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研究生： 阮玉鴛兒
Nhi, Nguyen Ngoc Uyen
論文名稱： 利用微衛星不穩定性分析技術分析B型肝炎病毒所引起肝癌之毛玻璃狀肝細胞
Microsatellite Instability Analysis of the Ground Glass Hepatocytes in Hepatitis B virus-related Hepatoma
指導教授： 黃溫雅
Huang, Wen-Ya
學位類別： 碩士
Master
系所名稱： 醫學院 - 醫學檢驗生物技術學系
Department of Medical Laboratory Science and Biotechnology
論文出版年： 2011
畢業學年度： 99
語文別： 英文
論文頁數： 88
外文關鍵詞： HBV, MSI, pre-S2 mutant LHBs, in vitro binding assay
相關次數： 點閱：107  下載：2 
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    • ABSTRACT
    Keywords: HBS, MSI, pre-S2 mutant LHBs, in vitro binding assay
    Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer death worldwide. Chronic infection of hepatitis B virus (HBV) is associated with the majority of HCC. However, the genetic events of hepatocarcinogenesis are relatively poorly understood. The pre-S1 and pre-S2 partially deleted large HBV surface proteins (LHBs), called pre-S1 and pre-S2 mutant LHBS (∆1, ∆2LHBs), are highly associated with HBV-induced HCC and are found in type I and type II ground glass hepatocytes (GGHs), respectively. These proteins accumulate in endoplasmic reticulum (ER) to induce strong ER stress, oxidative DNA damage and genomic instability. To observe the genomic alterations in clinical HCC samples, we performed microsatellite instability (MSI) analysis. We collected liver sections from 15 [13 HBV(+), 2 HCV(+)] HCC patients that received liver surgery at NCKU. The liver tissues were undergone HE and IHC staining for HBs. The tumor, GGH and normal liver parts were separately collected. Genomic DNA from each liver part as well as the corresponding peripheral blood was extracted and applied to microsatellite instability tests. Five fluorescence-labeled mononucleotide repeat MSI markers NR-21, BAT-26, BAT-25, NR-24, and MONO-27 and two pentanucleotide repeat markers Penta C and Penta D were co-amplified by multiplex PCR. The PCR products were analyzed using the Genescan analysis. Nine of the 13 HBV-positive HCC tissues displayed GGH morphology whereas the other 4 did not. For each patient, the MS patterns in the peripheral blood, normal liver, GGH, and tumorous sections were analyzed then compared with each other. The results of MSI study showed that 2 of the 13 (15.4%) HBV-positive HCC cases showed minor MSI in tumorous and GGH sections; whereas none of the non-HBV(+) cases showed MSI. In summary, some GGH, which expresses the pre-S mutant LHBS, presents minor MSI, the most sensitive biomarker for genomic instability.

    TABLE OF CONTENTS ABSTRACT I TABLE OF CONTENTS II LIST OF TABLES V LIST OF FIGURES VI LIST OF SUPPLEMENTARY TABLES VII LIST OF SUPPLEMENTARY FIGURES VIII LIST OF APPENDICES IX LIST OF ABBREVIATIONS AND SYMBOLS X 1 INTRODUCTION 1 1.1 Hepatitis B virus biology 1 1.1.1 Hepatitis B virus and hepatitis B 1 1.1.2 HBV serotypes 1 1.1.3 HBV genotypes and subgenotypes 2 1.1.4 Virion structure 3 1.1.5 Genome organization and viral proteins 3 1.1.6 Entry and replication 5 1.1.7 Transmission 6 1.1.8 Vaccination 7 1.2 Clinicopathological features of HBV infection. 7 1.2.1 Epidemiology 7 1.2.2 Chronic HBV infection 8 1.2.3 Hepatocellular carcinoma (malignant hepatoma) 9 1.2.4 Diagnosis and treatment of HBV infection 9 1.3 Molecular pathogenesis of Hepatitis B-induced hepatocarcinogenesis 10 1.3.1 HBV genome integrates into host chromosome 10 1.3.2 Role of HBx antigen (HBxAg) 10 1.3.3 HBV variants are associated with HCC. 11 1.3.4 Host factors correlated with HCC 12 1.3.5 Other HBV features (viral load, HBV genotypes) 12 1.4 Genetic alteration in hepatocarcinogenesis 13 1.5 Microsatellite instability 13 1.5.1 Microsatellite instability definition 13 1.5.2 Microsatellite instability in hepatocarcinogenesis 14 2 RESEARCH GOAL 15 3 MATERIALS AND METHODS 17 3.1 Patient tissues 17 3.2 DNA isolation 17 3.3 Multiplex PCR 18 3.4 Automated sequencing and data analysis 18 4 RESULTS 19 4.1 Clinicopathological features of hepatocellular carcinoma patients 19 4.2 HE and IHC staining for HBs showed the morphology of clinical liver tissues 19 4.3 15.4% HBV-positive HCC cases showed minor MSI in tumorous and GGH type II with 1bp shifted. 