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系統識別號 U0026-2003201522053600
論文名稱(中文) Epstein-Barr病毒對基質金屬蛋白酶基因的調控
論文名稱(英文) Regulation of Matrix Metalloproteinase Genes by Epstein-Barr Virus
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 103
學期 2
出版年 104
研究生(中文) 藍宇彥
研究生(英文) Yu-Yan Lan
學號 S58951489
學位類別 博士
語文別 英文
論文頁數 105頁
口試委員 指導教授-張堯
召集委員-蕭振仁
口試委員-蘇益仁
口試委員-王育民
口試委員-林鈺玲
口試委員-陳振陽
中文關鍵字 EB病毒  鼻咽癌  細胞侵襲  潛伏期膜蛋白質2A  含雙色胺酸功能區氧化還原酶  Zta  MMP9  MMP3 
英文關鍵字 EBV  nasopharynheal carcinoma  cell invasion  latent membrane protein 2A  WW domain-containing oxidoretuctase  Zta  MMP9  MMP3 
學科別分類
中文摘要 鼻咽癌是一種具有局部侵襲和遠端轉移傾向的上皮細胞惡性腫瘤,而已知EB病毒的潛伏期及溶裂期感染與鼻咽癌(NPC)的發展或惡化有關。本研究是去探討EB病毒蛋白質是否以及如何調控轉移相關基質金屬蛋白酶(MMP)的表現而賦予鼻咽癌細胞的侵襲能力。首先,我們發現病毒的潛伏期膜蛋白質2A (LMP2A)正向調控MMP9表現並藉此促進鼻咽癌細胞的侵襲。其分子機制涉及LMP2A所活化的ERK1/2及誘導其下游的Fra-1轉錄因子,因此經由兩個AP-1 結合位造成MMP9啟動子的轉錄活化。有趣的是,LMP2A與一個細胞蛋白質含雙色胺酸功能區氧化還原酶(WOX1)有交互作用,而且LMP2A所誘發的ERK1/2-Fra-1-MMP9訊息傳遞與細胞侵襲是需要內生性WOX1的存在。此外,我們檢驗鼻咽癌腫瘤組織標本,發現LMP2A不僅與MMP9的表現有相關性,也與腫瘤的淋巴結轉移有關。另一方面,EB病毒即初期的溶裂蛋白質Zta有助於增強病毒感染鼻咽癌細胞的移行和侵襲。在MMP陣列分析中, Zta正向調控鼻咽癌細胞表現MMP9和MMP3。其分子機制則涉及Zta對MMP啟動子的直接結合並經由AP-1結合位活化該啟動子。此外,我們發現了Zta誘發的細胞移動主要是透過誘導MMP3而非MMP9,然而MMP3和MMP9對於Zta所誘導的細胞侵襲產生協同促進的作用。我們的研究揭露了EB病毒的潛伏期及溶裂期蛋白質都可透過調控MMP的表現而促進鼻咽癌細胞的侵襲,為EB病毒如何促進鼻咽癌的轉移提供了解釋的連結。既然MMP是EB病毒聚焦調節的腫瘤轉移相關蛋白質,它們可能是治療鼻咽癌的潛在標靶。
英文摘要 Both latent and lytic infection of Epstein-Barr virus (EBV) has been associated with development or progression of nasopharyngeal carcinoma (NPC), an epithelial malignancy with a propensity toward local invasion and distant metastasis. This study is to explore whether and how EBV proteins regulate expression of metastasis-associated matrix metalloproteinses (MMPs) to confer the invasive potential on NPC cells. First, we found that viral latent membrane protein 2A (LMP2A) upregulates MMP9 and promotes MMP9-dependent invasion of NPC cells. The underlying mechanism involves LMP2A-triggered ERK1/2 activation and its downstream induction of the Fra-1 transcription factor, thus transactivating the MMP9 promoter through two AP-1 elements. Interestingly, LMP2A physically interacts with a cellular protein WW domain-containing oxidoretuctase (WOX1), and endogenous WOX1 is required for LMP2A-induced ERK1/2-Fra-1-MMP9 signal transduction and cell invasion. In addition, we found a correlation of LMP2A not only with MMP9 expression in NPC biopsy specimens, but also with lymph node metastasis of the tumors. On the other hand, Zta, an immediate-early lytic protein of EBV, contributes to enhanced migration and invasion of EBV-infected NPC cells. In MMP array analysis, Zta upregulates expression of MMP9 and MMP3 in NPC cells. The underlying mechanism involves direct binding of Zta to the target promoter and triggering promoter activation through AP-1 elements. Furthermore, we found that Zta induces cell migration mainly through inducing MMP3 but not MMP9, while MMP3 and MMP9 cooperate synergistically for Zta-induced cell invasion. Our study reveals that both latent and lytic proteins of EBV promote NPC cell invasion through regulating MMP expression, providing a link how EBV contributes to NPC metastasis. Since MMPs are convergent metastasis-associated proteins regulated by EBV, they may serve as a potential therapeutic target for NPC treatment.
