利用斑馬魚研究肝臟疾病和肝癌之發生：B型肝炎病毒X抗原，黃麴毒素，p53突變，src和edn1的致癌作用及其協同效應

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盧正偉(Jeng-Wei Lu) 查詢紙本館藏

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論文名稱

利用斑馬魚研究肝臟疾病和肝癌之發生：B型肝炎病毒X抗原，黃麴毒素，p53突變，src和edn1的致癌作用及其協同效應
(Study of liver disease and hepatocarcinogenesis in zebrafish: tumorigenicity and synergistic effect between HBx, AFB1, p53 mutant, src and edn1)

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摘要(中)

肝臟是人體中最大的器官，它調節許多生理功能如脂質及醣類合成、轉化、解毒、排泄及儲存的功能。過去許多研究已經證明脊椎動物中肝臟發育機制是具有高度保守性的。鑑別參與肝臟形成及肝病的基因及調控路徑提供診斷和治療的基礎。肝細胞癌（HCC）的形成是一個慢性進展，歷經肝炎，脂肪肝，肝纖維化，肝硬化最後發展成為肝癌。B型肝炎病毒（HBV）感染是肝癌的主要致病因素。B型肝炎病毒X抗原（HBx蛋白）在體外可增強細胞株的聚落形成及細胞轉型，並可在小鼠促使肝癌的發生。包括肝癌在內的人類癌症經常伴隨著p53基因突變，而黃麴毒素(AFB1)也是一種非常普遍可誘發肝癌形成之致癌因子。以白蛋白啟動子驅動表達HBx蛋白在小鼠模型，我們已證明肝癌形成前期Src, Edn1, Bmp4, 及Bmp7大量表達。由於斑馬魚的諸多優點，近年來斑馬魚已成為一個研究人類疾病新興的模式，斑馬魚的動物疾病模型提供了測試疾病標誌物及快捷的藥物篩選系統。
在本論文中，我將重點放在三個部分：第一、利用轉殖基因斑馬魚探討HBx蛋白與黃麴毒素對於肝臟疾病或肝癌之協同作用。第二、建立穩定表達HBx或src 在p53突變的轉殖基因斑馬魚，探討HBx蛋白src與p53基因突變對於肝癌之協同作用。第三、利用edn1轉殖基因斑馬魚探討edn1對於肝癌之作用。
我發現HBx蛋白和黃麴毒素協同促進脂肪肝和增加脂肪合成因子、酵素和脂質代謝相關基因的表現。處理黃麴毒素的HBx轉殖基因魚加速產生肝細胞異常增生和增強細胞週期相關基因的表現。我們的數據顯示黃麴毒素和HBx蛋白於調控脂質代謝相關基因具有協同作用有助於產生脂肪肝，在5.75個月增加細胞週期、細胞分裂相關基因表現，可能和肝細胞異常增生有關。
我發現肝臟專一性表現HBx蛋白，可誘發脂肪肝、肝纖維化和肝糖累積。HBx蛋白僅於p53突變斑馬魚中引發肝癌，並與 src激酶表現增加與活化下游訊息傳遞路徑有關。肝臟專一性表現src激酶可引發肝細胞異常增生、肝癌、肉瘤狀肝癌，並且src激酶與p53突變之間具有協同效應。在src轉殖基因斑馬魚，當肝臟形成增生、不典型增生、肉瘤狀肝癌和肝癌時，肝細胞中的磷酸化-erk、磷酸化-akt、myc、jnk1和vegf訊息蛋白表現增加。當HBx或src過度表現於p53基因突變斑馬魚中，細胞週期、腫瘤發生和轉移分子標記表現增加於後期階段。我的研究顯示，HBx蛋白和src激酶過度表現於p53突變斑馬魚中誘發肝癌生成。
在HBx誘導肝癌老鼠模型中，Edn1被鑑別出來是四個共同調節者其中之一。我使用轉殖基因斑馬魚進一步研究edn1在肝癌生成中扮演的角色。肝臟專一性表現edn1在斑馬魚中產生脂肪肝、纖維化、肝糖累積、膽管擴張、肝細胞異常增生和肝癌。脂質代謝相關基因在5個月增加表現可能與脂肪肝的形成有關，和細胞週期、增殖、腫瘤、轉移相關基因在11個月增加與肝細胞異常增生和肝癌的形成有關。利用異種移植方法發現穩定過度表現EDN1於293T細胞中可增強細胞遷移能力。在10種惡性人類腫瘤，EDN1增加表現於乳癌，腦癌，肝癌，前列腺癌和腎臟癌和降低表現於胃癌。此外，發現miR-1抑制EDN1表現和我們觀察到在肝癌病人中EDN1和miR-1為負關聯性。我們的研究意味著EDN1於肝癌生成過程中扮演重要角色並受到miR-1的調控。
我們的長期目標是要了解肝癌的分子機制，並制定對肝癌的治療方法。利用斑馬魚慢性肝病肝癌模式作為藥物篩選平台，藉由化學藥品庫，和斑馬魚動物模式的具體工具，我們希望找出針對HBx蛋白和其他致癌因素所造成慢性肝病及肝癌預防和治療的方法。總結而論，通過使用斑馬魚癌症模式，我們不僅可以從事分子機制研究，也可用來篩選治療癌症的小分子藥物。所建構的斑馬魚癌症模型，將為台灣的肝癌轉譯研究提供合作平台。

