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系統識別號 U0026-0208201315114100
論文名稱(中文) 丙型干擾素誘導肺上皮惡性腫瘤進行一種類胞外捕捉性死亡
論文名稱(英文) IFN-gamma induces a mimic extracellular trap cell death in lung epithelial maligancy
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 101
學期 2
出版年 102
研究生(中文) 錢舜益
研究生(英文) Shun-Yi Chien
學號 S46001058
學位類別 碩士
語文別 英文
論文頁數 70頁
口試委員 指導教授-林秋烽
口試委員-林以行
口試委員-郭志峰
中文關鍵字 丙型干擾素  細胞自噬作用  組蛋白瓜胺酸化  胞外捕捉性死亡  肺癌 
英文關鍵字 IFN-γ  autophagy  hitone H3 citrullination  ETosis  lung cancer 
學科別分類
中文摘要 丙型干擾素藉由細胞自噬作用來促進其訊息傳遞和生物功能包括發炎、抑菌以及抗癌。本篇研究著重探討細胞自噬作用對於丙型干擾素誘導細胞毒性的角色。丙型干擾素會造成肺癌細胞株A549生長抑制並產生細胞毒性。丙型干擾素不會造成細胞週期停滯卻誘導細胞凋亡的現象包括染色體的凝聚和磷脂醯絲胺酸胞外暴露,同時伴隨著細胞毒性相關的類細胞壞死現象。藉由細胞核的染色、體外核小體的偵測、電子顯微鏡觀察以及核纖層蛋白染色顯示丙型干擾素誘導類胞外捕捉性死亡,且這樣的現象是由caspase蛋白所調控。研究證實IRGM1以及ATF6蛋白調控細胞自噬作用進而促進丙型干擾素誘導細胞毒性、caspase-3蛋白的活化以及類胞外捕捉性死亡現象。由丙型干擾素誘導的NADPH氧化酶表現及下游活性氧化物會促使染色體損害進而促進類胞外捕捉性死亡。處理丙型干擾素會使得FADD蛋白會和細胞自噬體結合,顯示細胞自噬作用會誘導FADD蛋白調控caspase-3活化。在細胞自噬作用和caspase活化之後,丙型干擾素導致染色體損害並伴隨著ATR/ATM蛋白調控的類胞外捕捉性死亡以及細胞毒性產生。另外,丙型干擾素誘導的胞外捕捉性死亡取決於PAD4蛋白調控的組蛋白瓜胺酸化,而調控PAD4蛋白活化的機制包括染色體損害相關的ATR/ATM及NADPH氧化酶與內質網壓力相關的ATF6及鈣離子訊號。重要的是,生長抑制、細胞毒性、caspase-3蛋白活化、染色體損害以及類胞外捕捉性死亡在細胞自噬作用缺乏和具丙型干擾素抗性的肺癌細胞株PC14PE6/AS2無法產生。這些結果證實細胞自噬作用存在下,丙型干擾素誘導caspase調控的染色體損害伴隨著PAD4調控組蛋白瓜胺酸化的胞外捕捉性死亡現象,並提供新穎的丙型干擾素細胞毒性證據。
英文摘要 Interferon (IFN)-γ causes autophagy to facilitate signaling and bioactivities, including inflammation, anti-microbe, and anticancer. This study aims to investigate the role of autophagy in cytotoxicity of IFN-γ. IFN-γ induces growth inhibition and cytotoxicity in A549 human lung cancer cells. Without cell cycle arrest, the presence of apoptotic events, such as DNA condensation/fragmentation and phosphatidylserine externalization, accompanied by necrosis-like cell death was related to IFN-γ cytotoxicity. Surprisingly, nuclear staining, extracellular nucleosome detection, electronic microscopic observation, and lamin staining showed a mimic extracellular trap cell death (ETosis) caused by IFN-γ and regulated by caspases. Autophagy regulated by immunity-related GTPase family M protein (IRGM) 1 and activating transcription factor (ATF) 6 facilitated IFN-γ-induced cytotoxicity, caspase activation, and ETosis. Nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase-associated reactive oxygen species (ROS) generation also promoted Fas-associated protein with death domain (FADD) was co-localized with microtubule-associated protein 1 light chian (LC) 3 punctas under IFN-γ treatment, indicating that autophagy activates FADD-mediated caspase activation. Following autophagy and caspase activation, IFN-γ resulted in DNA damage followed by ataxia telangiectasia and Rad3-related protein (ATR)/ataxia-telangiectasia mutated (ATM)- and NADPH oxidase-regulated ETosis and cytotoxicity independent of p53. Moreover, IFN-γ-induced ETosis was depended on peptidyl arginine deiminase (PAD) 4-mediated histone 3 citrullination while the regulation of PAD4 was regulated by DNA damage-associated ATR/ATM and NADPH oxidase and endoplasmic reticulum stress-associated ATF6 and calcium signaling. Notably, growth inhibition, cytotoxicity, caspase-3 activation, DNA damage, and ETosis were defect in PC14PE6/AS2 human lung cancer cells while the cells showed autophagy insusceptibility as well as IFN-γ resistance. These results provide the novel evidence to demonstrate that, under autophagy, IFN-γ triggers caspase-mediated DNA damage-associated a mimic ETosis accompanied by PAD4-mediated H3 citrullination for cytotoxicity.
