哺乳動物Aurora絲氨酸/蘇氨酸激酶家族是有絲分裂的主要調節劑，並且在人類癌症中經常被過量表達。在小鼠乳腺癌中的研究已知Aurora-A激酶（AURKA）是透過活化Akt-mTOR途徑的潛在致癌基因。AURKA在肝癌中過量表達，與愈晚期及和愈嚴重成正相關，表明AURKA的過量表達在肝癌的發展和進展中起了重要作用，但機制尚不清楚。從臨床標本中，AURKA在氨基酸353位點從Valine產生突變成Isoleusine（FI）突變。我們對突變型AURKA的功能感到好奇，因此我們產生AURKA轉基因魚:利用肝特異性啟動子（fabp10a）在斑馬魚中驅動FI突變型和野生型AURKA，並檢查肝癌發生進程。並收集AURKA轉基因魚從3到11個月的肝組織，利用QPCR分析發現在FI突變型AURKA轉基因魚中，3個月時脂肪生成酶(dgat2，fasn和pap)和脂肪生成因子(pparg，srebp1和chrebp)的表達增加，3個月時纖維化相關基因col1a1表達增加，5〜7個月時細胞週期/增殖相關基因(ccne1，cdk1和cdk2)表達增加。在野生型AURKA轉基因魚中，5個月時脂肪生成酶和脂肪生成因子的表達增加，5個月時纖維化相關基因col1a1表達增加，5〜7個月時細胞週期/增殖相關基因表達增加。FI突變型AURKA轉基因魚中基因過度表達的量高於野生型。我們的研究結果說明，過量表達FI突變型AURKA引起脂肪生成酶和脂肪生成因子，纖維化相關基因過量表現早於野生型AURKA，表明FI突變型可加速肝癌進展。AURKA轉基因魚模型建立後，我們通過免疫組織染色檢測了PCNA增殖標誌物，磷酸化mTOR，磷酸化β-catenin，磷酸化 Akt和PTEN在斑馬魚模型以了解AURKA導致肝癌機制。我們發現AURKA轉基因斑馬魚會透過Akt調控下游的蛋白質如β-連環蛋白表現，進而造成肝癌的發生。FI突變型AURKA可以通過在轉基因魚中誘導更多的磷酸化-Akt來加速肝癌進展。

Over the past three decades, malignant tumors ranked first among the top ten mortality in Taiwan, liver cancer is the second of cancer related death. Moreover, liver cancer is often diagnosed at late stage and has the resistance to anti-cancer drug, as well as metastatic to other organ making it hard to be cured. Mammalian Aurora family of serine/threonine kinases are master regulators of mitotic progression and are frequently overexpressed in human cancers. It has been known that Aurora-A kinase (AURKA) is a potential oncogene in mammary gland tumors in mice through Akt-mTOR pathway. AURKA is overexpressed frequently in hepatocellular carcinoma (HCC), and correlated with high grade and high stage, indicating that overexpression of AURKA plays a role in the development and progression of HCC, however, the mechanism is still unclear. From clinical specimens, AURKA mutation on a.a.353 from Valine to Isoleucine (FI) was identified. We are curious about the function of mutant versus wild-type AURKA, so we have generated AURKA transgenic fish using liver specific promoter (fabp10a) to drive both FI mutant and wild-type human AURKA in zebrafish and examine the hepatocarcinogenesis at different stage. We have collected liver tissues from 3 to 11 months of AURKA transgenic fish, and analyzed the expression of lipogenic factor (pparg, srebp1 and chrebp), lipogenic enzyme (dgat2, fasn and pap), fibrosis markers (cola1a, ctgfa and hpse) and cell cycle related genes (ccne1, cdk1 and cdk2) by QPCR. In FI mutant, the expression of lipogenic enzyme and lipogenic factor were increased at 3 month, the fibrosis marker-col1a1 was upregulated at 3 month, and cell cycle/proliferation markers was up-regulated from 5 to 7 months. In WT, the expression of lipogenic enzyme and lipogenic factor were increased from 5~7 month, the fibrosis marker-col1a1 was upregulated at 5 month, and cell cycle/proliferation markers was up-regulated from 5 to 7 months. Furthermore, the fold of overexpression were higher in FI mutant than WT. In summary, our results suggested that overexpression mutant AURKA cause up-regulated lipogenic enzymes and factors also fibrosis marker earlier and higher than wild-type AURKA, indicating that the mutant may accelerate HCC progression. After AURKA transgenic fish model was established, we examined oncogenic mechanism in AURKA zebrafish model via IHC. We also use IHC to detect PCNA proliferation markers, phospho-mTOR, phospho-β-catenin, phospho-Akt, and PTEN. Finally, we found that AURKA transgenic zebrafish through Akt regulates downstream target genes such as β-catenin expression, and then induce liver cancer formation, FI mutant could accelerate HCC progression by induced more p-AKT in the transgenic fish.

