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研究生:凃曉蓁
研究生(外文):Tu, Hsiao-Chen
論文名稱:異常表達α-1,2甘露醣酶I亞型活化未折疊蛋白反應路徑促使肝癌形成
論文名稱(外文):Aberrant expression of α-1,2 mannosidases 1 subtypes promotes hepatocarcinogenesis via activation of unfolded protein response pathway
指導教授:喻秋華汪宏達
指導教授(外文):Yuh, Chiou-HwaWang, Horng-Dar
口試委員:劉扶東鍾邦柱周玉山
口試委員(外文):Liu, Fu-TongChung, Bon-ChuJou, Yuh-Shan
口試日期:2017-07-11
學位類別:博士
校院名稱:國立清華大學
系所名稱:生物科技研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:英文
論文頁數:148
中文關鍵詞:肝癌α-12甘露醣酶I未折疊蛋白反應路徑
外文關鍵詞:HCCα-12 mannosidases 1MAN1A1MAN1C1UPR
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α-1,2甘露醣酶是N-醣基化的主要酵素,其參與真核生物中醣蛋白的形成。目前研究發現α-1,2甘露醣酶的調控異常會導致癌症的發生,然而確切的機轉仍不明。在我們的研究中發現α-1,2甘露醣酶I的四個亞型:α-1,2甘露醣酶IA1、α-1,2甘露醣酶IB1、α-1,2甘露醣酶IA2及α-1,2甘露醣酶IC1分別在肝癌形成的過程中扮演不同的角色。從臨床病理特性分析發現:A1、B1及A2三個亞型的高度表達與臨床階段、腫瘤大小、甲型蛋白含量及侵襲程度呈正相關;而C1亞型,其表達量在肝癌初期極低的現象與另外三者截然不同。依據臨床病理分析結果進而發現若是肝癌病人的A1、B1及A2亞型過度表達伴隨著C1亞型低表現,其五年存活率有明顯降低的情形發生。因此從α-1,2甘露醣酶I亞型的功能分析發現:α-1,2甘露醣酶IA1的過量表達顯著的提升細胞增生、遷移、轉形能力及細胞在斑馬魚體內的遷移能力;然而α-1,2甘露醣酶IC1的過量表達展現相反的現象並且造成細胞週期停滯。更進一步針對引發細胞現象變化的相關基因群觀察,其表達量也隨著上升(α-1,2甘露醣酶IA1)或降低(α-1,2甘露醣酶IC1),同時發現α-1,2甘露醣酶IA1的過量表達所誘發上述的細胞現象改變,是由於活化未折疊蛋白反應路徑的主要調控因子。最後在我們所建立的肝臟特異性表達α-1,2甘露醣酶IA1與α-1,2甘露醣酶IC1轉殖基因斑馬魚動物模式中證實,α-1,2甘露醣酶IA1是一個高潛力致癌基因,其高度表達會誘發肝癌產生藉由活化未折疊蛋白路徑反應;而α-1,2甘露醣酶IC1在肝癌癌化過程中的高度表達可能具備了抑制腫瘤的能力。
α-1,2 mannosidases, key enzymes in N-glycosylation, are required for the formation of mature glycoproteins in eukaryotes. Aberrant regulation of α-1,2 mannosidases can result in cancer although the underlying mechanisms are unclear. Here we report the distinct roles of α-1,2 mannosidase subtypes in the formation of hepatocellular carcinoma (HCC). Clinicopathological analyses revealed that the clinical stage, tumor size, α-fetoprotein level and invasion status were positively correlated with the expression levels of MAN1A1, MAN1B1, and MAN1A2. In contrast, the expression of MAN1C1 was decreased as early as stage I of HCC. Survival analyses showed that high MAN1A1, MAN1A2, and MAN1B1 expression levels, combined with low MAN1C1 expression levels, were significantly correlated with shorter overall survival rate. Functionally, the overexpression of MAN1A1 promoted proliferation, migration, and transformation as well as in vivo migration in zebrafish. Conversely, overexpression of MAN1C1 reduced the migration ability both in vitro and in vivo, decreased the colony formation ability, and shortened the S phase of the cell cycle. Furthermore, the expression of genes involved in cell cycle/proliferation- and migration was increased in MAN1A1-overexpressing cells but decreased in MAN1C1-overexpressing cells. Besides, MAN1A1 activated the expression of key regulators of the unfolded protein response while treatment with ER stress inhibitors blocked the expression of MAN1A1-activated genes. Consequently, using the MAN1A1 liver-specific overexpression zebrafish model, we observed steatosis and inflammation at earlier stages and HCC formation at a later stage accompanied by the increased expression of the UPR modulator, BiP. These data suggest that the up-regulation of MAN1A1 activates UPR and might initiates metastasis. Together our study demonstrates that MAN1A1 represents a novel oncogene while MAN1C1 plays a role in tumor suppression in hepatocarcinogenesis.