19 4.4 Pattern of microsatellites stable (MSS) 20 5 DISCUSSION 21 REFERENCES 24 6 SUPPLEMENTARY MATERIALS: VERIFICATION THE INTERACTION DOMAIN OF ∆2LHBS WITH JAB1 BY IN VITRO GST PULL-DOWN ASSAY 55 6.1 Suppl. Abstract 55 6.2 Suppl. Introduction: ∆2-LHBs – JAB1 interaction involved in hepatocarcinogenesis 56 6.2.1 Previous methods to determine protein-protein interactions 56 6.2.2 ∆2-LHBs – Jun activation domain-binding protein 1 (JAB1) interaction 57 6.2.3 Pre-S2 mutant LHBs – JAB1 interaction domain is on N-terminal amino acid residues 61-119 of Pre-S2 mutant LHBs. 57 6.3 Suppl. research aim: 58 6.4 Suppl. method: In vitro GST-pull-down assay 59 6.4.1 Construction of expression vectors (pre-S variants and JAB1) 59 6.4.2 Protein expression 61 6.4.3 Single step purification of pre-S2 variants using Ni-NTA beads 62 6.4.4 Single step purification of fusion GST-JAB1 constructs using GST beads 62 6.4.5 Determination of protein concentration 62 6.4.6 Protein electrophoresis (SDS-PAGE) 63 6.4.7 In vitro GST pull-down assay 63 6.4.8 Western blotting 63 6.5 Results 64 6.5.1 Generation of recombinant GST-tagged full-length JAB1 peptide 64 6.5.2 Generation of recombinant 6XHis-tagged N-terminus partially deleted of pre-S2 mutant LHBs 64 6.5.3 Functional characterization of the purified proteins showed by in vitro GST pull-down assay. 65 6.5.4 The N-terminus amino acid residue 61-119 of ∆2/pre-S binds to JAB1 as confirm by in vitro protein-protein interaction analysis. 65 6.6 Discussion 66 SUPPLEMENTARY REFERENCES 68 APPENDICES 78   LIST OF TABLES Table 1: The 15 analyzed HCC patients for microsatellite instability 35   LIST OF FIGURES Figure 1: HE and IHC staining for HBs showed the histological morphology in the livers of HBV-positive HCC patient S00390. 37 Figure 2: HE and IHC staining for HBs showed the histological morphology in the livers of HBV-positive HCC patient 0437. 38 Figure 3: HBV-negative HCC patient S00715 displays the pattern of microsatellites stable. 39 Figure 4 : HBV-positive HCC patient 0437 displays the pattern of minor microsatellites instability. 41 Figure 5: GGHs type II harboring the minor microsatellites instability in MONO-27 marker of two HBV-positive HCC patients. 42 Figure 6: The summary of MSI analysis results in this study 43 Figure 7: Pattern of MSI analysis from HBV-positive HCC patient 0117 44 Figure 8: Pattern of MSI analysis from HBV-positive HCC patient 0225 45 Figure 9: Pattern of MSI analysis from HBV-positive HCC patient 0956 46 Figure 10: Pattern of MSI analysis from HBV-positive HCC patient 1057 47 Figure 11 : Pattern of MSI analysis from HBV-positive HCC patient S00427 and S00587 48 Figure 12: Pattern of MSI analysis from HBV-positive HCC patient S00687 and S00338 49 Figure 13: Pattern of MSI analysis from HBV-positive HCC patient S0016 50 Figure 14: Pattern of MSI analysis from HBV-positive HCC patient S02112 51 Figure 15: Pattern of MSI analysis from HBV-positive HCC patient S00390 52 Figure 16: Pattern of MSI analysis from HBV-positive HCC patient S01189 53 Figure 17: Pattern of MSI analysis from non HBV-positive HCC patient S00696. 54   LIST OF SUPPLEMENTARY TABLES Suppl. Table 1: Reagents 69 Suppl. Table 2: Buffers 71   LIST OF SUPPLEMENTARY FIGURES Suppl. Figure 1: Generation of recombinant GST-tagged JAB1 (Immobilized-GST fusion protein) 73 Suppl. Figure 2: Generation of recombinant 6XHis-tagged pre-S peptides used in this study. 74 Suppl. Figure 3: N-terminus a.a residue 61-119 of 2-LHBs is necessary for the interaction of ∆2-LHBs and JAB1. 75 Suppl. Figure 4: Purification of 6X His-tagged pre-S variants 76 Suppl. Figure 5: Generation of purified GST protein 77   LIST OF APPENDICES Appendix 1: HBV serotypes 78 Appendix 2: HBV virion and genome structure 79 Appendix 3: The replication cycle of Hepatitis B virus 80 Appendix 4: pre-S variants and GGH morphology 81 Appendix 5: Schematic depiction of the potential signals induced by pre-S mutants and in ground glass hepatocyte (GGH). 82 Appendix 6: Model of pre-S2 mutant LHBs-related HCC 83 Appendix 7: MSI analysis system locus information. 84 Appendix 8: Example of MSI analysis system by Genescan 85 Appendix 9: Association of JAB1 with 2-LHBs is through N-terminal amino acid residues 61-119 of 2-LHBs. 86 Appendix 10: Schematic of in vitro GST pull-down assay using bacterial expression of bait and prey proteins. 87 Appendix 11: pET-21 and PGEX-5X-1 vector maps. 88

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