肝細胞癌(Hepatocellular carcinoma)為原發性肝癌中最常見的一型，也是全球致死率第二名的癌症。肝炎病毒感染所引起的慢性肝臟發炎是造成HCC最主要的危險因子，當促發炎因子：丙型干擾素(Interferon-γ, IFN-γ)刺激肝癌細胞後，細胞內酵素：吲哚胺2,3-雙加氧酶(Indoleamine 2,3-dioxygenase, IDO)的表現量會大量上升並參與在抑制免疫反應的過程，進而改變腫瘤微環境。近年來，IDO對於非免疫細胞的調控開始受到關注，然而IDO對於HCC細胞自身的影響目前還有待探討。
在本篇研究中我們發現利用IFN-γ刺激Huh7 shCtrl細胞後，IDO的表現量與活性都會大量上升，我們也觀察到IDO的活性與癌細胞的增生和轉移能力呈正相關，在給予細胞犬尿胺酸(kynurenine, KYN)後，可以回復Huh7 shIDO cells增生和轉移的能力，因此暗示著IDO和其代謝產物會促進肝癌細胞的惡化。KYN為多環芳香烴感受器 (aryl hydrocarbon receptor, AhR)的內源性配體，在過去研究中AhR的活化被報導會參與在多種癌症中，我們發現在細胞受到IFN-γ刺激後，KYN表現量的提升會活化並促進AhR進入細胞核，活化的AhR會提升snail的轉錄，進而抑制E-cadherin的表現量，當E-cadherin的表現量下降時會釋放β-連環蛋白(β-catenin)，因此β-catenin可以進入細胞核中調控與增生相關分子的轉錄。此外，在細胞核中AhR和β-catenin會有物理上的連接並共同調控snail轉錄的提升，進而促進細胞轉移的能力。我們也推測活化的AhR會釋放Src來抑制PTEN的蛋白表現量，使Akt訊息傳遞路徑不斷活化，因此β-catenin將不再受destruction complex抑制，得以進入細胞核。根據本篇論文的實驗結果，我們觀察到IDO促進肝癌細胞發展的機制，其中AhR和β-catenin訊息傳遞路徑的活化扮演重要角色。

Hepatocellular carcinoma (HCC), the major type of primary liver cancer, is the second most common cause of cancer-related death worldwide. Chronic liver inflammation caused by hepatitis virus infection is the main risk factor of HCC. Once pro-inflammatory factor IFN-γ stimulates liver cancer cell, Indoleamine 2,3- dioxygenase (IDO) will be activated to mediate tumor immune escape, which is crucial in the promotion of HCC. Recently, IDO has been the focus of much attention because of its non-immunological role. However, the role of IDO in liver cancer remains to be elucidated.
In our studies, we showed that IFN-γ induced IDO expression and activity in Huh7 cells, and there was a positive correlation between IDO activity and cell proliferation and metastatic abilities. Moreover, the proliferation and metastatic capability could be rescued after kynurenine (KYN) treatment in Huh7 shIDO cells. These results implicated that IDO and its metabolite were involved in HCC progression. KYN was an endogenous ligand of aryl hydrocarbon receptor (AhR), which had been reported to play a role in tumorigenesis. We found that KYN enhanced signaling activation and nuclear translocation of AhR. Activated AhR promoted transcription of snail and reduced E-cadherin expression. Downregulation of E-cadherin led to release of β-catenin, then β-catenin was able to translocate to the nucleus and promoted the expression of proliferation-related molecules. In the nucleus, AhR and β-catenin had physical interaction and corporately promoted transcription of snail, which was responsible for the increased cell migratory and invasive abilities. We also speculated AhR released Src to downregulate PTEN expression and promote Akt signaling, which abolished the destruction complex from β-catenin, and finally led to activation of β-catenin. In conclusion, these results showed the tumor-promoting function of IDO in HCC, and it was mediated by activating both AhR and β-catenin signaling pathway.

