肝癌是一個緩慢的，多步驟的過程。我們利用B型肝炎病毒X抗原(HBx)誘導肝癌的小鼠模型，找出了五個共同監管基因。其中內皮素-1(EDN1)在12個月的階段的表現增加，可能藉由上調某些基因促進癌症發生在16~18個月。我們也發現肝癌患者組織的三種阿爾法-甘露糖苷酶1A1, 1A2及1B1 (MAN1A1、 MAN1A2、MAN1B1)表現量比正常肝組織增加2倍以上；但94%的第一期B型肝炎病毒肝癌患者中肝癌組織阿爾法-甘露糖苷酶1C(MAN1C)表現則是比正常肝組織低2倍以上。在本論文中，我進一步探討內皮素-1以及阿爾法-甘露糖苷酶1C在肝癌形成的分子機制。
過去的研究發現，相較於正常組織，許多種腫瘤組織中內皮素-1有較高表現。當內皮素-1表現失衡時，會對細胞增生、血管新生、細胞凋亡和癌症轉移等多種層面造成影響。首先我們實驗室建立了內皮素-1轉殖基因斑馬魚，研究內皮素-1在肝癌生成中扮演的角色。結果顯示，肝臟專一性過度表現內皮素-1在11個月形成肝細胞異常增生和肝癌，伴隨著和細胞週期、增殖、腫瘤、轉移相關基因的表現增加。在本論文中，我進一步利用細胞株，探討當大量表現內皮素-1時，對細胞造成什麼影響和其分子作用機制。我發現穩定表現內皮素-1的293T細胞株，會加快細胞增生、促進細胞遷移的能力。利用異種移植方法也發現穩定過度表現EDN1於293T細胞中可增強細胞遷移能力。在這過程中伴隨著和細胞增生與細胞遷移相關的基因表現量上升。分子機制上，我發現未摺疊蛋白質反應路徑的調控因子，例如spliced XBP1、ATF6、 IRE1、PERK，在核糖核酸和蛋白質表現都有明顯增加。過去研究發現，內皮素-1可經由磷脂酰肌醇3-激酶/蛋白質激酶B路徑而達成其作用。利用蛋白質激酶B的抑制劑處理穩定表現內皮素-1的293T細胞株後，原先增加的基因表現都會消失，細胞遷移的能力也會降低。我們推測內皮素-1可能藉由活化蛋白質激酶B傳遞路徑，增加下游基因的表現，造成細胞功能的改變。內皮素-1可能藉由活化磷脂酰肌醇3-激酶/蛋白質激酶B訊號傳遞路徑，來調控下游基因(包括未摺疊蛋白質反應路徑的調控因子)的表現，在肝癌症形成中扮演一個重要的角色。
由實驗室先前研究成果發現，針對人類中的四個α-1,2 Mannosidase I [MAN1A1, MAN1A2, MAN1B1 and MAN1C] 進行大量表現和shRNA抑制其表現的方式去看是否影響肝癌細胞[Hep3B, PLC5] 遷移能力。發現過度表現MAN1A1的肝癌細胞遷移能力上升，而過度表現MAN1C會使細胞遷移能力下降；利用shRNA抑制MAN1A1, MAN1A2 和MAN1B1表現則會使肝癌細胞遷移能力下降。在本研究中，我們想去探討，當MAN1C在Hep3B細胞株大量表現時，會如何調控細胞的分子作用機制。我發現在Hep3B細胞株大量表現阿爾法-甘露糖苷酶 IC時，會造成細胞增生與細胞遷移相關的基因表現量下降，未摺疊蛋白質反應路徑的調控因子也會受到影響。我們推測阿爾法-甘露糖苷酶IC可能是藉由減少下游細胞增生與細胞遷移相關的基因的表現，造成Hep3B細胞株功能的改變。
在我的論文的兩項研究中，我們可以發現未摺疊蛋白質反應路徑都有受到影響，或許未摺疊蛋白質反應路徑的調控因子在癌症形成中也扮演一個重要的因子，它可能可以作為藥物治療的標靶，預防癌症的生成。

