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研究生： 謝逸璇
Hsieh, Yi-Hsuan
論文名稱： B型肝炎病毒pre-S2突變型大型表面抗原在細胞壓力所扮演的角色
The roles of hepatitis B virus pre-S2 mutant large surface antigen in cellular stress-induced hepatocellular carcinogenesis
指導教授： 黃溫雅
Huang, Wenya
學位類別： 博士
Doctor
系所名稱： 醫學院 - 基礎醫學研究所
Institute of Basic Medical Sciences
論文出版年： 2007
畢業學年度： 95
語文別： 英文
論文頁數： 205
中文關鍵詞： 內質網壓力 、pre-S2 突變型大型B型肝炎表面抗原 、氧化性DNA損傷 、肝癌 、Jun活性區結合蛋白
外文關鍵詞： Hepatocellular carcinoma, ER stress, oxidative DNA damage, JAB1, pre-S2 mutant LHBs
相關次數： 點閱：100  下載：1 
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    • 慢性B型肝炎感染是導致肝癌的主要原因，表現pre-S2 突變型大型B型肝炎表面抗原(pre-S2 mutant LHBs)的肝細胞呈現乾小節的形成，單株細胞增生和生長優勢。pre-S2 mutant LHBs主要表現在B型肝炎病毒相關性的肝癌病人的肝細胞中，這表示pre-S2 突變型大型B型肝炎表面抗原與肝癌的發生息息相關。初步研究顯示pre-S2 突變型大型B型肝炎表面抗原會累積在內質網中並引發內質網壓力和氧化性DNA損傷。在這個研究中，我的研究目標是探討pre-S2 突變型大型B型肝炎表面抗原引發肝癌的機制和尋找預防及治療pre-S2 突變型大型B型肝炎表面抗原誘發的肝癌方法。我們發現pre-S2 突變型大型B型肝炎表面抗原誘發的氧化性DNA損傷是內質網壓力依賴性的，在表現pre-S2 突變型大型B型肝炎表面抗原的細胞經過內質網壓力抑制劑vomitoxin或是TMB8處理後會顯著地減少pre-S2 突變型大型B型肝炎表面抗原所誘發的氧化壓力和DNA損傷。經由酵母菌雙雜交試驗，我們發現Jun活性區結合蛋白 (JAB1) 會與pre-S2 突變型大型B型肝炎表面抗原結合，JAB1是COP9 signalolsome的組成單元之一。有研究指出JAB1會與p27Kip1結合並將之帶到細胞質被降解。我們發現pre-S2 突變型大型B型肝炎表面抗原與JAB1結合使得JAB1進入細胞核的量增多，並增加p27Kip1的降解，造成Cdk2活化，而導致Cdk2下游的抑癌蛋白RB被去活化。在pre-S2 突變型大型B型肝炎表面抗原轉殖基老鼠中也相同的發現，表示在in vitro和in vivo中pre-S2 突變型大型B型肝炎表面抗原會引發細胞週期的進行。此結果意味著pre-S2 突變型大型B型肝炎表面抗原經由去活化RB而驅使細胞週期進行，因此可能導致HCC的發生。

    最後一部分的實驗我們尋找能夠預防及治療pre-S2 突變型大型B型肝炎表面抗原誘發肝癌的方法。有報導指出維他命D3和組蛋白乙醯化抑制劑SAHA會增加thioredoxin 結合蛋白2 (TBP2) 的表現和JAB1-TBP2的結合增加，導致JAB1-p27Kip1的結合受阻，因而使p27Kip1穩定。我們發現VitD3和組蛋白乙醯化抑制劑SAHA，Trichostatin A和sodium butyrate會增加表現pre-S2 突變型大型B型肝炎表面抗原細胞中的p27Kip1的穩定。我們以維他命D3和組蛋白乙醯化抑制劑處理表現pre-S2 突變型大型B型肝炎表面抗原的細胞也發現可降低氧化性DNA損傷。以上結果表示維他命D3和組蛋白乙醯化抑制劑可作為治療pre-S2 突變型大型B型肝炎表面抗原誘發的p27Kip1降解和氧化壓力的的藥物。這個研究提供了一個新的預防及治療方向來防止pre-S2 突變型大型B型肝炎表面抗原誘發的肝癌。

    Chronic hepatitis B virus (HBV) infection is a major global cause of hepatocellular carcinoma (HCC). Hepatocytes expressing the HBV large surface antigen (LHBs) pre-S2 mutant, which is partially deleted in the pre-S2 region on HBV surface gene, exhibited nodule formation, clonal expansion and growth advantage. The majority of HBV-related HCC patients harbored pre-S2 mutant LHBs, indicating that pre-S2 mutant LHBsis highly associated with hepatocellular carcinogenesis. It was found that pre-S2 mutant LHBs accumulates in endoplasmic reticulum (ER) inducing ER stress and oxidative DNA damage. In this study, we aim to explore the molecular mechanisms regulated by pre-S2 mutant LHBs and seek potential prophylaxis and therapeutic approaches for pre-S2 mutant LHBs-associated HCC. We found that the oxidative stress and DNA damages induced by pre-S2 mutant LHBs were dependent on ER stress, as the ER stress inhibitors vomitoxin or TMB8 dramatically decreased such oxidative stress. By yeast two-hybrid screening assays, the pre-S2 mutant LHBs was found to directly interact with the Jun activation domain-binding protein 1 (JAB1), a subunit of COP9 signalosome. JAB1 has been shown to interact with p27Kip1 cyclin-dependent kinase inhibitor and target it to cytosolic 26S proteasome for degradation. We found that JAB1 and pre-S2 mutant LHBs enhanced the nuclear translocation of JAB1 and trigger p27Kip1 degradation and Cdk2 activation, resulting in inactivation of the tumor suppressor retinoblastoma (RB), a downstream molecule regulated by Cdk2. In transgenic mice carrying the pre-S2 mutant LHBs, p27Kip1 degradation, Cdk2 activation and RB inactivation were also seen, indicating the pre-S2 mutant LHBs triggers cell cycle progression in vivo and in vitro. These results suggest that cell cycle progression caused by RB inactivation might contribute to HCC associated with pre-S2 mutant LHBs.
