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系統識別號 U0026-2308201119020400
論文名稱(中文) 探討去乙醯化酶抑制劑蘿蔔硫素對於肝癌細胞株之毒殺能力
論文名稱(英文) Studies of the killing effects of HDAC inhibitor sulforaphane on hepatoma cell lines
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) 高慧齡
研究生(英文) Hui-Ling Kao
學號 t36984043
學位類別 碩士
語文別 英文
論文頁數 68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 蘿蔔硫素  去乙醯化酶抑制劑  肝癌 
英文關鍵字 sulforaphane  HDAC inhibitor  hepatoma 
學科別分類
中文摘要 肝癌是世界上最常見的內臟腫瘤之一,尤其在亞洲盛行率比北美以及歐洲都來的高許多,目前已有許多策略用於癌症的預防上,本篇的研究主要目的想要尋找一個天然化合物,用在肝癌的預防上。而我們主要針對具有去乙醯化酶抑制效果的天然物上。目前已有許多去乙醯化酶抑制劑被報導發現針對癌症細胞特別具有毒殺效果。在本篇研究中,我們主要研究一個存在於十字花科的蔬菜當中具有去乙醯化酶抑制劑特性的天然物-蘿蔔硫素sulforaphane (SFN),並測試觀察SFN分別對於肝癌及非惡性肝細胞株細胞增殖之影響。在集落形成實驗中,我們發現SFN對於肝癌細胞株Hep3B,HepG2具有較高的殺傷力,然而非惡性的不朽肝細胞株WRL-68則對於SFN具有較高的耐受力。另外在annexin V染色以及細胞週期分析的實驗當中也發現肝癌細胞HuH-7在受SFN作用之下比起WRL-68會產上較高細胞凋亡的情形。這些結果都顯示SFN對於肝癌細胞具有較高的毒殺能力。另外,在細胞周期分析中也發現,SFN會引發細胞周期G2/M-arrest。而在研究SFN誘發細胞死亡的機制中,我們發現SFN會促進E2F1活性上升;E2F1為重要的轉錄調節因子之一,可調控細胞增殖以及細胞凋亡,然而從實驗結果發現,E2F1的上升進一步會正向調控E2F1傾細胞凋亡下游基因bim RNA以及其蛋白的表現。從bim promoter 報導基因試驗發現,E2F1 在bim promoter 主要的結合位點是在於-1250/-1000區間。並且,在SFN作用之下增強了E2F1的作用。因此,可以知道SFN誘發細胞凋亡是透過E2F1作用路徑所調控的。總論來說,天然的去乙醯化酶抑制劑SFN是一個有潛力的肝癌治療藥物。
英文摘要 Hepatocellular carcinoma (HCC) is the most common visceral neoplasm in the world, especially Asia. Some chemo-preventive approaches have been shown to be able to prevent the carcinogenesis process. This study aims to seek a natural product that can serve as a chemo-preventive agent for HCC. We focus on the natural compounds which have the activity of histone deacetylase inhibitor (HDACi), because some HDACi compounds have been shown to present strong killing effects to cancer cells but not to non-malignant cells. Here we used sulforaphane (SFN) that is a natural HDACi compound found in cruciferous vegetables to test for its effects on proliferation of HCC cells and normal hepatocytes. By MTT assays, we found that the hepatoma cell lines were more susceptible than the non-cacerous hepatic cell WRL-68 to SFN treatment. And by colony formation assays, we found that SFN inhibited cell proliferation of Hep3B and HepG2 hepatoma cells more than WRL-68 cells, an immortalized non-cancerous hepatocyte cell line. By annexin V staining analysis, we also found that HuH-7 cells exhibited higher levels of apoptosis than the WRL-68 cells did. These results indicate that SFN exhibits a preferential killing effect to hepatoma cells. By using cell cycle profile analysis, SFN was found to induce G2/M cell cycle arrest. In addition, we explored the molecular mechanisms of how SFN induces cancer cell death. We found that SFN may enhance E2F1 transactivation activity. E2F1 is an important transcription factor in control of cell cycle progression and cell apoptosis. Bim, a apoptotic downstream molecule of E2F1, was upregulated by SFN treatment. By bim promoter reporter assays, we found that the putative E2F1 binding site in bim promoter locates within -1250/-1000 region. Moreover, bim promoter activities triggered by E2F1 were enhanced after SFN treatment. Taken together, this suggests that SFN induced cell death may through an E2F1-mediated pathway. This study provides an evidence that the natural HDACi compound SFN may stand as a good potential chemo-preventive agent for HCC.