中文摘要 I
Abstract II
誌謝 IV
目錄 V
Chapter 1 Introduction 1
1.1 Hepatocellular carcinoma (HCC) 1
1.2 Zebrafish models 2
1.3 Aurora-A kinase 3
1.4 Cell cycle 5
1.5 PI3K/Akt/PTEN/mTOR pathway 7
Chapter 2 Materials and Methods 10
2.1 Transgenic zebrafish line and maintenance 10
2.2 Liver tissue collection and paraffin section 11
2.3 Hematoxylin and Eosin Staining (H&E staining) 12
2.4 Immunohistochemistry staining (IHC staining) 13
2.5 Immunoreactive score (IRS) 14
2.6 Total RNA isolation 15
2.7 Reverse transcription-polymerase chain (RT-PCR) 17
2.8 Quantitative polymerase chain reaction (qPCR) 18
2.9 Statistical analysis 19
Chapter 3 Results 20
3.1 Overexpressed AURKA is dramatically increased in AURKA transgenic zebrafish compared to control zebrafish 20
3.2 HE staining reveals that AURKA (FI) promotes HCC at 7 month, while AURKA(WT) promote HCC at 9 month 21
3.3 In AURKA (FI) mutant transgenic fish, the expression of lipogenic enzyme and lipogenic factor were much higher and at earlier stage than in AURKA WT transgenic fish 21
3.4 AURKA (FI) has the more probability in promoting fibrosis at 3 months. 23
3.5 Expression of cell cycle-related genes/proliferation markers were significantly much higher and earlier in AURKA (FI) than in AURKA (WT) transgenic zebrafish 24
3.6 Proliferating cell nuclear antigen (PCNA) staining indicated cell proliferation in AURKA (FI) was more serious than AURKA (WT) and control fish from 3 to 7 months 25
3.7 Less membrane bound β-catenin for metastatic behavior of hepatocyte in AURKA (FI) transgenic fish for EMT transition 25
3.8 The phospho-AKT in AURKA (FI) was significantly higher than AURKA (WT) and control fish in all stages 26
Chapter 4 Discussions 27
Figures and Tables 32
Figure 1 Expression of AURKA in transgenic zebrafish is increased compared with control fish. 32
Figure 2 H&E staining reveals that AURKA (FI) would dramatically promote HCC at 7 months. 34
Figure 3 The expression of lipogenic factors (pparg, srebp1, chrebp) were higher than control. 37
Figure 4 Other AURKA (FI) mutant transgenic lines (TG2 and TG4) also showed the same expression pattern of lipogenic factor. 39
Figure 5 The expression of lipogenic enzymes (dgat2, fasn, pap) were higher than control. 41
Figure 6 Other AURKA (FI) mutant transgenic lines (TG2 and TG4) also showed the same expression pattern of lipogenic enzyme 43
Figure 7 Expression of fibrosis markers were more significant in AURKA(FI) than AURKA(WT) transgenic fish at earlier stages. 45
Figure 8 The expression of cell cycle related genes (ccne1, cdk1, cdk2) were more severe in AURKA (FI) than AURKA (WT) transgenic fish. 47
Figure 9 The immunoreactive score of immunohistochemistry for PCNA antibody was greater in AURKA (FI) and (WT) than control fish at 5 and 7 months. 49
Figure 10 The immunoreactive score of immunohistochemistry for β-catenin reveals that AURKA (FI) is more significantly lower than control and AURKA (WT) at 3, 5 and 7 months. 52
Figure 11 The immunoreactive score of PTEN immunostaining reveals that PTEN is no difference between control and AURKA transgenic zebrafish. 55
Figure 12 The immunoreactive score of phospho-Akt immunostaining reveals that Akt is much significantly activated in AURKA (FI) than in AURKA (WT). 58
Figure 13 The immunoreactive score of phospho-mTOR (at Ser2448, inactive form) immunostaining for AKT/ mTOR pathway reveals that the expression of mTOR has no significant difference between control and AURKA transgenic fish. 61
Figure 14 Our mode of AURKA(FI) and AURKA(WT) overexpressed in tumorigenesis. 64
Table 1. The primer sequence of QPCR for lipogenic factors (pparg, srebp1, chrebp), lipogenic enzymes (dgat2, fasn, pap), fibrosis markers (col1a1, ctgfa, hpse) and cell cycle related genes (ccne1, cdk1, cdk2). 66
Reference 68
Appendix 80
Appendix 1 Cloning of pTol2-fabp10a: AURKA (FI/WT), myl7: EGFP 80
Appendix 2 Comparison between human and zebrafish AURKA in protein sequence 86
Appendix 3 The gene expression profile of AURKA (FI) TG2 (fabp10a: AURKA(FI), myl7:EGFP) transgenic fish. 87
Appendix 4 The AURKA protein expressed low level in normal tissue and overexpressed in cancer cell line (HuH-7 and HepG2). 88

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