Abstract............................................................................................................................... I
中文摘要.............................................................................................................................II
誌謝................................................................................................................................... III
目錄................................................................................................................................... IV Chapter 1 Introduction......................................................................................................1
1.1 Liver diseases and Hepatocellular carcinoma............................................................1
1.2 Discovery of Class I α-1, 2 mannosidases as biomarkers for HCC...........................2
1.3 The function of α-1, 2-mannosidases.........................................................................2
1.4 Dysregulation of α-1,2 mannosidases participated in cancer progression.................4
1.5 α-1,2 mannosidases represent novel biomarkers in HCC..........................................5
Chapter 2 Materials and Methods....................................................................................7
2.1 Human HCC samples.................................................................................................7
2.2 Cell culture.................................................................................................................7
2.3 Plasmid and reagents..................................................................................................7
2.3.1 Constructs for functional assay...........................................................................7
2.3.2 Constructs for transgenic fish .............................................................................8
2.4 Transfection and reagents ..........................................................................................9
2.4.1 Transient transfection..........................................................................................9
2.4.2 Selection for stably expression clone..................................................................9
2.4.3 shRNA knockdown...........................................................................................10
2.5 Functional assay.......................................................................................................10
2.5.1 In vitro Migration Assay...................................................................................10
2.5.2 Colony Formation Assay ..................................................................................10
2.5.3 Cell Proliferation Assay....................................................................................11
2.5.4 Flow Cytometry ................................................................................................11
2.6 Analysis for RNA expression level..........................................................................12
2.6.1 RNA extraction .................................................................................................12
2.6.2 Reverse-transcription Polymerase Chain Reaction (RT-PCR).........................12
2.6.3 Quantitative Polymerase Chain Reaction (Q-PCR)..........................................12
2.7 Zebrafish Husbandary..............................................................................................13
2.8 Xenotransplantation and image analysis..................................................................13
2.9 Histopathological Staining.......................................................................................14
2.9.1 Immunohistochemistry staining........................................................................14
2.9.2 Oil Red O staining ............................................................................................15
2.9.3 Sirius Red O staining ........................................................................................15
2.10 SDS-PAGE and Western Blotting .........................................................................16

2.11 Statistical Analysis.................................................................................................16
Chapter 3 Results.............................................................................................................17
3.1 Differential Expression of α-1, 2-mannosidase I Subtypes in Human HCC Tissues.................................................................................................................... 17
3.2 Determined cell lines for functional assay...............................................................18
3.3 In In Vitro Assays, Overexpression of MAN1A1 Increases Cell Migration Ability While MAN1C1 Overexpression Decreases Cell Migration..................................19
3.4 Utilized xenotransplantation to observe metastasis in vivo .....................................20
3.5 In Colony Formation Assays, the Overexpression of MAN1A1 and MAN1C1
have Opposite Effects on Cellular Transformation ...............................................21
3.6 Overexpression of MAN1A1 Increases Cell Proliferation While Overexpression
of MAN1C1 Leads to Cell Cycle Arrest ................................................................22
3.7 MAN1A1 and MAN1C1 Have Opposite Effects on MMP9, PCNA, and CCNA2 Expression in Cell Migration, Proliferation, and Cell Cycle Regulation ..............22
