臺灣博碩士論文加值系統

肝細胞癌（hepatocellular carcinoma, HCC）是全球最主要的肝癌種類，也是世界上重要的醫藥衛生議題之一。在肝細胞癌發病的過程中，癌組織的免疫逃脫（immune escape）是相當重要的步驟，而色氨酸經由吲哚胺2,3-雙加氧酶（indoleamine 2,3-dioxygenase, IDO）降解成犬尿氨酸（kynurenine, KYN）則為此步驟中的關鍵。多環芳香烴感受器（aryl hydrocarbon receptor, AhR）在過去研究中被發現會受到KYN這類內源性配體刺激而活化，進而導致肝癌之發生。近期研究則指出IDO在35%的肝癌病理切片中過量表現，且導致較差的預後結果，然而IDO在HCC中所扮演的角色尚未釐清。
在本篇研究中我們利用丙型干擾素（Interferon-γ, IFN-γ）刺激IDO蛋白表現及其酵素活性。有鑒於KYN被報導為AhR的內源性配體，我們進一步測試IDO酵素活性在HCC中的角色。實驗結果顯示KYN能回復因IDO基因減弱（knockdown）而導致的生長抑制。我們更深入發現IDO酵素活性之所以能提升癌細胞增生，是藉由同時活化AhR及β-連環蛋白（β-catenin）訊息傳遞路徑。我們依此提出假設，持續活化的AhR會刺激上皮變間質型轉換（epithelial mesenchymal transition, EMT）相關蛋白的產生，而這些蛋白會降低E-cadherin的轉錄使得β-catenin不受其抑制。結果顯示IDO酵素活性確實提升了snail及SLUG的表現量，且與KYN劑量呈正相關，相反的，與E-cadherin表現量呈負相關。後續實驗更發現IDO酵素活性能啟動Akt訊息傳遞路徑，導致磷酸化的Akt及GSK-3β增加，使得在細胞質中自由移動的β-catenin不受抑制。總結本篇論文，我們發現IDO酵素活性可以同時活化AhR及β-catenin訊息傳遞路徑導致癌細胞增生。再者，IDO酵素活性所產出的KYN藉由啟動AhR來刺激EMT相關蛋白的產生，進而引發β-catenin訊息傳遞路徑。最後，因IDO酵素活性而啟動的Akt訊息傳遞路徑能繼續維持β-catenin訊息傳遞路徑不受抑制。本篇論文提出了IDO在癌症發展中不同於以往的新功能，更加顯明了IDO作為癌症治療標的無窮的潛力。

Hepatocellular carcinoma (HCC), the main type of primary liver cancer, is a serious healthcare problem worldwide. Tumor immune escape is involved in the initiation and progression of HCC, which may result from indoleamine 2,3-dioxygenase (IDO)-mediated metabolism of tryptophan to kynurenine (KYN). Activation of the aryl hydrocarbon receptor (AhR) by KYN, which is an endogenous ligand for AhR, has been implicated in liver carcinogenesis. Recently, it has been demonstrated that IDO was overexpressed in 35.5% of HCC resection samples and resulted in significantly poor prognosis, whereas the precise role of IDO remain to be elucidated.
Here we showed that IFN-γ induced IDO expression and activity in Huh7 shCtrl but not in shIDO cells. Since KYN is capable of activating AhR signaling pathway, we examined the function of IDO activity in HCC cells. We found that KYN can rescue the proliferation rate which had been suppressed by loss of IDO activity. IDO activity can coordinately activate both AhR and β-catenin signaling pathway, which is directly responsible for the increased proliferation. Moreover, immunoblotting analysis confirmed that IDO enhanced the nuclear translocation and signaling activation of both AhR and β-catenin. We thus tested the hypothesis that constitutive AhR signaling may drive EMT-related molecules, which result in loss of E-cadherin and spoil the down-regulation of β-catenin. As hypothesized, IDO activity enhanced snail and SLUG proteins dose-dependently, which is highly correlated to the inhibition of E-cadherin. We then investigated the Akt signaling in the presence of IDO activity and found that level of p-Akt and p-GSK-3β was significantly increased, which abolished the inhibition of free cytosolic β-catenin. In conclusion, we found that IDO enzymatic activity coordinately activated both AhR and β-catenin signaling that is responsible for increased proliferation. Furthermore, IDO activity-derived KYN promoted β-catenin signaling through induction of EMT-related molecules via AhR activation. In addition, IDO activity-mediated activation of Akt signaling resulted in constitutive activation of β-catenin signaling. These results provide evidence for previously unknown tumor-promoting function of IDO and indicates its potential as a therapeutic target.

誌謝 i
中文摘要 ii
ABSTRACT iv
Abbreviations vi
CONTENTS viii
LIST OF TABLES AND FIGURES xi
Chapter 1 Introduction 1
1.1 Hepatocellular carcinoma: global epidemiology and risk Factors 1
1.2 Development of liver carcinogenesis: chronic inflammation and immune tolerance 2
1.3 Indoleamine 2,3-Dioxygenase (IDO) plays a crucial role in the induction of immune tolerance to tumors 3
1.4 Aryl hydrocarbon receptor pathway and its endogenous ligand, Kynurenine 5
1.5 Crosstalk between AhR pathway and β-catenin pathway 7
1.6 Akt signaling Pathway regulates β-catenin 8
1.7 Specific Aim 9
Chapter 2 Experiment Materials 11
2.1 Huh7 Human hepatoma cell 11
2.2 Instruments 11
2.3 Reagents and kits 12
2.4 Antibodies 14
2.5 Software 15
Chapter 3 Experiment Methods 16
3.1 Cell culture 16
3.2 Cell proliferation assay 16
3.3 Immunofluorescence analysis 17
3.4 Immunoblotting analysis 17
3.5 Cell fractions of nucleus and cytoplasm 18
3.6 Chromatin immunoprecipitation (ChIP) assay 18
3.7 Quantification of kynurenine in cell culture condition medium 19
3.8 Reverse transcriptase-polymerase chain reaction (RT-PCR) 20
3.9 Statistical analysis 20
Chapter 4 Results 22
4.1 IFN-γ induced IDO protein expression and enzymatic activity in Huh7 22
4.2 Functional analysis of Huh7 shCtrl and shIDO cells 22
4.3 IDO enzyme activity directly activated AhR pathway 23
4.4 IDO activity coordinately increased AhR and β-catenin signaling 23
4.5 IDO activity induced β-catenin nuclear translocation and signaling activation 24
4.6 IDO induced EMT-related molecules through AhR pathway 25
4.7 IDO expression promotes Akt signaling pathway 26
4.8 Conclusion 26
Chapter 5 Discussion 28
5.1 IDO activity promoted cancer proliferation 28
5.2 IDO activity enhanced AhR activation 28
5.3 Coordinate activation of AhR and β-catenin 29
5.4 IDO activity induced EMT-related molecules 31
5.5 β-catenin signaling activated Akt signaling 32
Chapter 6 Tables and Figures 33
References 47

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