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系統識別號 U0026-1708201117364300
論文名稱(中文) B型肝炎病毒引發肝癌在轉殖小鼠中之基因不穩定性
論文名稱(英文) Genomic instability in hepatitis B virus-induced hepatoma in transgenic mice
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系碩博士班
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 99
學期 2
出版年 100
研究生(中文) 劉仁傑
研究生(英文) Ren-Jie Liou
學號 t3696401
學位類別 碩士
語文別 英文
論文頁數 90頁
口試委員 指導教授-黃溫雅
口試委員-蘇益仁
口試委員-王憶卿
口試委員-王慧菁
中文關鍵字 B型肝炎病毒  肝癌  基因不穩定性  X蛋白  pre-S2突變大型表面抗原 
英文關鍵字 pre-S2 LHBS  HBx  HCC  genomic instability  HBV 
學科別分類
中文摘要 慢性B型肝炎病毒感染是造成肝癌的主要原因。目前已有兩個B型肝炎所表現的病毒致癌蛋白被發現,X蛋白與pre-S2大型變種表面蛋白。由於X蛋白可使纖維母細胞轉型且可使轉殖鼠長出肝癌,因此被認為與肝癌高度相關。X蛋白同時也參與在核苷酸切除修復及細胞週期調控。pre-S2大型變種表面蛋白是在大型表面蛋白的pre-S2區域有缺失,這樣的蛋白在肝癌及慢性B型肝炎感染病人是蠻常見的。pre-S2大型變種表面蛋白會造成細胞內質網壓力、去氧核醣核酸氧化傷害及細胞週期的進行。因此,在本篇研究中,我們想要探討是否這兩個病毒致癌蛋白會造成宿主的基因不穩定性及是否參與調控基因穩定性相關基因的表現。我們成功建立了三種基因型的小鼠,分別表現pre-S2大型變種表面蛋白、X蛋白及pre-S2大型變種表面蛋白/X蛋白共同表現,這些小鼠分別在平均22、16、13個月大時有觀察到肝癌發生。我們利用晶片式全基因體定量分析來偵測小鼠的基因變異。發現在所有分析的檢體中,都有發現基因體變異的情形,且在小鼠中pre-S2大型變種表面蛋白引起較X蛋白高的基因變異。除此之外,利用cDNA微陣列及Metacore™軟體分析,我們發現基因穩定性相關路徑,包括去氧核醣核酸傷害反應、細胞週期調控及細胞凋亡都明顯受到病毒致癌蛋白所影響。更詳細地,在細胞週期調控的子路徑中,參與在G2/M細胞週期的基因Wee1明顯的受到影響。利用逆轉錄聚合酶鏈式反應來驗證cDNA微陣列的結果,發現參與在調控Cdk1磷酸化及有絲分裂的Wee1,有明顯隨著年紀往下掉。表示G2/M細胞週期檢查點被這兩個病毒致癌蛋白所破壞。相反地,細胞週期抑制劑Cdkn1a的表現量卻是明顯上升。總結我們的發現,B型肝炎病毒所表現的X蛋白與pre-S2大型變種表面蛋白會分別造成細胞週期調控失常及基因不穩定性,最後導致肝癌的發生。
英文摘要 Chronic hepatitis B virus (HBV) infection is the major cause of hepatocellular carcinoma (HCC) globally. Two HBV-encoded proteins have been identified as viral oncoproteins, the X protein (HBx) and the pre-S2 mutant large surface antigen (Δ2-LHBS). HBx is strongly implicated in hepatocellular carcinogenesis by inducing transformation of the fibroblasts and causing the development of HCC in transgenic mice. It is also found to inhibit nuclear excision repair and promote cell cycle progression. The Δ2-LHBS, which contains a deletion in the pre-S2 region of LHBS, is predominant in HCC patients with chronic HBV infection. The Δ2-LHBS was shown to induce ER stress, oxidative DNA damage and cell cycle progression. We aim to address whether viral oncoproteins, Δ2-LHBS and HBx, involve in genomic instability of host cell, and affect genomic stability-related gene expression profiles. We have established the transgenic (TG) mice carrying the Δ2-LHBS, HBx, and both of the two genes, which were found to develop HCC at approximate 22, 16 and 13 months old, respectively. The array-based comparative genomic hybridization (aCGH) was applied to detect the genomic aberrations in these TG mice. We found that all the samples analyzed contained genomic aberrations. Additionally, the Δ2-LHBS caused higher global genomic aberrations than HBx did in the TG mice at similar ages. On the other hand, we identified the genomic stability-related pathways were greatly perturbed by the transgenes in gene expression microarray studies and Metacore™ software analysis. We found that the genomic stability-related pathways