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???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
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dc.contributor.advisor | 葉秀慧(Shiou-Hwei Yeh) | |
dc.contributor.author | Chiao-Ling Li | en |
dc.contributor.author | 李巧玲 | zh_TW |
dc.date.accessioned | 2021-07-11T15:20:51Z | - |
dc.date.available | 2024-03-11 | |
dc.date.copyright | 2019-03-11 | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019-02-15 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78808 | - |
dc.description.abstract | 肝癌之性別差異於乙型肝癌病毒相關肝癌中最為顯著,此類肝癌通常會發生乙型病毒之基因嵌入現象。其中位於telomerase (TERT) 啟動子之基因嵌入頻率最高,且可增加TERT基因表現並可能參與致癌機制。乙型肝炎病毒中包含雄激素反應序列及雌激素反應序列,因此我們提出乙型肝炎病毒相關肝癌之病毒嵌入可能會使得被嵌入之宿主基因受到性激素路徑之調控,而使得乙型肝炎病毒相關肝癌較好發於男性。為測試此假說,我們利用Capture-NGS平台辨識101個乙型肝炎病毒相關肝癌的乙型肝炎病毒嵌入序列以及TERT啟動子與TP53基因中常見於肝癌之體突變。結果顯示於TERT啟動子之乙型肝炎病毒嵌入及點突變為互斥事件,且皆較顯著發生於男性。(乙型肝炎病毒嵌入 P = 0.0285*; 點突變, P = 0.0201*; 兩者合計, P < .0001***). 我們進一步利用reporter assay研究性激素路徑藉由乙型肝炎病毒嵌入及點突變影響TERT表現之機制。嵌入的HBV DNA使TERT受性激素路徑調控,藉由HNF4α此轉錄因子,雄激素路徑可促進但雌激素可抑制TERT之轉錄。此外,雄激素路徑亦可藉由參與轉錄因子GABPA於TERT啟動子點突變之調控而促進TERT轉錄。此二機制皆可促進乙型肝炎病毒相關肝癌好發於男性之現象。
由NGS分析得知高於九成之乙型肝炎病毒相關肝癌中皆可發現乙型肝炎病毒DNA隨機嵌入所產生的乙型肝炎病毒-宿主嵌合DNA (vh-chimera DNA),此病毒感染產生之極具特異性之基因變異有潛力作為腫瘤之新穎指標。此部分研究之目的即為調查病毒-宿主嵌合DNA可否作為腫瘤切除後殘存腫瘤細胞之血液指標。因此我們蒐集50位乙型肝炎病毒相關肝癌病患之腫瘤組織,及其術前與術後兩個月之血液檢體。我們利用caputure-NGS平台可於88% (44/50) 之乙型肝炎病毒相關肝癌中偵測到HBV DNA之嵌入。結果顯示目前之偵測敏感度為1-2公分大小之腫瘤,且術前血之vh-chimera DNA含量與腫瘤大小呈正相關。而於26.2% (11/42) 之術後兩個月血漿中可偵測到與術前血相同之vh-chimera DNA,顯示這些個案可能有殘餘腫瘤細胞。實際上,其中82% (9/11) 的個案的確於一年內發生腫瘤復發。因此目前結果支持vh-chimera DNA可作為一新穎之乙型肝炎病毒相關肝癌生物指標。且顯示vh-chimera DNA對於偵測術後之殘存腫瘤及一年內復發極具潛力,但仍需對未來臨床應用性進一步研究。 | zh_TW |
dc.description.abstract | The gender disparity of hepatocellular carcinoma (HCC) is most striking in hepatitis B virus (HBV)‐related HCC. The majority of such HCC cases contain integrated HBV. Some hotspot integrations, such as those in the telomerase (TERT) promoter may activate gene expression to drive carcinogenesis. As the HBV genome contains both androgen‐responsive and estrogen‐responsive motifs, we hypothesized that the integrated HBV DNA renders a similar regulation for downstream gene expression and thus contributes to male susceptibility to HCC. To test this hypothesis, the HBV integration sites and the common mutations in the TERT promoter and TP53 coding region were analyzed in 101 HBV‐related HCC cases using a capture‐next‐generation sequencing (Capture-NGS) platform. The results showed that both HBV integration and –124G>A mutation in the TERT promoter region, occurring in a mutually exclusive manner, were more frequent in male than in female patients with HCC. (HBV integration, P = 0.0285*; promoter mutation, P = 0.0201*; in combination, P < .0001***). The effects of sex hormone pathways on the expression of TERT with both genetic changes were investigated using a reporter assay. HBV integration in the TERT promoter rendered the TERT transcription responsive to sex hormones, with enhancement by androgen receptor (AR) but suppression by estrogen receptor, both of which were dependent on hepatocyte nuclear factor 4 alpha (HNF4α). Besides, AR also increased TERT expression by targeting TERT promoter mutations in a GA binding protein transcription factor subunit alpha (GABPA)–dependent manner. Therefore, TERT elevation by AR through integrated HBV and point mutation at the TERT promoter region was identified as a mechanism for the male dominance of HBV‐related HCCs.