    In the last part of our study, we seek potential targeted prophylaxis and therapeutic approaches for HCC induced by pre-S2 mutant LHBs. Vitamin D3 (VitD3) and the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) have been found to enhance thioredoxin binding protein 2 (TBP2) expression and JAB1-TBP2 interactions, resulting in blockage of JAB1-p27Kip1 interaction and stabilization of p27Kip1. We found VitD3 and the HDAC inhibitors SAHA, trichostatin A and sodium butyrate enhanced p27Kip1 stabilization in the cells expressing the pre-S2 mutant LHBs. We also found that the oxidative DNA damages induced by pre-S2 mutant LHBs were dramatically decreased after treatments with vitD3 and HDAC inhibitors, indicating that HDAC inhibitors are effective targeted drugs to repress p27Kip1 degradation and oxidative stress caused by the pre-S2 mutant LHBs. The HDAC inhibitors might provide a novel therapeutic approach for the pre-S2 mutant LHBs-induced hepatocellular carcinogenesis.

    Table of contents i List of Tables v List of Figures vi List of Supplementary Materials vii List of Supplementary Figures viii List of Appendices ix Abstract 1 Abstract in Chinese 2 List of abbreviations and symbols 3 1. Introduction 5 1.1. Hepatitis B virus 6 1.1.1. HBV replication 7 1.1.2. Epidemiology of hepatitis B virus 7 1.1.3. Pathogenesis of HBV 8 1.1.4. Acute HBV infection 9 1.1.5. Chronic HBV infection 9 1.1.6. Phases of chronic HBV infection 10 1.2. Chronic HBV infection associated with HCC 11 1.2.1. HBV genome integrates into host chromosome 11 1.2.2. HBx antigen (HBxAg) 12 1.2.2.1. Transcriptional activation and cellular signaling affected by HBxAg 13 1.2.2.2. HBxAg affects cell cycle 13 1.2.2.3. HBxAg implicates apoptosis 14 1.2.2.4. HBxAg impairs DNA repair 14 1.2.2.5. Others 15 1.2.3. Mutations in viral genomes are associated with HCC 15 1.2.4. HBV genotype 16 1.2.5. Viral load 16 1.2.6. Host factors correlated with HCC 17 1.2.7. Pre-S mutant large surface antigen of HBV in HCC 17 1.3. Ground glass hepatocytes (GGHs) caused by LHBs retained in the ER and induces ER stress signaling 18 1.4. Pre-S mutant LHBs induces COX-2 and cyclin A overexpression 19 1.5. ER stress 20 1.5.1. Unfolded protein response (UPR) 21 1.5.1.1. IRE1-XBP1 pathway 21 1.5.1.2. PERK pathway 22 1.5.1.3. ATF6 pathway 22 1.5.2. ER-overloaded response (EOR) 22 Specific aims 24 2. Materials and methods 25 2. 1. Reagents 25 Primers and PCR conditions: 28 Antibodies used in this study 29 2.2. Methods 31 2.2.1. Cell culture 31 2.2.2. Transfection of HuH-7 cells performed by LipofectamineTM 2000 31 2.2.3. Transfection of HuH-7 cells performed by SAINT reagents 31 2.2.4. Transfection of NIH3T3 cells performed by LipofectamineTM 2000 31 2.2.5. Transfection of T24 cells performed by LipofectamineTM 2000 32 2.2.6. Induction of LHBs expression by ponasterone A in HuH-7 cells 32 2.2.7. Host-cell reactivation assay 32 2.2.8. hprt gene mutation assays 32 2.2.9. Yeast two-hybrid 33 2.2.10. Co-immunoprecipitation assay 33 2.2.11. Western blotting 33 2.2.12. RNA extraction 34 2.2.13. Reverse transcription (RT) 34 2.2.14. Polymerase chain reaction (PCR) 34 2.2.15. Immunofluorescence staining