such as DNA damage responses, cell cycle regulation and apoptosis were greatly affected. Specifically, among the cell cycle regulation sub-pathways, the factors involved in G2/M phase cell cycle transition, such as Wee1, were found greatly affected. By RT-PCR studies to validate the microarray results, we found that Wee1, which inhibited the entry into mitosis through phosphorylating Cdk1, was age-dependently down-regulated in all the TG mice analyzed, suggesting that the G2/M cell cycle checkpoint was compromised by these two viral oncoproteins. Contrarily, Cdkn1a, a cyclin dependent-kinase inhibitor, was up-regulated in HBx and Δ2-LHBS/HBx double TG mice, suggesting that the HBx aberrantly regulated the gene expression profiles of the transgenic mice. In summary, the HBV oncoproteins, HBx and Δ2-LHBS, may lead to hepatocarcinogenesis through different mechanisms, perturbed transcriptomic gene expression and inducing genomic aberrations, respectively.
論文目次 Abstract I
中文摘要 II
Acknowledgment III
Table of Contents IV
List of Tables VI
List of Figures VII
List of Appendices VIII
List of Abbreviations and Symbols IX
1. Introduction 1
1.1 Hepatocellular carcinoma (HCC) 1
1.1.1 Epidemiology of HCC 1
1.1.2 Etiology of HCC 2
1.2 Hepatitis B virus (HBV) 2
1.2.1 Epidemiology of HBV 2
1.2.2 Virology of HBV 3
1.3 Pathogenesis of HBV-associated HCC 4
1.3.1 Integration of HBV DNA into host genome 5
1.3.2 HBV X protein (HBx) 5
1.3.2.1 HBx in cell cycle regulation 6
1.3.2.2 HBx in apoptosis 6
1.3.2.3 HBx in DNA repair 7
1.3.2.4 HBx in host gene transactivation 7
1.3.3 The pre-S2 mutant large hepatitis B surface antigen (Δ2-LHBS) 7
1.3.3.1 Δ2-LHBS in ER stress 8
1.3.3.2 Δ2-LHBS in cell cycle regulation 9
1.3.3.3 Δ2-LHBS in DNA damage 9
1.4 Genomic instability 9
1.4.1 Basis of genomic instability 10
1.4.2 Genomic instability in hepatocarcinogenesis 10
1.4.3 Genomic instability induced by HBV 10
2 Materials and Methods 13
2.1 Chemicals and reagents 13
2.2 Transgenic mice 13
2.3 Genomic DNA extraction 13
2.4 Array-based comparative genomic hybridization (aCGH) 14
2.5 Quantification of degree of aberrations 15
2.6 cDNA microarray 15
2.7 Pathways analysis of microarray data 15
2.8 RNA extraction 16
2.9 Reverse transcription-Polymerase chain reaction (RT-PCR) 16
3 Results 18
3.1 aCGH to identify genomic instability induced by ∆2-LHBS, HBx and ∆2-LHBS/HBx 18
3.1.1 Chromosomal aberrations in ∆2-LHBS, HBx and ∆2-LHBS/HBx double transgenic mice 18
3.1.2 ∆2-LHBS induced higher genomic instability than HBx 19
3.1.3 Carcinogenesis-related genes within the aberration regions 20
3.2 cDNA microarray to identify age-dependent gene expression profiles in transgenic mice 20
3.2.1 Genomic stability-related cellular pathways were greatly affected by transgenes 21
3.2.2 Age-dependent gene expression profile verified by RT-PCR 21
4 Discussions 23
4.1 HBV and host genomic instability 23
4.2 Role of Wee1 and Cdkn1a in the carcinogenesis 25