論文目次 Abstract in Chinese I
Abstract in English II
Acknowledgement III
Contents IV
Abbreviation 1
Introduction 3
I. Epstein-Barr virus (EBV) 3
I-1. Virion structure and DNA genome of EBV 3
I-2. Life cycle of EBV 3
I-2-1. Latent infection 3
I-2-2. Lytic infection 4
I-3. LMP2A of EBV 5
I-3-1. Structure of LMP2A 5
I-3-2. Signaling events caused by LMP2A 5
Hijacking of the B cell receptor (BCR) signaling pathway 5
Regulation of the phosphotidylinositol 3-kinase (PI3-K)/Akt pathway 6
Regulation of the mitogen-activated protein kinase (MAPK) pathway 6
Regulation of nuclear factor-κB (NF-κB) and STAT3 pathways 7
I-4. Zta of EBV 7
I-4-1. Structure of Zta protein 7
I-4-2. Transactivation activity of Zta 7
I-4-3. Cellular genes regulated by Zta 8
I-5. EBV-associated cancers (except NPC) 8
I-5-1. BL 8
I-5-2. HL 9
I-5-3. Nasal NK/T cell lymphoma 9
I-5-4. Gastric carcinoma 9
II. NPC 10
II-1. Epidemiology 10
II-2. Etiology 10
II-2-1. Environmental factors 10
II-2-2. Genetic factors 10
II-2-3. Viral factor 11
Association between EBV and NPC 11
Latent infection of EBV in NPC 11
EBV lytic infection in NPC 12
III. MMPs 13
III-1. Introduction of MMPs 13
III-2. Structure of MMPs 13
III-3. Regulation of MMP gene expression 13
III-4. Functions of MMPs in tumor metastasis 14
III-5. Functions of MMP9 in cancer progression 15
III-6. Functions of MMP3 in cancer progression 15
IV. WW domain-containing oxidoreductase (WOX1) 16
IV-1. Structure of WOX1 16
IV-2. WOX1 in tumor suppression 16
IV-3. WOX1 in protein-protein interaction and cellular signaling 16
V. Aims of this study 17
Materials and Methods 19
1. Cell culture and drug treatment 19
2. Plasmids and siRNAs 19
3. Transfection with plasmid DNA or siRNA 21
4. Total RNA extraction 21
5. Quantitative real-time PCR 22
6. Immunoblotting assay 22
7. Immunoprecipitation assay 23
8. Ras activation assay 23
9. Reporter gene assay 23
10. Chromatin immunoprecipitation (ChIP) assay 23
11. MMP antibody array and enzyme-linked ommunosorbent assay (ELISA) 24
12. Gelatin zymography 24
13. Matrigel invasion assay 25
14. Transwell cell migration assay 25
15. Immunohistochemical staining 25
16. Statistics 26
Results 28
I. LMP2A correlates with lymph node metastasis of NPC and promotes NPC cell invasion through induction of MMP9 28
I-1. The expression of LMP2A is correlated with lymph node metastasis of NPC 28
I-2. LMP2A upregulates MMP9 expression in NPC cells 28
I-3. LMP2A-induced activation of the MMP9 promoter requires two AP-1 elements in the promoter 29
I-4. LMP2A upregulates Fra-1, which is required for LMP2A-induced MMP9 expression 30
I-5. LMP2A activates an ERK1/2 signaling pathway, which is required for LMP2A-triggered induction of Fra-1 and MMP9 30
I-6. LMP2A-induced ERK1/2 activation requires de novo protein synthesis and proteasome-mediated protein degradation but is independent of Ras 31
I-7. LMP2A is unable to induce MMP9, ERK, and Fra-1 in some non-NPC epithelial cell lines 31
I-8. PY motifs of LMP2A are required for ERK1/2 activation, Fra-1 upregulation, and MMP9 induction 32
I-9. MMP9, Fra-1, and ERK1/2 are required for LMP2A-induced invasion of NPC cells 32
I-10. WOX1 is required for LMP2A-induced ERK1/2-Fra-1-MMP9 pathway and cell invasion 33
1-11. Interaction of WOX1 and LMP2A is important for activation of the ERK1/2-Fra-1-MMP9 pathway 33
I-12. LMP2A, Fra-1, and MMP9 are associated in NPC tumor biopsy
specimens 34
II. Zta upregulates MMP3 and MMP9 that synergistically promote cell
invasion 36
II-1. Zta upregulates MMP3 and MMP9 36
II-2. Zta induces MMP3 expression 36
II-3. Endogenous Zta contributes to induction of MMP3 expression, migration and invasion of EBV-infected cells 36
II-4. Zta-induced activation of the MMP3 promoter requires three
AP-1 elements 37
II-5. The DNA-binding domain of Zta is required for recruitment to the MMP3 promoter and for induction of MMP3 expression 38
II-6. Zta-induced cell migration requires MMP3 while Zta-induced cell invasion requires both MMP3 and MMP9 38
II-7. MMP3 enhances cell migration and synergizes with MMP9 to promote cell invasion 39