and confocal microscopy 34 2.2.16. Immunohistochemical staining 35 2.2.17. Immunofluorescent staining of OGG1 in HCC patients 35 2.2.18. Isolation of nuclear and cytoplasmic extraction 35 2.2.19. Propidium iodide staining and flow cytometry analysis 36 2.2.20. The level of JAB1 was silenced by using SiRNA system 36 2.2.21. Double strand break repair activity 36 2.2.22. Luciferase activity assay 36 2.2.23. AP-1 transactivation assay 36 2.2.24. Transgenic mice study 37 2.2.25. ROS detection by H2-DCFDA stain 37 2.2.26. NFkB activation assay 37 2.2.27. iNOS activity assay 38 2.2.28. Preparation of genomic DNA from mammalian cells 38 2.2.29. Phenol/chloroform extraction and ethanol precipitation of DNA 38 2.2.30. South-Western blotting 38 2.2.31. Comet assay 39 3. Results 40 3.1. Part I: Oxidative stress and DNA damage induced by pre-S mutant LHBs 40 3.1.1. Reactive oxygen species induced by pre-S mutant LHBs 40 3.1.2. Induction of base excision repair activity by 2-LHBs 40 3.1.3. hprt gene mutation was enhanced by 2-LHBs 41 3.1.4. 2-LHBs induces oxidative stress through ER stress 42 3.1.5. Oxidative DNA damages in the 2-LHBs transgenic mice and GGHs 42 3.1.6. Conclusion 43 3.2. Part II: RB-E2F1 pathway is affected by 2-LHBs 43 3.2.1. 2-LHBs induced retinoblastoma (RB) hyperphosphorylation 43 3.2.2. p27Kip1 degradation induced by 2-LHBs 44 3.2.3. 2-LHBs triggers cell cycle progression 44 3.2.4. RB hyper-phosphorylation induced by 2-LHBs is partially dependent on ER stress 45 3.2.5. Jun activation domain-binding protein 1 (JAB1) is associated with 2-LHBs 45 3.2.6. 2-LHBs disrupts the association of JAB1-MIF and JAB1-IRE1 complexes 46 3.2.7. JAB1 nuclear translocation and AP-1 transcriptional activation induced by 2-LHBs 46 3.2.8. RB hyper-phosphorylation in 2-LHBs transgenic mice 46 3.2.9. Proposed model: the mechanism of 2-LHBs induced RB hyper-phosphorylation 47 4. Discussion 48 4.1. Intracellular retention of pre-S mutant LHBs 48 4.2. ER stress signals and carcinogenesis 49 4.3. ROS production induced by ER stress though iNOS dependent / independent pathways 51 4.4. The potential of 2-LHBS in hepatocellular carcinogenesis 51 4.4.1. 2-LHBs induces ER stress, oxidative DNA damage and mutations 51 4.4.2. 2-LHBs induces cell proliferation 52 4.4.3. The functions of JAB1 were enhanced by 2-LHBs 53 4.4.4. The function of importin 1 protein was impaired by 2-LHBs 55 4.4.5. The double strand break repair activity was diminished in the cells carrying 2-LHBs 57 4.5. The potential therapeutic approach for 2-LHBs-indcued oncogenic properties 57 5.References 60 6. Supplementary Materials 127 7. References of Supplementary 160 8.Appendices 201 List of Tables Table I. hprt mutation frequencies in the ML-1 cells expressing the pre-S LHBs 101 Table II. The 2-LHBs interactive proteins 102 List of Figures Figure 1. LHBs was expressed in the HuH-7 cells. 103 Figure 2. Oxidative stress and DNA damage induced by pre-S mutants LHBs 104 Figure 3. Base excision repair activity was enhanced by pre-S mutant LHBs. 106 Figure 4. DNA damages induced by pre-S mutant LHBs through ER stress. 107 Figure 5. Oxidative DNA damage in 2-LHBs transgenic mice and type II GGHs. 109 Figure 6. The proposed model for the hepatocellular carcinogenesis associated with the HBV pre-S mutant LHBs 110 Figure 7. 2-LHBs induces RB hyper-phosphorylation at threonine 821 on RB 113 Figure 8. 