As revealed by the NGS analysis, more than 90% of HBV-related HCC contain integrated HBV randomly distributing in chromosomes, which generates a unique HBV-human chimera DNA (vh-chimera DNA) for individual HCC as potential signature tumor marker. This study aims to investigate if the vh-chimera DNA could be a cell free circulating signature DNA biomarker for HBV related HCC, in monitoring the presence of residual tumor cells after tumor resection. Fifty HBV related HCC cases were recruited. In addition to the tumor tissues, the plasma samples were collected just before and 2 months after surgery. The HBV integration sites were identified in 44 cases (88%) by capture-NGS platform. The results showed that the copy number of vh-chimera DNA in plasma at surgery well correlated with the tumor size, with the detection limit at 1-2 cm. Among the plasma collected at 2 months after surgery, 26.2% (11 out of 42) of samples contained the same signature vh-chimera DNA as baseline plasma, indicating the presence of residual HCC. Consistently, 82% (9 out of 11) of these cases suffered HCC recurrence in one year. Therefore, this part of study well supports the vh-DNA as a new circulating DNA marker for detecting HCC in HBV-related HCC patients. Moreover, vh-chimera DNA shows great potential for detecting residual HCC in HBV-related HCC after surgery and for monitoring recurrence within one year of surgical resection, which warrants more investigations for future clinical use. | en |
dc.description.provenance | Made available in DSpace on 2021-07-11T15:20:51Z (GMT). No. of bitstreams: 1 ntu-108-D01445002-1.pdf: 3848978 bytes, checksum: df74963508ac6abf63c13a8e6977cd21 (MD5) Previous issue date: 2019 | en |
dc.description.tableofcontents | ABSTRACT I
摘要 III PART I CONTRIBUTION OF HEPATITIS B VIRUS DNA INTEGRATION TO THE GENDER DIFFERENCE OF HBV-RELATED HCC 1 INTRODUCTION 2 Hepatocellular carcinoma (HCC) 2 Gender difference of HCC 2 Hepatitis B virus (HBV) 3 Life cycle of HBV 4 Transcriptional regulation of HBV 5 Carcinogenic mechanisms contributed by HBV infection 6 HBV integration into the genome of hepatocytes 7 Telomerase (TERT) 8 Lysine methyltransferase 2B (KMT2B/ MLL4/ WBP7) 9 Cyclin E1 (CCNE1) 10 HBV transcription regulated by sex hormone pathway 10 HYPOTHESIS AND SPECIFIC AIMS 12 MATERIAL AND METHODS 13 Study subjects 13 Genomic DNA extraction 13 Capture-NGS 14 Capture probe set 14 Bioinformatics analysis 15 Validation of HBV integration and somatic mutations 16 RNA extraction 16 Reverse transcription 17 Quantitative real-time PCR 17 Cell culture 18 Plasmid construct 18 Cloning 19 Dual-luciferase reporter assay 19 Western blot 20 Lentivirus production 21 Statistics and figure 21 RESULTS 22 Validation of the Capture-NGS platform for identifying HBV integration in HCC: Results comparable to genomic sequencing 22 HBV integrations and point mutations in the TERT promoter region preferentially occur in male patients with HCC 23 Inverse effects of androgen and estrogen pathways in regulating TERT transcription through the