謝誌 i
中文摘要 ii
Abstract iii
縮寫 v
目錄 vii
圖表目錄 xi
附錄目錄 xii
第一章 導論 1
一、 肝癌 1
1.1肝癌的流行病學 1
1.2肝癌的臨床病理 1
1.3肝癌的致病原因 2
二、 肝癌演進的機制：慢性發炎引發癌化與免疫抑制 3
三、 IDO參與腫瘤演進 3
3.1 IDO於癌症中大量表現 3
3.2促發炎因子提升IDO表現量並抑制免疫反應 4
3.3 IDO促進癌細胞的發展 4
3.4 IDO調控的訊息傳遞路徑：AhR signaling pathway 5
四、 AhR (Aryl hydrocarbon receptor) signaling pathway 5
4.1 AhR的特性 5
4.2活化AhR的ligand 6
4.3 AhR調控的分子機制 6
4.4 AhR參與癌症的演進 7
五、 AhR和β-catenin交互作用 8
5.1在肝臟細胞中AhR和β-catenin signaling pathway的交互作用 8
5.2 β-catenin的特性 8
5.3異常活化的β-catenin signaling pathway促進癌化 9
六、 Akt signaling調控β-catenin活化 9
6.1 Akt的特性 9
6.2 PI3K/Akt 抑制GSK-3β使得β-catenin signaling持續活化 10
6.3 Akt signaling受PTEN抑制 10
七、 研究動機 11
第二章 實驗材料 12
一、 細胞株 12
二、 儀器 12
三、 藥品 13
四、 試劑組 15
五、 抗體 15
六、 分析軟體 16
第三章 實驗方法 17
一、 肝癌細胞之培養 17
1.1培養基(medium)的配置 17
1.2細胞培養 17
二、 小髮夾RNA(shRNA)抑制目標蛋白 17
2.1菌株培養 17
2.2純化含有shRNA之質體 18
2.3含有shRNA之慢病毒(Lentivirus)製備 18
2.4慢病毒載體感染肝細胞癌細胞 19
三、 蛋白質分析 19
3.1蛋白質萃取及濃度測定 19
3.2十二烷基磺酸鈉-聚丙烯醯胺凝膠電泳法(SDS-PAGE) 19
3.3西方墨點法(Western Blot) 20
四、 Co-IP (Co-Immunoprecipitation) 21
五、 ChIP (Chromatin Immunoprecipitation) 22
5.1固定DNA與蛋白質(Cross-linking) 與震斷DNA (soniciation) 22
5.2免疫沉澱 (Immunoprecipitation) 22
5.3 DNA純化 23
5.4 聚合酶鏈鎖反應(PCR)與瓊脂凝膠電泳(agarose gel electrophoresis) 23
六、 細胞傷口癒合實驗(wound healing assay) 24
七、 細胞侵襲實驗(transwell assay) 24
7.1 裝置transwell 24
7.2 侵襲能力偵測 24
八、 RT-PCR 25
8.1 RNA萃取(RNA extraction) 25
8.2反轉錄聚合酶鏈式反應(Reverse transcription) 25
8.3聚合酶鏈鎖反應(PCR)與瓊脂凝膠電泳(agarose gel electrophoresis) 25
第四章 實驗結果 26
一、 IDO調控與增生相關分子(proliferation-related molecules)的表現量 26
二、 IDO參與促進Huh7轉移的能力 27
三、 IDO促進與轉移相關分子(EMT-related molecules)的表現量 27
四、 IDO活化後促進AhR和β-catenin相互作用(interaction) 28
五、 AhR和β-catenin共同調控snail的轉錄 29
六、 IDO透過抑制PTEN使Akt signaling pathway活化 30
七、 AhR活化後釋放Src以抑制PTEN/PI3K/Akt signaling pathway 30
八、 總結 31
九、 IDO在肝癌病患中的基因表現量 31
第五章 討論 33
一、 肝癌細胞中IDO的活化促進細胞增生與轉移 33
二、 IDO促進AhR的活化 33
三、 AhR和β-catenin訊息傳遞的相互調控 34
四、 AhR和β-catenin在細胞核中共同調控基因的轉錄 35
五、 AhR透過抑制PTEN使Akt活化進而啟動β-catenin 36
六、 IDO於癌症醫療的應用 38
第六章 參考文獻 41
第七章 圖表與說明 51
第八章 附錄 64

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