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系統識別號 U0026-0108201415142900
論文名稱(中文) Gelsolin對頭頸癌化療抗藥性之影響及其分子機制之探討
論文名稱(英文) The role of gelsolin in head-and-neck cancer drug resistance and its molecular mechanisms
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 102
學期 2
出版年 103
研究生(中文) 王佩文
研究生(英文) Pei-Wen Wang
學號 s58961052
學位類別 博士
語文別 英文
論文頁數 109頁
口試委員 指導教授-謝達斌
召集委員-賴明德
口試委員-蘇五洲
口試委員-陳玉玲
口試委員-張國威
口試委員-劉柯俊
中文關鍵字 GSN  XIAP  含鉑抗癌藥物  cisplatin  頭頸癌  抗藥性 
英文關鍵字 GSN  XIAP  cisplatin  chemoresistance  head-and-neck cancer 
學科別分類
中文摘要 Gelsolin (GSN) 是一個多功能的蛋白,除了與actin結合來調控actin纖維的延伸以及縮短此功能之外,其表現與否會影響到細胞的生長、分化和細胞凋亡(apoptosis)的產生。依照細胞的不同病理條件和類型,GSN分別有促進或抑制細胞凋亡的功能存在,因此在許多的癌症組織中都有發現GSN的表現且對於癌症的發生以及癌化的進行扮演很重要的角色。近年來對於癌症的治療通常是透過外科手術切除同時再伴以化學抗癌藥物的治療,但是化學治療的抗藥性仍然是治療成功的主要障礙。Cisplatin是一種有效含鉑抗癌藥物,被廣泛的應用在治療各個部位所發生的惡性腫瘤。最近的證據發現,促進細胞凋亡的蛋白[例如Fas, caspases and p53]和抵抗細胞凋亡的蛋白[例如Akt, X-linked inhibitor of apoptosis protein (XIAP), FLICE-like inhibitory protein (FLIP)]的訊息傳遞路徑被不正常的調控,進而去抑制細胞凋亡的訊息傳遞,已被發現是含鉑抗癌藥物產生抗藥性的一個關鍵決定因素。因此本篇論文想要探討GSN的表現量是否會透過與細胞凋亡有關的蛋白作用,進而去誘導細胞凋亡而造成細胞對於抗癌藥物產生抗藥性。本篇論文我們觀察GSN在頭頸部癌症患者與卵巢癌患者中的表現,發現這些有經過含鉑抗癌藥物化學治療的病患,若檢體中GSN表現高則治療後再復發的機率也會比較高,且有高GSN表現的病人,治療後的存活率也會較差。這一發現也同樣在cisplatin敏感性和抗藥性不同的頭頸癌細胞株觀測到相同的結果。同樣的若是調控GSN在細胞中的表現量增加或減少亦會發現可以影響到細胞對cisplatin的敏感度。在GSN大量表現的細胞中可觀察到Caspase-3的活化、I- GSN轉化為CL- GSN以及Cisplatin引起的線粒體膜電位(Δψ)損失都會比GSN低表現量的細胞有顯著的減弱。另外利用SCID小鼠誘導生成的腫瘤動物實驗也支持這一發現。因此調控Gelsolin的表現量增加或減少,在細胞實驗以及動物實驗同樣被證實可以影響其對Cisplatin的敏感度以及對Cisplatin的治療效果。另外,我們亦證實GSN會與抑制細胞凋亡的蛋白XIAP產生交互作用,而此交互作用會因給予cisplatin而減少。因此,GSN的表現可能在腫瘤中對於化學治療產生抗藥性扮演一重要角色,或許可作為往後化學治療的癌症分子標靶之一。
英文摘要 Gelsolin (GSN) is a cytoskeleton-associated protein that regulates actin dynamic and is aberrantly regulated in many tumor types. GSN promotes or inhibits apoptosis in vitro, depending on the pathological conditions and cell types. Cisplatin is commonly used for chemotherapy in patients with head-and-neck cancer (HNC), but it increases control of the disease by only 10-15%. Recent evidence indicates that down-regulation of the apoptotic pathways is a key determinants for cisplatin resistance. Dysregulation of pro-apoptotic [e.g. Fas, caspases and p53] and anti-apoptotic [e.g. Akt, X-linked inhibitor of apoptosis protein (XIAP), FLICE-like inhibitory protein (FLIP)] pathways have been found in chemoresistant cancer cells. Downregulation of pro-apoptotic pathways is a key determinant for chemoresistance in which GSN is critically involved. We hypothesized that gelsolin serve as a mobile docking protein interacts with intracellular intermediates and cross-talks with their signaling pathways to determine whether cells are sensitive or resistant to chemotherapy. In this study, high GSN expression in the 58 cisplatin-treated patients with HNC and 102 ovarian cancer (OVCA) patients were observed which were compared to their recurrence status after therapeutic with cisplatin. We analyzed the association between GSN expression and cisplatin resistance in HNC cell lines and animals with HNC. GSN expression levels were positively associated with chemoresistance in vitro and in vivo. Cisplatin-induced GSN downregulation was associated with the cleavage of GSN and the promotion of apoptosis. GSN silencing facilitated cisplatin-induced apoptosis in chemoresistant cells. In contrast, intact GSN (I-GSN) was pro-survival in the presence of cisplatin by interacting with XIAP. In chemosensitive cells, cisplatin suppressed GSN-XIAP interaction, promoted translocation of XIAP from the perinuclear region to the nucleus, and induced apoptosis. In chemoresistant cells, GSN was highly expressed, and cisplatin had no significant effect on GSN-XIAP interaction and apoptosis. We conclude that GSN is important for chemoresistance in HNC and may be an appropriate therapeutic target in chemoresistant cancers.