integrated HBV in the TERT promoter region 24 The androgen pathway increases TERT transcription through the common point mutation in the TERT promoter, which is dependent on GA binding protein transcription factor subunit alpha 26 DISCUSSION 27 Affirmation of the gender difference in HBV-TERT integration and TERT promoter mutation in HCC 27 HBV-TERT integration in female HBV-related HCC 28 Other mechanisms for TERT reactivation 28 Possible outcome of HBV-MLL4 integration 29 Mutual exclusiveness of HBV-TERT, HBV-MLL4 and TERT promoter mutation 29 TERT as a target for tumor treatment 30 HBV integrations at non-hotspot genes in HCC 31 Elements required for the sex hormone pathways in regulating HBV integrated gene and TERT promoter mutation 31 Proposed model from our study 32 PART II CIRCULATING CELL-FREE HBV-HUMAN CHIMERA DNA AS A NEW MARKER FOR HCC RECURRENCE AFTER CURATIVE RESECTION 34 INTRODUCTION 35 Treatment of HCC 35 HCC recurrence after curative resection 35 Detection of recurrent HCC after tumor resection 36 Cell-free DNA (cfDNA) 38 Application of cfDNA in prenatal diagnosis 38 Application of cfDNA in tumor detection 39 Challenges in the detection of HCC by ctDNA 41 HBV integration into genome of hepatocytes 42 HYPOTHESIS AND SPECIFIC AIMS 44 MATERIAL AND METHODS 46 Study subjects 46 Extraction of cell-free DNA 46 Identification of HBV integration by capture-NGS 47 Vh-chimera DNA specific PCR primer design 47 Droplet digital PCR (ddPCR) 48 Statistics and figure 48 RESULTS 50 Identification of HBV integration site in the genome of HBV-related HCC, as an individual tumor specific tumor DNA marker 50 Validation of the vh-chimera DNA as signature tumor DNA marker for each HCC 50 The vh-chimera DNA can be detected in the pre-OP plasma, and well correlates with the tumor burden 51 Presence of vh-chimera DNA in post-resection plasma well predicts the recurrence of HCC within one year after resection 52 DISCUSSION 55 Vh-chimera DNA may be a complementary marker of AFP in tumor detection 55 Detection specificity of vh-chimera DNA for tumor 56 Limitations of vh-chimera DNA as a cell-free tumor marker 57 Other applications of vh-chimera DNA 58 SUMMARY 60 FIGURES 62 Figure 1. Flow chart of capture-NGS. 62 Figure 2. Validation of the HBV-human junctions identified by the capture-NGS platform. 63 Figure 3. Identification of HBV-human chimera DNA in 101 tumor gDNA samples by capture-NGS. 64 Figure 4. Sanger sequence validation of -124G>A mutation of TERT promoter. 66 Figure 5. Gender differences in HBV integration patterns between male and female HCCs. 67 Figure 6. Illustration of the HBV integrations in the TERT promoter region identified in 28 out of 101 HCC samples. 69 Figure 7. Gender differences in HBV-TERT integration and TERT promoter mutation in HBV-related HCCs. 70 Figure 8. Integration positions for HBV-TERT, HBV-MLL4 and HBV-CCNE1 in the genome of male and female HCCs. 71 Figure 9. Relative mRNA expression level of TERT, MLL4, and CCNE1 in HBV-related HCC, stratified by integration or mutation. 72 Figure 10. The androgen pathway promotes, but the estrogen pathway inhibits, transcription of the TERT gene containing an HBV integration in its promoter, mediated through HNF4α. 73 Figure 11. Examine the effects of AR and ERα pathways, and the importance of HNF4α on the HBV-TERT-Luc (M15) reporter activity, containing the integrated HBV from the HCC in patient M15, in Huh-7 cells. 