3.8 UPR Regulators are Activated in MAN1A1-Overexpressing Cells and Repressed
in MAN1C1-Overexpressing Cells.........................................................................23
3.9 ER stress inhibitors revised the expression of MAN1A1-induced genes .................24
3.10 Overexpression of MAN1A1 Induces Hepatocarcinogenesis in Zebrafish...........25
3.11 Treatment with a Mannosidase Inhibitor, ER Stress Inhibitors, or MAN1A1 shRNA Reduced MAN1A1-Overexpression-Mediated Cell Proliferation in the Xenotransplantation Assay ....................................................................................26
Chapter 4 Discussion .......................................................................................................28
4.1 The expression patterns of α-1,2 mannosidases.......................................................28
4.2 The activation of UPR during hepatocarcinogenesis...............................................28
4.3 The possible mechanism of ER stress induction......................................................29
4.4 Conclusion ...............................................................................................................30
4.5 Future perspective....................................................................................................32
List of Tables ....................................................................................................................34
Table 1 primers and shRNA target sequences ...............................................................34
Primer for PCR cloning: ............................................................................................34
Primers for sequencing ..............................................................................................34
shRNA target sequence..............................................................................................34
Primers for Gateway cloning .....................................................................................35
Primers for real-time PCR (Human gene) .................................................................35
Primers for real-time PCR (Zebrafish gene)..............................................................36
Table 2. Summary of the Clinicopathological Correlation with MAN1A1 Expression Levels in the HBV(+)-HCC Patients .....................................................................37
V
Table 3. Summary of the Clinicopathological Correlation with MAN1A2 Expression Levels in the HBV(+)-HCC Patients .....................................................................38
Table 4. Summary of the Clinicopathological Correlation with MAN1B1 Expression Levels in the HBV(+)-HCC Patients .....................................................................39
Table 5. Summary of the Clinicopathological Correlation with MAN1C1 Expression Levels in the HBV(+)-HCC Patients .....................................................................40
List of Figures and Figure Legends................................................................................41
Figure 1. The mRNA Level of the Four Human MAN1 Genes in Different Stages of Hepatocellular Carcinoma. ....................................................................................41
Figure 2. The mRNA Level of the Four Human MAN1 Genes in Hepatoma Cell Lines.......................................................................................................................43
Figure 3. The Protein Expression Patterns of the MAN1A1 and MAN1C1 in
Different Stages of Hepatocarcinogenesis.............................................................45
Figure 4. Statistical Analysis of the Protein Levels of MAN1A1 and MAN1C1
Showed an Upregulation of MAN1A1 and Downregulation of MAN1C1
During Hepatocarcinogenesis. ...............................................................................47
Figure 5. Survival Curve Analysis Showed High Level of MAN1A2, A2, B1 and Low Level of MAN1C1 Correlated to Poor Overall Survival........................................49
Figure 6 In vivo Xenotransplantation Assay for Different Cell Lines. .......................... 51
Figure 7. In Vitro Migration Assay of PLC5 and Hep3B and Selection of Cells..........53
Figure 8. Transient overexpression of MAN1A1 Enhances, and MAN1C1 Decreases
the Migration Ability of Cells In Vitro. .................................................................55
Figure 9. shRNA knockdown of MAN1A1, MAN1A2, and MAN1B1 Decreases the Migration Ability of Cells In Vitro. .......................................................................57
Figure 10. shRNA Knockdown of MAN1C1 Increased the Migration Ability of Cells
In Vitro...................................................................................................................59
Figure 11. Stable Overexpression of MAN1A1 Enhances, and MAN1C1 Decreases
the Migration Ability of Cells In Vitro. .................................................................61
Figure 12. In Vivo Xenotransplantation Assay for MAN1A1-Overexpressing Cells labeled by DiI.........................................................................................................63
Figure 13. In Vivo Xenotransplantation Assay for MAN1C1-Overexpressing Cells labeled by DiI.........................................................................................................65