摘要(英)

The liver is the largest organ in the body; it regulates many physiological functions such as lipid and carbohydrate synthesis, transformation, detoxification, excretion and storage functions. Previous studies have demonstrated liver development mechanisms are highly conserved in vertebrate. Identification of genes involved in the formation of the liver and liver diseases regulatory pathways provide diagnostic and therapeutic foundation. Hepatocellular carcinoma (HCC) is a chronic progressive process, from chronic inflammation, to steatosis, fibrosis and cirrhosis eventually developed into liver cancer. Hepatitis B virus (HBV) infection is a major risk factor in liver cancer. Hepatitis B virus X antigen (HBx protein) can enhance colony formation and cell transformation in vitro cell lines, and can induce liver cancer in mice. Human cancers including liver cancer often associated with p53 mutations, and aflatoxin (AFB1) is a very common carcinogenic factor. Using albumin promoter driven expression of HBx protein in a mouse model, I have shown up-regulation of four common regulators including Src, Edn1, Bmp4, and Bmp7 are associated with HCC formation. Because of the many advantages of zebrafish, the zebrafish has become an emerging model for human diseases; zebrafish animal models provide an in-vivo model for test the oncogenicity of candidate genes, and a high throughput drug screening platform.
In this dissertation, I focus on three parts: first, using transgenic zebrafish to investigate the synergistic effect between HBx protein and aflatoxin on liver disease and cancer formation. Second, by establishing HBx transgenic fish in p53 mutant background, and src transgenic fish, explore the role of HBx, src and p53 mutant in the formation of HCC and their synergy. Third, through edn1 transgenic fish, discover the role of edn1 in hepatocarcinogenesis.
I found that HBx and AFB1 synergistically promoted steatosis as indicated by histopathological examinations and the increased expression of lipogenic factors, enzymes, and genes related to lipid metabolism. Moreover, treatment of AFB1 in HBx transgenic fish accelerated the development of liver hyperplasia and enhanced the expression of cell cycle related genes. PCNA was co-localized with active caspase 3 protein expression in HBx zebrafish liver samples and human HBV positive HCC samples by double fluorescence immunostaining. Finally, I found that in human patients with liver disease, the significant glycogen accumulation in the inflammation, cirrhosis stage, and all cases of hepatocellular and cholangiocellular carcinoma showed a moderate cytoplasmic accumulation of glycogen. Our data demonstrated a synergistic effect of AFB1 and HBx on the regulation of lipid metabolism related genes and cell cycle/division-related genes which might contribute to enhanced steatosis and hyperplasia at 5.75 months.
Liver-specific expression of HBx in wild-type zebrafish caused steatosis, fibrosis and glycogen accumulation. However, HBx induced tumorigenesis was observed only in p53 mutant fish in association with up-regulation and activation of src tyrosine kinase pathway. Furthermore, overexpression of src in the p53 mutant zebrafish also caused hyperplasia, HCC, and sarcomatoid HCC, which is accompanied with increased levels of the signaling proteins p-erk, p-akt, myc, jnk1 and vegf. Increased expression levels of lipogenic factors and the genes involved in lipid metabolism and glycogen storage were detected at the earlier stage of hepatocarcinogenesis of the HBx and src transgenic zebrafish. Up-regulation of the molecules in cell cycle, tumor progression and other molecular hallmarks of human liver cancer were found at later stages of both the HBx and src transgenic in the p53 mutant zebrafish. Together, our study demonstrates that HBx and src overexpression in the p53 mutant both induced hepatocarcinogenesis in zebrafish, which both mimic human HCC formation and provide potential in vivo platforms for drug screening to find therapy for human liver cancer.
Liver-specific edn1 expression caused steatosis, fibrosis, glycogen accumulation, bile duct dilation, hyperplasia, and HCC in zebrafish. Overexpression of EDN1 in 293T cells enhanced cell migration in xenotransplantation assays, and was accompanied by the up-regulation of migration related genes. Lipid metabolism-related genes were up-regulated at five months, may be related to the formation of fatty liver. The cell cycle, proliferation, tumor metastasis-related genes were up-regulated at 11-month, correlated to the formation of hyperplasia and HCC. Using xenotransplantation method, I found stable overexpression EDN1 in 293T cells can enhance cell migration. Using tissue array of ten different malignant human tumors, I found EDN1 up-regulated in breast cancer, brain cancer, liver cancer, prostate cancer and kidney cancer, and down-regulated in stomach cancer. Additionally, miR-1 was found to inhibit the expression of EDN1, and I observed an inverse correlation between EDN1 and miR-1 in HCC patients. In conclusion, our data suggest that EDN1 plays an important role in HCC progression and is regulated by miR-1.
Our long term goal is to understand the molecular mechanisms of liver cancer, and the development the therapeutic means for liver cancer treatment. The use of zebrafish as a model of chronic liver disease and HCC can be used as drug screening platform. With chemical libraries and zebrafish animal models, I hope to find out prevention and treatment method for liver disease and liver cancer induced by HBx protein and other carcinogenic factors. Our findings imply that, through the use of zebrafish cancer model, I can not only engage molecular mechanisms, I can also use it to screen small molecule drugs to treat cancer. The established transgenic zebrafish liver disease and cancer models should provide a cooperation platform for the translational research of liver cancer study in Taiwan.