5 References 27
6 Appendices 84

List of Tables
Table 1 Chemicals and reagents 38
Table 2 Primers and PCR conditions 39
Table 3 Number of mice used in aCGH study 40
Table 4 Number of mice used in RT-PCR study 41
Table 5 Summaries of genomic aberrations in the ∆2-LHBS transgenic mice 42
Table 6 Summaries of genomic aberrations in HBx transgenic mice 43
Table 7 Summaries of genomic aberrations in the ∆2-LHBS/HBx double transgenic mice 45
Table 8 Common aberration regions in different transgenic strains 50
Table 9 The common genomic aberrations regions that identified in the ∆2-LHBS, HBx and ∆2-LHBS/HBx double transgenic mice 51
Table 10 Gain of oncogenes in the aberration regions of transgenic mice 52
Table 11 Loss of tumor suppressor genes in aberration regions of transgenic mice 53
Table 12 Gain of other oncogenesis-related genes in aberration regions of transgenic mice 54
Table 13 Loss of other oncogenesis-related genes in aberration regions of transgenic mice 55
Table 14 The rankings of cellular pathways that were most affected by ∆2-LHBS 56
Table 15 The rankings of cellular pathways that were most affected by HBx 57
Table 16 The rankings of cellular pathways that were most affected by ∆2-LHBS/HBx 58
Table 17 The fold changes of genomic stability-related genes 59


List of Figures
Figure 1 HBV LHBS genes and hepatocarcinogenesis in our transgenic mice model. 60
Figure 2 Chromosomal aberrations in the Δ2-LHBS transgenic mice. 62
Figure 3 Chromosomal aberrations in HBx transgenic mice. 65
Figure 4 Chromosomal aberrations in the Δ2-LHBS/HBx double transgenic mice. 69
Figure 5 CNV levels in Δ2-LHBS, HBx and Δ2-LHBS/HBx double transgenic mice. 70
Figure 6 PCR of genomic DNA from transgenic mice liver tissues 71
Figure 7 Genomic stability-related genes expression changes in 3-month-old Δ2-LHBS, HBx and Δ2-LHBS/HBx double transgenic mice. 73
Figure 8 Genomic stability-related genes expression changes in 6-month-old Δ2-LHBS, HBx and Δ2-LHBS/HBx double transgenic mice. 75
Figure 9 Genomic stability-related genes expression changes in 12-month-old Δ2-LHBS, HBx and Δ2-LHBS/HBx double transgenic mice. 77
Figure 10 Genomic stability-related genes expression changes in 18-month-old Δ2-LHBS, HBx and Δ2-LHBS/HBx double transgenic mice. 79
Figure 11 Age-dependent Genomic stability-related genes expression changes analyzed by RT-PCR in Δ2-LHBS, HBx and Δ2-LHBS/HBx double transgenic mice. 81
Figure 12 Age-dependent Genomic stability-related genes expression changes analyzed by gene expression microarray in Δ2-LHBS, HBx and Δ2-LHBS/HBx double transgenic mice. 83


List of Appendices
Appendix 1 HBV genome and replication cycle 84
Appendix 2 GGH and staining pattern of HBsAg 85
Appendix 3 Construction maps of the Δ2-LHBS and HBx transgenic mice 86
Appendix 4 Examples of cellular pathways that the selected genomic stability-related genes are involved in 90
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