論文目次 Abstract in Chinese I
Abstract in English II
Acknowledgement III
Abbreviations IV
Contents VIII
I. Introduction 1
I-1. Interferon (IFN)-γ 1
I-2. The Role of IFN-γ in Cancer 1
I-3. Autophagy 2
I-4. The Role of Autophagy in Cancer 3
I-5. Autophagy Induction by IFN-γ 4
I-6. Extracellular Traps Cell Death (ETosis) 4
I-7. The Regulation of ETosis 5
II. Objective and Specific Aims 7
Specific Aim 1: To clarify the effects of IFN-γ on lung epithelial malignancy. 7
Specific Aim 2: To investigate the role of autophagy in IFN-γ-induced cell death. 7
Specific Aim 3: To verify the mechanisms of IFN-γ-induced autophagy-related cell death. 7
III. Materials and Methods 8
III-1. Cells and Cell Culture 8
III-2. Reagents and Antibodies 8
III-3. Proliferation Assay 9
III-4. Cytotoxicity Assay 9
III-5. Cell Cycle and Cell Death Analysis 9
III-6. Western Blot Analysis 10
III-7. Immunostaining 10
III-8. Enzyme-linked Immunosorbent Assay 11
III-9. Lentiviral-based RNA Interference Transfection 11
III-10. Luciferase Reporter Assay 12
III-10. Transmission Electron Microscopy 12
III-11. Determination of ROS Generation 13
III-12. Determination of Calcium Release 13
III-13. Live Cell Imaging 13
III-13. Statistical Analysis 14
IV. Results 15
IV-1. IFN-γ Induces Cell Proliferation Inhibition and Cytotoxicity in Lung Epithelial Cancer Cell A549 Accompanied by Apoptosis and Non-apoptotic Cell Death 15
IV-2. Cell Death Caused by IFN-γ, which Regulated by Caspase-3, is Characterized as a Mimic ETosis 15
IV-3. Autophagy and ROS are Required for IFN-γ-induced a Mimic ETosis 17
IV-4. IFN-γ Induces IRF-1-regulated but CD95-independent Caspase-8/Caspase-3 Activation and a Mimic ETosis through Atg5/FADD-regulated Manner 18
IV-5. IFN-γ Induces Caspase-3-regulated DNA Damage Followed by ATR/ATM-associated a Mimic ETosis 19
IV-6. ATR/ATM Regulates PAD4 Activation While PAD4-mediated Histone H3 Hypercitrullination Is Required for IFN-γ-induced a Mimic ETosis 20
IV-7. Autophagy Resistant PC14PE6/AS2 Lung Cancer Cells Are Resistant to IFN-γ Response 21
V. Discussion 22
VI. Conclusion and Implication 28
References 29
Table 38
Figures and Figure Legends 40
Figure 1. Exogenous IFN-γ causes cell proliferation inhibition and cytotoxicity accompanied by concurrent apoptosis as well as non-apoptotic cell death. 40
Figure 3. Nuclear staining, extracellular nucleosome detection, nuclear lamin A/C staining, and electronic microscopic observation, which characterized with vacuolization, autophagy, chromatin de-condensation, nuclear membrane destruction, show a mimic to ETosis that is unusually regulated by caspase-3. 43
Figure 4. Gene silence in A549 cells used in this study. 45
Figure 5. Autophagy, IRGM1, and ATF6 dependently, facilitates IFN-γ-induced cytotoxic ETosis. 46
Figure 6. IFN-γ causes ROS generation and NADPH oxidase expression followed by ETosis. 48
Figure 7. An IRF1-regulated non-CD95-mediated caspase-8/ caspase-3 signaling axis following Atg5/FADD/caspase-8 interaction around autophagosomes is required for ETosis. 49
Figure 8. IFN-γ results in DNA damage followed by ATR/ATM- but not p53-regulated ETosis. 51
Figure 9. ATR/ATM acts upstream of PAD4-mediated histone 3 hyper- citrullination and ETosis. 53
Figure 10. ETosis is defect in cells which are originally presenting IFN-γ and autophagy resistance. 55
Figure 11. Schematic model for the molecular mechanisms of IFN-γ in regulating a mimic ETosis in lung epithelial malignancy. 57
Appendix 58
A. Figures 58
B. Materials 59
B-1 Chemicals 59
B-2 Antibodies 60
B-3 Kits 62
B-4 Consumables 62
B-5 Apparatus 62
C. Methods 63
C-1 Cell culture 63
C-2 Western blot 65
C-3 Lentiviral-based shRNA knockdown 67
C-4 PI staining 68
C-5 Intracellular ROS assay 69
C-6 Intracellular calcium assay 69
CURRICULUM VITAE 70
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