75 Figure 12. Examine the effects of AR and ER pathways on the HBV-TERT-Luc reporter activity, containing the integrated HBV from HCC patients M15, M52, and F36, in female SNU387 HCC cell line. 77 Figure 13. Examine the effects of AR and ER pathways on the HBV-TERT-Luc reporter activity, containing the integrated HBV from HCC patients M33, M52, M57, and F36, in HepG2 and Huh-7 cells. 78 Figure 14. AR enhances the transcription of TERT activated by the mutated TERT promoter, mediated through GABPA. 80 Figure 15. AR enhances the transcription of TERT activated by the mutated TERT promoter, mediated through GABPA, in HepG2 cells. 82 Figure 16. A proposed model for the contribution of HBV integration and point mutation at TERT promoter region to male HCC. 84 Figure 17. The experimental design of current study. 86 Figure 18. HBV integration in 50 HBV-related HCC identified by capture-NGS. 87 Figure 19. The high frequency integrations in the 50 HBV-related HCC. 88 Figure 20. Representative data for the tumor specificity of vh-chimera DNA by vh-chimera DNA specific qPCR. 89 Figure 21. Representative data for the linearity of vh-chimera DNA specific ddPCR. 90 Figure 22. Correlation of vh-chimera DNA copy number/ mL plasma with tumor size (N=42). 91 Figure 23. Comparison of detection sensitivity of vh-chimera DNA and AFP in pre-OP plasma of HBV-related HCC (N=42). 92 Figure 24. Detection sensitivity and recurrence analysis of vh-chimera DNA in post-OP plasma (N=42). 93 Figure 25. Overview of vh-chimera DNA ddPCR and follow up results in current study (N=42). 94 TABLES 95 Table 1. Clinicopathological characteristics of 101 HCC patients 95 Table 2. Nucleotide sequence for the primer sets 96 Table 3. HBV viral integrations identified in 101 HCCs by capture-NGS platform 98 Table 4. Somatic mutations at TERT promoter and TP53 CDS 113 Table 5. The HBV genotype and ARE/ HNF4α binding site sequences in 94 HCC containing integrated HBV 116 Table 6. HBV viral integrations identified in 50 HCCs by capture-NGS platform 119 Table 7. Clinicopathological characteristics of 44 HCC patients 126 Table 8. The primer sequence of vh-chimera DNA specific PCR 127 REFERENCE 131 | |
dc.language.iso | en | |
dc.title | 乙型肝炎病毒DNA嵌入對肝細胞基因體對肝癌性別差異之調控及其臨床應用 | zh_TW |
dc.title | Hepatitis B virus DNA integration in contributing to the gender difference of liver cancers and its clinical application | en |
dc.type | Thesis | |
dc.date.schoolyear | 107-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 陳培哲(Pei-Jer Chen),何明志(Ming-Chih Ho),鄭永銘(Yung-Ming Jeng),徐志宏(Chih-Hung Hsu) | |
dc.subject.keyword | 乙型肝炎病毒,肝癌,性別差異,生物標記, | zh_TW |
dc.subject.keyword | hepatitis B virus (HBV),hepatocellular carcinoma (HCC),gender difference,biomarker, | en |
dc.relation.page | 143 | |
dc.identifier.doi | 10.6342/NTU201900566 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2019-02-15 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 微生物學研究所 | zh_TW |
dc.date.embargo-lift | 2024-03-11 | - |
Appears in Collections: | 微生物學科所 |
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