Discussion 40
I. The possible mechanisms of LMP2A-induced NPC cell invasion 40
I-1. High LMP2A expression is associated with lymph node metastasis of NPC and LMP2A contributes to NPC cell invasion by inducing MMP9 expression 40
I-2. MMP9 expression is induced by LMP2A through ERK1/2-Fra-1 pathway in NPC cells 41
I-3. A positive association among LMP2A, Fra-1 and MMP9 is found in NPC tumor specimens 41
I-4. Physical association between LMP2A and WOX1 is important for activation of the ERK1/2-Fra-1-MMP9 pathway 42
I-5. The LMP2A-WOX1-ERK1/2-Fra-1 signaling pathway may affect NPC progression 43
II. The possible mechanisms and consequences of Zta-induced MMP
expression 44
II-1. Zta promotes cell migration and invasion by inducing MMPs 44
II-2. Zta does not induce all MMP genes with promoters containing AP-1
elements 44
II-3. Zta may also indirectly induce MMP3 production through other
mechanisms 45
II-4. Zta induces cell migration via inducing MMP3 expression 45
II-5. Zta-induced MMP3 and MMP9 synergistically promote cell
invasion 46
II-6. Zta-induced MMP3 and MMP9 may potentially play other roles in cancer progression 47
III. The possible roles of MMP induction from EBV’s or NPC’s points of view and potential implication for clinical treatment 48
III-1. Latent EBV infection may suppress innate antiviral immune response through inducing MMPs 48
III-2. Latent EBV infection in NPC cells may achieve local immune evasion through inductions of MMPs 48
III-3. Latent EBV infection in NPC cells may suppress epithelial differentiation by inducing MMPs 49
III-4. Some possible factors are involved in the switch of EBV infection from latency into the lytic cycle in NPC cells 49
III-5. MMPs induced by EBV lytic proteins may promote NPC cell escape from the unfavorable microenvironment 50
III-6. MMPs are potential therapeutic targets of NPC 50
Conclusion 52
References 53
Tables and Figures 80
Table 1. Characteristics of the 71 nasopharyngeal cancer patients 80
Table 2. Comparing the mean % IHC level of LMP2A by patients’ baseline characteristics 81
Fig. 1. LMP2A upregulates MMP9 expression in NPC cells 82
Fig. 2. LMP2A-induced activation of the MMP9 promoter requires two AP-1 elements in the promoter 83
Fig. 3. LMP2A upregulates Fra-1, which is required for LMP2A-induced MMP9 expression 84
Fig. 4. LMP2A did not significantly increase Fra-1 mRNA in NPC cells 85
Fig. 5. LMP2A activates the ERK1/2 signaling pathway, which is required for LMP2A-triggered induction of Fra-1 and MMP9 86
Fig. 6. LMP2A-induced ERK1/2 activation requires de novo protein synthesis and proteasome-mediated protein degradation but is independent of Ras 87
Fig. 7. LMP2A is unable to induce MMP9, ERK, and Fra-1 in some non-NPC epithelial cell lines 88
Fig. 8. PY motifs of LMP2A are required for ERK1/2 activation, Fra-1 upregulation, and MMP9 induction 89
Fig. 9. MMP9, Fra-1, and ERK1/2 are required for LMP2A-induced invasion of NPC cells 90
Fig. 10. WOX1 is required for the LMP2A-induced ERK1/2-Fra-1-MMP9 pathway and cell invasion 92
Fig. 11. WOX1 physically interacts with LMP2A 93
Fig. 12. Upon knockdown of endogenous WOX1, the LMP2A-induced ERK1/2-Fra-1-MMP9 pathway is restored by exogenous wild-type WOX1, but not by a LMP2A-binding-defective WOX1 mutant 94
Fig. 13. LMP2A, Fra-1, and MMP9 are associated in NPC tumor biopsy
specimens 95
Fig. 14. MMP3 and MMP9 are upregulated by Zta 97
Fig. 15. Zta induces MMP3 expression 98
Fig. 16. Endogenous Zta contributes to induction of MMP3 expression, migration and invasion of EBV-infected cells 99
Fig. 17. Zta-induced activation of the MMP3 promoter requires three
AP-1 elements 100
Fig. 18. The DNA-binding domain of Zta is required for induction of MMP3 expression 101
Fig. 19. Zta-induced cell migration requires MMP3 while Zta-induced cell invasion requires both MMP3 and MMP9 102
Fig. 20. MMP3 enhances cell migration and synergizes with MMP9 to promote cell invasion 104
Fig. 21. A model for EBV-induced MMP expressions and their potential
functions 105
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