外,我利用蛇毒蛋白(Rhodostomin)來破壞整合蛋白與細胞外基質之間的結合而抑制子宮肌瘤細胞增生。最後,我證實了轉化生長因子可以刺激整合蛋白β1的表現。綜合而言,我的研究發現了轉化生長因子β1及β3會促進子宮肌細胞表達過多的整合蛋白β1。細胞外基質便會和這些整合蛋白β1結合,透過一連串的訊息傳遞路徑而促進細胞的伸展及增生。而利用蛇毒蛋白或類似的小分子蛋白來阻斷細胞外基質與整合蛋白β1的結合,則可能是一種可以用來治療子宮肌瘤的方式。
英文摘要 Uterine leiomyoma is a benign tumor derived from uterine smooth muscle layer. It is one of the most common gynecological diseases in women of reproductive age. Symptoms of leiomyoma include pelvic pressure, abnormal uterine bleeding, and infertility. Due to the presence of excessive amount of extracellular matrix (ECM), leiomyoma is also called fibroid. Besides contributing to the huge volume in leiomyoma, ECM may play an important role in the development of leiomyoma. Integrins are the major ECM-receptor on cell surface. Binding of ECM to integrins leads to cell adhesion and initiates a cascade of signaling for cell spreading, migration, proliferation, and differentiation. However, the role of integrin-ECM in leiomyomal pathogenesis remains largely unclear. The aim of this study is to elucidate the pathological processes of leiomyoma regulated by integrin, especially integrin β1. Results from my study showed that the expression of integrin β1 in leiomyomal cells was greater than that in myometrium. Although knockdown of integrin β1 did not affect cell adhesion on fibronectin, laminin, and collagen, it significantly reduced cell spreading and stress fiber formation in leiomyomal cells, which leads to a decrease in focal adhesion and contraction force. Furthermore, knockdown of integrin β1 inhibited the phosphorylation of focal adhesion kinase and extracellular signal-regulated kinase, resulting in reduction of cyclin D1 and cyclin A expression and leiomyomal cell proliferation. Treatment with rhodostomin, a small protein that disrupts interaction of ECM and integrins, reduced the expression of cyclin D1 and cyclin A and cell proliferation. Finally, I demonstrated that overexpression of integrin β1 is induced by transforming growth factor βs (TGF βs). Taken together, these data demonstrate that overexpression of integrin β1 in leiomyomal cells is induced by TGF β1 and β3. Interaction of ECM and overexpressed integrin β1 enhances initiates a cascade of signaling transduction pathways to increase cell spreading and proliferation. Results of this study also provide novel information in designing a treatment regimen by targeting the disruption of ECM-integrin interaction using rhodostomin or similar RGD-containing small molecules.
論文目次 Table of Content V
List of Figures and Table VIII
摘要 X
Abstract XII
Chapter 1 Introduction 1
1-1. Leiomyoma 1
1-1.1 Histologic features, classification, and symptoms 1
1-1.2 The role of growth factors and hormone in leiomyoma 2
1-1.3 Expression and arrangement of ECM in leiomyomas 3
1-2. Integrins 4
1-2.1 Category of integrins 4
1-2.2 Structure of integrins 5
1-2.3 The downstream signaling pathways initiated by integrins-ECM interaction 6
1-2.4 FAK 7
1-2.5 Mediators that regulate the expression of integrin 8
1-2.6 The integrins regulate cell behavior 8
1-2.7 Abnormal expression of integrins in diseases 9
1-3. Focal adhesion and stress fiber formation 10
1-3.1 Focal adhesion 10
1-3.2 Stress fibers 11
1-3.3 Progression of focal adhesion and stress fiber formation 12
1-3.4 The mechanism of stress fiber contraction 13
1-4. Integrins regulate cell proliferation 13
1-4.1 Activation of growth factors by integrins 13
1-4.2 Activation of downstream signaling by integrins 14
1-5. Hypothesis and specific aims 15
Chapter 2 Materials and Methods 17
2-1. Antibodies 17
2-2. Cell cultures 17
2-3. Small interfering RNA (siRNA) transfection 18
2-4. Protein extraction and Western blot 18
2-5. Adhesion assay 19
2-6. Immunocytochemistry 19
2-7. Cell spreading and stress fiber assembly 20
2-8. Collagen gel contraction 21
2-9. Proliferation assay 21
2-10. Disintegrin treatment 22
2-11. Detection of apoptosis by Annexin V 22
2-12. RNA extraction and RT-PCR 23
2-13. Statistical analysis 23
Chapter 3 Results 24
3-1. Integrin β1 is overexpressed in leiomyomal cells 24
3-2. Integrin β1 knockdown affects leiomyomal cell spreading but not adhesion 24
3-3. Integrin β1 knockdown affects tensional force of leiomyomal cells 26
3-4. Activation of integrin β1 induces FAK phosphorylation and focal adhesion complex formation 26
3-5. Integrin β1 promotes leiomyomal cell proliferation 28
3-6. Disruption of integrin-ECM binding by rhodostomin inhibits cell proliferation 29
3-7. TGF β1 and β3 induces the expression of integrin β1 30
Chapter 4 Discussion 31
4-1. The role of integrin β1 in regulation of leiomyoma tumor progression 31
4-2. Integrin β1 is overexpressed in leiomyomal cells 31
4-3. Integrin β1 is required for cell spreading, but not adhesion 32
4-4. The integrin β1 regulates organization of cytoskeleton and generation of tensional force 34
4-5. The relationship between spreading and proliferation 34
4-6. Integrin β1 regulates leiomyomal cell proliferation through FAK/ERK signaling pathway 35
4-7. Rhodostomin inhibits the leiomyomal cell proliferation 36
4-8. TGF β1 and β3 increase the expression of integrin β1 38
Summary 39
References 41
Table 56
Figures 58
Curriculum Vitae 84
Conference Proceedings 85
Publications 86
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