關鍵字(中)

★ B型肝炎病毒X抗原
★ 黃麴毒素
★ p53突變
★ src
★ edn1
★ 斑馬魚

關鍵字(英)

★ HBx
★ AFB1
★ p53 mutant
★ src
★ edn1
★ zebrafish

論文目次

Declaration..........................................................................................................................I
Acknowledgements............................................................................................................II
Abbreviation......................................................................................................................III
Abstract (Chinese).............................................................................................................IV
Abstract (English).............................................................................................................VI
Table of Contents..............................................................................................................IX
List of tables and figures................................................................................................XIII
Chapter I Introduction
I-1 Overall background.......................................................................................................1
I-2 Liver disease and hepatocarcinogenesis.......................................................................2
I-3 Genetic alterations in hepatocellular carcinoma...........................................................3
I-4 Alterations in the p53 gene...........................................................................................4
I-5 Hepatocarcinogenesis related to the HBV x antigen....................................................5
I-5-1 HBx enhances genomic instability .....................................................................5
I-5-2 Signal transduction pathways affected by HBx..................................................6
I-5-3 Transactivation of cellular genes........................................................................6
I-5-4 Physical binding and functional inactivation of the p53 cellular tumor
suppressor protein..............................................................................................7
I-5-5 Epigenomic changes associated with HBx .........................................................7
I-6 A zebrafish animal model for the study of liver diseases and HCC.............................8
I-6-1 New transgenic technology for studying HCC using zebrafish..........................9
I-6-2 Studying metastasis in zebrafish using the xenotransplantation method..........10
I-7 Future perspectives.....................................................................................................11
I-8 Tables..........................................................................................................................13
I-9 Figures........................................................................................................................14
Chapter II Materials and Methods
II-1 Zebrafish maintenance..............................................................................................15
II-2 Generation of transgenic zebrafish using the Tol2 transposon system.....................15
II-3 Microinjection...........................................................................................................15
II-4 AFB1 treatment, liver tissue collection, and paraffin sectioning..............................16
II-5 Histological and immunohistochemistry analyses.....................................................16
II-5-1 Immunohistochemistry.....................................................................................16
II-5-2 Sirius red staining.............................................................................................17
II-5-3 TUNEL assay....................................................................................................17
II-5-4 Periodic Acid-Schiff Stain................................................................................18
II-5-5 Oil red staining.................................................................................................18
II-6 Human tissue microarray...........................................................................................18
II-7 RNA isolation and quantitative RT-PCR...................................................................19
II-8 Western blot analysis..................................................................................................20
II-9 miRNA in situ hybridization......................................................................................20
II-10 Zebrafish tumor xenograft metastasis assays...........................................................21
II-11 Statistics...................................................................................................................21
Chapter III Hepatitis B virus X antigen and Aflatoxin B1 synergistically cause hepatitis, steatosis and liver hyperplasia in transgenic zebrafish
III-1 Abstract....................................................................................................................22
III-2 Introduction...............................................................................................................22
III-3 Results.......................................................................................................................24
III-3-1 Expression of the HBx-mCherry fusion protein and formation of AFB1
-DNA adducts in transgenic fish.......................................................................24
III-3-2 Histopathological examination of synergistic effect of HBx and AFB1
in the transgenic zebrafish model......................................................................25
III-3-3 Glycogen accumulation occurred in the inflammation stage and
reappeared in the hyperplasia stage ..................................................................26
III-3-4 Synergistic effect of HBx and AFB1 on the expression of lipogenic