2-LHBs induces Cdk-2 activation 114 Figure 9. p27Kip1 degradation enhanced by 2-LHBs 115 Figure 10. RB inactivation and cell cycle progression are triggered by 2-LHBs. 116 Figure 11. RB hyper-phosphorylation induced by 2-LHBs is partially dependent on ER stress. 117 Figure 12. In vivo interaction of 2-LHBs and JAB1 in HuH-7 cells 118 Figure 13. 2-LHBs disrupts JAB1-MIF association. 119 Figure 14. JAB1-IRE1 interaction was interfered by 2-LHBs in partially ER stress dependent manners 120 Figure 15. JAB1 nuclear localization and AP-1 transcriptional activity were enhanced by 2-LHBs in HuH-7 cells 123 Figure 16. RB hyperphosphorylation in the transgenic mice carrying the 2-LHBs .125 Figure 17. A model of genomic instabilities caused by 2-LHBs 126 List of Supplementary Materials Supplementary part I: Search for proteins that interacts with the 2-LHBs 127 Suppl. 1.1. Importin 1 interacts with 2-LHBs in vivo and disrupts importin 1 into nucleus 128 Suppl. 1.2. The functions of importin 1 were blocked by 2-LHBs 128 Supplementary part II: Therapeutic and prophylactic approach for 2-LHBs induced p27Kip1 degradation and DNA damages 129 Suppl. 2.1. Up-regulation of TBP2 and p27Kip1 by VitD3 and histone deacetylase inhibitor SAHA 129 Suppl. 2.2. Nuclear localization of TBP2 and importin 1 were increased while the cells exposure to VitD3 and SAHA 129 Suppl. 2.3. The association of JAB1 with TBP2 was enhanced by VitD3 and SAHA 130 Suppl. 2.4. Suppression of 8-oxoguanine accumulation induced by D2-LHBs is blocked by VitD3 and SAHA 130 Suppl. 2.5. TBP2 and p27Kip1 levels were induced by histone deacetylase i nhibitors, sodium butyrate and trichostatin A 131 Suppl. 2.6. p27Kip1 stabilization and TBP2 gene expression induced by VitD3 and histone deacetylase inhibitors 131 Suppl. 2.7. Conclusion 131 Supplementary part III: Differetial ER stress signaling pathways mediated by iNOS 132 Suppl 3.1. ER stress induces oxidative stress and DNA damage 133 Suppl. 3.2. Oxidative stress induced by thapsigargin is regulated by iNOS….133 Suppl. 3.3. Oxidative stress induced by tunicamycin is regulated by oxidative protein folding 134 Suppl 3.4. Oxidative stress and DNA damage in mice injected with tunicamycin 135 Suppl 3.5. Conclusion 135 List of Supplementary Figures Suppl. Fig. 1.1. In vivo interaction of 2-LHBs and importin 1 in HuH-7 cells 137 Suppl. Fig. 1.2. LHBS does not appear in the nucleus 138 Suppl. Fig. 1.3. NBS1 nuclear localization was impaired by 2-LHBs. 140 Suppl. Fig. 1.4. 2-LHBs affects double strand break repair. 141 Suppl. Fig. 2.1. p27Kip1 stabilization induced by VitD3 and SAHA. 142 Suppl. Fig. 2.2. VitD3 and SAHA induce nuclear localization of importin 1 and TBP2 143 Suppl. Fig. 2.3. The association of TBP2 and JAB1 were enhanced by VitD3 and SAHA. 144 Suppl. Fig. 2.4. Accumulation of 8-oxoguanine induced by 2-LHBs was abolished by VitD3 and SAHA 145 Suppl. Fig. 2.5. Sodium butyrate and trichostatin A enhance p27Kip1 stabilization and TBP2 induction in HuH-7 cells 146 Suppl. Fig. 2.6. VitD3 and histone deacetylase inhibitors up-regulate TBP2 and stabilized p27Kip1 147 Suppl. Fig. 3.1. Induction of GRP78 by ER stress inducers, tunicamycin and thapsigargin. 148 Suppl. Fig. 3.2. Oxidative stress and DNA damage induced by ER stress inducers tunicamycin or thapsigargin 150 Suppl. Fig. 3.3. iNOS expression induced by thapsigargin 151 Suppl. Fig. 3.4. Oxidative stress induced by thapsigargin through iNOS 154 Suppl. 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