論文目次 中文摘要 ...................................I
Abstract..................................... II
Acknowledgement ................................ III
Contents...........................................IV
List of Tables ......................................VI
List of Figures...............................VII
List of Appendices ................................ VIII
I. Introduction ................................. 1
1.1 Hepatocellular carcinoma (HCC) ................ 1
1.1.1 HBV-related HCC in Taiwan........................ 1
1.1.2 Therapeutic strategies for HCC................. 2
1.2 Epigenetic alteration and cancer.................. 3
1.2.1 DNA methylation ............................ 3
1.2.2 Histone acetylation .......................... 4
1.3 Cancer therapeutic strategies through epigenetic regulations ................................. 5
1.3.2 Histone acetylase inhibitors (HDACi)............. 5
1.4 HDACi-mediated anti-carcinogenic pathways............. 6
1.4.1 Cell cycle arrest regulated by HDACi............... 6
1.4.2 Apoptosis induced by HDACi..................... 7
1.4.3 Regulation of ROS production by HDACi............. 7
1.4.4 Inhibition of tumour angiogenesis................... 8
1.4.5 HDAC inhibitors in clinical trial ................. 8
1.5 Dietary HDAC inhibitors ............................ 8
1.6 Sulforaphane (SFN).................................... 9
1.6.1 Anti-cancer properties of SFN................... 9
1.6.2 Characteristics of HDAC inhibitors .............10
1.6.3 Clinical trials of SFN..................... 10
II. Materials and methods ........................ 11
2.1 Cell lines and reagents........................... 11
2.1.1 Cell lines......................................... 11
2.1.2 D,L-Sulforaphane (SFN) ................. 11
2.2 MTT assay ................................... 11
2.3 Colony formation assay............................. 12
2.4 Western blot analysis ............................... 12
2.5 Gene expression profile............................. 12
2.5.1 Extraction of total RNA from cells ............... 12
2.5.2 Reverse transcription PCR (RT-PCR) ............... 13
2.6 Cell death assay.................................... 13
2.6.1 Cell cycle profile ........................... 13
2.6.2 Annexin V staining........................ 14
2.7 Reporter assay for promoter activity................. 14
2.7.1 Plasmid transfection ................... 14
2.7.2 Luciferase assay .......................... 14
2.7.3 β-galactosidase assay..................... 15
III. Specific aims ................................... 16
IV. Results ............................................. 18
4.1 The hepatoma cell lines are susceptible to SFN....... 18
4.2 SFN selectively inhibited proliferation of hepatoma cells ... 18
4.3 SFN induced E2F1 pro-apoptotic downstream gene bim upregulation. ............... 18
4.4 The apoptosis induced by SFN in HuH-7 was higher than in WRL-68 cells ....... 19
4.5 SFN induced cell cycle arrest in G2/M phase ........ 20
4.6 Cancer cells were more sensitive than non-cancerous cells to the SFN-induced stress ................ 20
4.7 SFN enhanced the E2F1 transactivation activity ..... 21
4.8 SFN may enhanced E2F1 transactivities on bim promoter.. 21
4.9 SFN inhibited the colony formation efficacies of wild-type and pre-S2 mutant LHBS expressing cells ...... 22
V. Discussion........................................... 23
VI. References.......................................... 29
VII. Tables ............................................. 37
VIII. Figures .................................... 42
IX. Appendix ......................................... 59
List of Tables
Table 1: RT-PCR primers........................ 37
Table 2: bim promoter construction primers ............. 38
Table 3: Reagents and Kits ...................... 39
Table 4: Buffer preparation...................... 41
List of Figures
Figure 1: Hepatoma cell lines were more susceptible than WRL-68 under SFN treatment..................... 42
Figure 2: SFN preferentially inhibited the cell proliferation of some hepatoma cell lines............... 43
Figure 3: SFN induced transcription factor E2F1 decrease in protein level. ...... 45
Figure 4: SFN induced E2F1 pro-apoptotic downstream target bim upregulation. ............................. 48
Figure 5: The apoptosis caused by SFN in HuH-7 was higher than in WRL-68.50
Figure 6: SFN induced cell cycle arrest in G2/M phase. .. 52
Figure 7: Cancer cells were more sensitive than non-cancerous cells to the stress which caused by SFN........ 55
Figure 8: SFN enhanced the E2F1 transactivation activity. ..... 56
Figure 9: SFN slightly enhanced E2F1 tranactivation activities on bim promoter. ...................... 57
Figure 10: SFN inhibited the colony formation efficacies of wild type and pre-S2 mutant LHBS expressing cells. ...... 58
List of Appendices
Appendix 1: DNA metylation................. 59
Appendix 2: Genes commomly hypermethylation in cacers (Herman et al., 2003) (Das, 2004) ................. 60
Appendix 3: The dynamic equilibrium of histone acetylation .... 61
Appendix 4: Non-histone proteins substrates of HDACs (Xu et al., 2007) ........ 62
Appendix 5: Functions of HDAC inhibitors ............. 63
Appendix 6: Four classes of HDAC Inhibitors ............ 64
Appendix 7: HDAC inhibitors in clinical trial (Xu et al., 2007) ......................... 65
Appendix 8: Metabolism of sulforaphane. ............... 66
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