factors and cell cycle-related genes...................................................................27
III-3-5 Co-localization of PCNA with caspase 3 in HBx zebrafish liver
samples and human HBV positive HCC samples.............................................30
III-4 Discussion.................................................................................................................30
III-5 Tables........................................................................................................................33
III-6 Figures.......................................................................................................................36
Chapter IV Liver-specific expression of HBx and its downstream effector-src in p53 mutant drives hepatocarcinogenesis in transgenic zebrafish
IV-1 Abstract....................................................................................................................48
IV-2 Introduction..............................................................................................................48
IV-3 Results......................................................................................................................50
IV-3-1 Liver-specific expression of HBx-mCherry fusion protein in the
transgenic zebrafish..........................................................................................50
IV-3-2 A synergistic interaction between HBx and the p53 mutation facilitates
hyperplasia and HCC formation in the liver of transgenic fish........................51
IV-3-3 Early pathological alterations in fibrosis, glycogen accumulation,
apoptosis and PCNA staining in the liver of HBx transgenic fish in p53
mutant...............................................................................................................53
IV-3-4 Up-regulation of lipogenic factors, fibrosis markers, cell cycle related
genes, tumor markers and metastasis-associated genes in HBx transgenic
fish in p53 mutant............................................................................................54
IV-3-5 Differential activation of src pathways in the HBx transgenic p53 mutant
zebrafish developed to hyperplasia and HCC..................................................55
IV-3-6 Generation of stable liver-specific src transgenic zebrafish in p53 mutant...56
IV-3-7 Src transgenic in p53 mutant zebrafish model shows good correlation with
HBx induced HCC in p53 mutant zebrafish on hepatocarcinogenesis........56
IV-3-8 Enhanced tumor incidence and onset in double HBx and src transgenic
zebrafish...........................................................................................................57
IV-3-9 Activation of p-erk, p-akt, myc, vegf and jnk1 in the liver tumors of the src
transgenic zebrafish of p53 mutant..................................................................57
IV-3-10 The Penetrance of HBx and src in p53 mutant background induced
chronic inflammation, steatosis, hyperplasia, dysplasia and HCC...................58
IV-4 Discussion................................................................................................................58
IV-5 Tables.......................................................................................................................62
IV-6 Figures.... .................................................................................................................68
Chapter V Endothelin 1 induced hepatocarcinogenesis in transgenic zebrafish and promotes cell migration
V-1 Abstract......................................................................................................................92
V-2 Introduction................................................................................................................92
V-3 Results........................................................................................................................94
V-3-1 Liver-specific edn1 transgenic zebrafish..........................................................94
V-3-2 Histopathological examination of edn1 transgenic zebrafish .........................95
V-3-3 Pathological alterations in the livers of the edn1 transgenic zebrafish ...........95
V-3-4 Up-regulation of lipid metabolism, fibrosis markers, cell cycle related genes,
tumor markers and metastasis-associated genes in edn1 transgenic fish ........96
V-3-5 Screening for EDN1 protein expression in multiple samples of normal and
cancerous tissue................................................................................................97
V-3-6 Stable overexpression EDN1 in 293T cell increase in-cell migration ability
in xenotransplantation assay.............................................................................97
V-3-7 Association of EDN1 and miR-1 expression in patients with HCC.................98
V-4 Discussion.................................................................................................................98
V5-5 Tables.....................................................................................................................101
V-6 Figures.....................................................................................................................103
Chapter VI Conclusion and future perspective
VI-1 Summary................................................................................................................114
VI-2 Figures ...................................................................................................................118
References ......................................................................................................................119
Publications ....................................................................................................................136

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指導教授

喻秋華、金秀蓮
(Chiou-Hwa Yuh、Shiow-Lian Catherine Jin)

審核日期

2013-7-17

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