Liver cancer is a slow, multi-step process. We have used the hepatitis B virus X antigen (HBx)-induced liver cancer mouse model to identify the five common regulatory genes. In which Endothelin-1 (EDN1) is up-regulated at 12-month and may regulate many downstream targets genes to promote cancer formation in 16 to 18 months. We also found hepatocellular carcinoma patients with up-regulation of three α-mannosidase genes (MAN1A1, MAN1A2, MAN1B1) compared with normal liver tissue increased more than 2 fold, while 94% of the stage I-HBV(+)-HCC patients had compared to normal liver tissue the α-mannosidase 1C is down-regulated more than 2 fold. In my thesis, I further explored the molecular mechanism of endothelin-1 and α-mannosidase 1C in the liver cancer formation.
In previous studies, EDN1 has been found high expression in many tumor tissues compared to normal tissues. Abnormal EDN1 expression implicated cell proliferation, angiogenesis, apoptosis and metastasis. Our lab had established the liver-specific edn1 transgenic fish, and found edn1 caused hyperplasia and HCC in 11 months accompanied by up-regulation of genes involved in cell cycle, proliferation, tumor markers and metastasis related genes. Using cell culture system, I continue to explore the molecular mechanisms of EDN1 in hepatocarcinogenesis. Overexpression of EDN1 in 293T cells enhanced cell proliferation, cell migration ability in vitro and in xenotransplantation assays, and was accompanied by the up-regulation of cell cycle/proliferation and migration related genes. Furthermore, the expression of UPR pathway-related mediators, such as spliced XBP1, ATF6, IRE1 and PERK, were also up-regulated in both RNA and protein level. In the presence of EDN1 or AKT inhibitor, these increased expression levels were diminished, and the migration ability enhanced by EDN1 was also disappeared, suggesting that EDN1 acts through the AKT pathway to enhance the UPR and subsequently activate the expression of downstream genes to achieve its function. Those data suggest that EDN1 plays an important role in cancer progression by activating the PI3K/AKT pathway to regulate downstream genes expression.
According to hepatitis B virus X antigen-induced hepatocellular carcinoma (HCC) mouse model in our lab, we identified α-mannosidase 1C significantly down-regulated while other three MAN1 genes (MAN1A1, MAN1A2 and MAN1B1) were up-regulated. The α-mannosidase inhibitors treatment in tumor cells, suppressing tumor cells growth and led the tumor cells to apoptosis. I found overexpression of MAN1C1 in Hep3B cells inhibits the expression of cell cycle/proliferation and migration related genes. Furthermore, the expression of UPR pathway-related mediators was affected in RNA level. Our data suggest MAN1C1 inhibit the expression of downstream genes to achieve its function.
UPR pathway-related genes have been implicated in above, that suggests the regulation of UPR pathway-related mediators is important in cancer formation; it might serve as drug target for preventing cancer formation.

中文摘要 I
Abstract III
Table of contents V
List of Figures VIII
List of Appendix IX
Chapter I Introduction 1
I.1 Hepatocellular Carcinoma 1
I.1.1 Carcinogenesis 4
I.1.2 Metastasis 7
I.2 Endothelin 1 7
I.3 Α-1,2 mannosidase I 9
I.4 Endoplasmic reticulum stress 11
Chapter II Materials and Methods 15
II.1 Constructs 15
II.2 Transformation 15
II.3 Colony PCR 15
II.4 Plasmind preparation (mini-prep) 16
II.5 Plasmind preparation (midi-prep) 17
II.6 Cell culture 18
II.7 Transfection 18
II.8 Selection of stable expression clone 19
II.9 Cell proliferation assay 19
II.10 In vitro Cell migration assay 20
II.11 Total RNA extraction 20
II.12 Reverse transcribed polymerase chain reaction (RT-PCR) 21
II.13 Quantitative polymerase chain reaction (Q-PCR) 22
II.14 Western blotting analysis 23
II.15 Inhibition assay 24
II.16 Statistical analysis 25
Chapter III Overexpression of endothelin 1 promotes cell proliferation and migration through the AKT pathway 26
III.1 Abstract 26
III.2 Introduction 27
III.3 Results 29
III.3.1 The edn1 transgenic zebrafish induced hyperplasia and HCC at 11 months accompanied with up-regulation of cell-cycle, proliferation, tumor marker and metastasis related genes 29
III.3.2 Stable overexpression of EDN1 in 293T cells promotes cell proliferation, migration in Transwell and xenotransplantation assays 30
III.3.3 EDN1 overexpression results in the regulation of genes related to cell cycle, migration, and the UPR pathway 31
III.3.4 EDN1 or AKT inhibitors treatment affected the regulation of genes related to cell cycle, migration, and the UPR pathway in 293T/EDN1 stable cell line 32
III.3.5 PI3K or AKT inhibitors treatment affected 293T/EDN1 cell migration ability 33
III.4 Discussion 33
Chapter IV The molecular mechanism of overexpression MAN1C1, a potential tumor suppressor gene using cell culture 35
IV.1 Abstract 35
IV.2 Introduction 36
IV.3 Results 38
IV.3.1 Differential expression of α-1,2 mannosidase I in hepatocellular carcinoma and cell lines 38
IV.3.2 Establishment of stable overexpression MAN1C1 in Hep3B cell line 39
IV.3.3 Overexpression of MAN1A1 increased and MAN1C1 decreased the migration ability 39
IV.3.4 In vivo xenotransplantation assay demonstrated MAN1A1 enhanced and MAN1C1 decreased the migration ability 41
IV.3.5 Q-PCR analysis of the genes affected by over-expression of MAN1A1 and MAN1C1: MMP9, CCNA2 and PCNA is increased in MAN1A1 over-expression cell and decreased in MAN1C1 over-expression cell 42
IV.3.6 MAN1C1 overexpression results in the regulation of genes related to cell cycle, migration, and the UPR pathway 43
IV.4 Discussion 43
Chapter V Conclusion and future perspective 47
Figures 52
Appendix 62
References 71

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