Figure 14. In Vivo Xenotransplantation Assay for MAN1A1-Overexpressing Cells labeled by CFSE. ...................................................................................................67
Figure 15. In Vivo Xenotransplantation Assay for MAN1C1-Overexpressing Cells labeled by CFSE. ...................................................................................................69
Figure 16. In Vivo Proliferation Assay for MAN1A1-Overexpressing Cells labeled by CFSE. ..................................................................................................................... 71
VI
Figure 17. In Vivo Proliferation Assay for MAN1C1-Overexpressing Cells labeled by CFSE. ..................................................................................................................... 73
Figure 18. Colony Formation of MAN1A1 or MAN1C1 Overexpressing Cell Lines. ...75
Figure 19. Proliferation Ability of MAN1A1 or MAN1C1 Overexpressing Cell Lines. 78
Figure 20. Cell Cycle of MAN1C1 Overexpressing Cell Lines.....................................80
Figure 21. Expression Patterns of MMP9, CCNA2, PCNA and UPR Regulator in MAN1A1 or MAN1C1 Overexpressing Stable Cell Lines......................................82
Figure 22. MAN1A1 Overexpression Activates the UPR and the Expression of Downstream Genes. ...............................................................................................86
Figure 23. Histopathological Analysis of Hepatocytes in MAN1A1 and MAN1C1 Transgenic Fish at 3, 5, 7, 9 and 11 Months of Age...............................................91
Figure 24. Symptoms of MAN1A1 and MAN1C1 Transgenic Fish at 3, 5, 7, 9 and
11 Months of Age...................................................................................................95
Figure 25. Examination of the Progression of Hepatocarcinogenesis in MAN1A1
and MAN1C1 Overexpressing Transgenic and Control Fish by Oil Red O and Sirius Red Staining. ...............................................................................................97
Figure 26. Quantifications of Fibrosis Level in MAN1A1 Overexpressing, MAN1C1 Overexpressing Transgenic and control Fish by Sirius Red Staining....................99
Figure 27. Q-PCR Analysis of the Expression of Lipogenic Factors in Zebrafish Overexpressing MAN1A1 or MAN1C1 in the Liver. .........................................101
Figure 28. Q-PCR Analysis of the Expression of Cell Cycle Related Genes in
Zebrafish Overexpressing MAN1A1 or MAN1C1 in the Liver..........................103
Figure 29. Q-PCR Analysis of the Expression of ER Stress Related Genes in
Zebrafish Overexpressing MAN1A1 or MAN1C1 in the Liver..........................105
Figure 30. Examination of the Expression of the UPR mediator BiP in Transgenic
Fish Overexpressing MAN1A1 and MAN1C1 by IHC Staining. .......................107
Figure 31. In Vivo Xenotransplantation Assay for Different Inhibitors or MAN1A1 shRNA Treatment in MAN1A1-Overexpressing Cells. .......................................109 References.......................................................................................................................111 Appendixes...................................................................................................................... 129
Appendix 1: The expression level of α-1, 2 mannosidases in HBx induced HCC
mouse ................................................................................................................... 129
Appendix 2: Protein sequencing of MAN1A1.............................................................130
Appendix 3: protein sequencing of MAN1C1.............................................................131
Appendix 4: Tg(fabp10a:MAN1A1)(up) & Tg(fabp10a:MAN1C1)(down) at 2dpf...132
Appendix 5: the expression vector used in functional assay (picture from Clontech) 133
Appendix 6: protein expression in normal tissues and cancer cell lines for
MAN1A1 .............................................................................................................134
Appendix 7: protein expression in normal tissues and cancer cell lines for
MAN1A2 .............................................................................................................136
Appendix 8: protein expression in normal tissues and cancer cell lines for MAN1B1..............................................................................................................138
Appendix 9: protein expression in normal tissues and cancer cell lines for MAN1C1.............................................................................................................. 140
Appendix 10: ERSE and NF-kB binding site in the downstream target genes that
might be activated by MAN1A1..........................................................................142
Appendix 11: Dysregulation of α-1, 2 mannosidases I promoted proliferation and migration ability via UPR ....................................................................................143
Appendix 12: Comparative glycomic mapping in Hep3B, MAN1A1/Hep3B and MAN1A1 shRNA/Hep3B....................................................................................144
Appendix 13: Comparative glycomic mapping in 293T, MAN1A1/293T and
MAN1A1 shRNA/293T.......................................................................................145
Appendix 14: Comparative glycomic mapping in Hep3B and MAN1C1/Hep3B ......146
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