論文目次 中文摘要 I
ABSTRACT II
誌謝 III
Contents IV
Table Contents VIII
Figure Contents IX
Chapter 1. Introduction 1
1-1. Gelsolin 2
1-1.1 Actin and gelsolin structure 2
1-1.2 GSN and apoptosis 3
1-1.3 GSN and cancer 4
1-2 Chemotherapy and chmoresistance 6
1-2.1 Platinum-based cancer chemotherapy 6
1-2.2 Therapies for head-and-neck cancer (HNC) 7
1-2.2 Therapies for ovarian cancer (OVCA) 8
1-3 GSN: Cell Signaling Mechanisms and Cross-talk 10
1-3.1 X-Linked inhibitor of apoptosis (XIAP) 11
1-3.2 FLICE inhibitory protein (FLIP) 13
Chapter 2. Motivation and Research Goal 14
Aim1: To examine the regulation of GSN in the induction of apoptosis in HNC cells by cisplatin 15
Aim2: To study the role of GSN and its signaling mechanisms and cross-talk in the regulation of apoptosis and chemosensitivity in HNC cells 16
Chapter 3. Materials and Methods 17
3-1 Reagents 18
3-2 Yeast two-hybrid screening and Metacore pathway analysis 19
3-3 Patient population. 20
3-4 Immunohistochemistry 21
3-5 Grading of GSN expression level and statistical analyses 21
3-6 Cell lines and cell culture 22
3-7 Construction for GSN 22
3-8 Transfection and establishment of stable clones 23
3-9 RNA Interference 23
3-10 Caspase-3 activity assay 24
3-11 Caspase-3 specific inhibitor (DEVD) experiment. 24
3-12 Isolation of RNA and Quantitative Real-Time RT-PCR 24
3-13 Protein isolation and Western blot 25
3-14 Mitochondrial Membrane Potential (Δψ) Assessment 26
3-15 Assessment of Cell viability 27
3-16 Determining cell apoptosis. 28
3-17 Animal model 28
3-18 Immunoprecipitation (IP) 28
3-19 Immunocytochemistry and Confocal Microscopy (IF) 29
3-20 Statistical analyses 30
Chapter 4. Results 31
4-1 Identification and analysis of GSN interacting proteins in a yeast-two-hybrid screening 32
4-2 GSN expression is associated with tumor recurrent status in HNC patients 33
4-3 The relationship with GSN expression and OVCA cancer progression 33
4-4 GSN expression and OVCA patient survivals 34
4-5 Cisplatin-resistant cancer cells had higher I-GSN expression levels. 35
4-6 CDDP-resistant cancer cells exhibit attenuated mitochondrial membrane potential (Δψ) loss, caspase-3 activation, and decreased CL-GSN content. 36
4-7 I-GSN expression attenuated CDDP-induced and other chemotherapeutic agent induced cytotoxicity. 37
4-8 Modulating I-GSN expression altered CDDP-induced mitochondria membrane potential (Δψ) loss, caspase-3 activation, and GSN cleavage. 38
4-9 I-GSN expression conferred cisplatin resistance in a xenograft cancer model. 38
4-10 Cisplatin treatment resulted in the dissociation of XIAP-GSN complex in chemosensitive cells (HONE1) but not in chemoresistant cells (HONE1-CIS6). 39
Chapter 5. Discussions 41
5-1 GSN expression and the clinical application 42
5-2 The relationship with GSN expression and chemoresistant in vitro 44
5-3 GSN expression and cellular apoptosis 46
5-4 The relationship with GSN and other anti-apoptosis proteins 47
5-4.1 Regulation of cell attachment: involvement of XIAP, FAK and Gelsolin 49
5-4.2 Regulation of apoptosis: involvement of p53, Akt and Gelsolin 50
Chapter 6. Conclusion 53
Further application 55
REFERENCES 57
TABLES 70
FIGURES 78
Curriculum Vitae 107
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