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研究生：	洪妤萱 Hung, Yu-Hsuan
論文名稱：	脂質與胺基酸代謝改變對癌症進展之影響 The Contribution of Altered Metabolism in Lipid and Amino Acid to Cancer Development
指導教授：	賴明德 Lai, Ming-Derg
學位類別：	博士 Doctor
系所名稱：	醫學院 - 基礎醫學研究所 Institute of Basic Medical Sciences
論文出版年：	2017
畢業學年度：	105
語文別：	英文
論文頁數：	81
中文關鍵詞：	癌症代謝、脂質分解、醯基輔酶 A 硫酯酶、精氨酸代謝、精氨基琥珀酸裂解酶、肝癌、乳癌
外文關鍵詞：	Cancer metabolism, lipolysis, acyl-CoA thioesterase, arginine metabolism, argininosuccinate lyase, liver cancer, breast cancer
相關次數：	點閱：212 下載：1
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癌症代謝失衡為其一發展指標，且巨分子代謝失衡，包含其於醣類、脂質、蛋白質之失衡，均調控癌症發展。於脂質部分，除脂質生成外，脂質分解亦調控癌症發展，透過影響游離脂肪酸可得性以供應癌症能量。於胺基酸部分，除麩醯胺酸、絲氨酸、甘氨酸，精氨酸代謝亦調控癌症發展，透過影響精氨酸可得性以供應癌症生長。於本研究中，我們探得代謝失衡於癌症發展之重要性，透過給予範例關於脂質分解酵素醯基輔酶A硫酯酶8所增加之活體外肝癌發展、脂質分解酵素醯基輔酶A硫酯酶7所增加之活體外乳癌發展、及精氨酸生產酵素精氨基琥珀酸裂解酶-細胞週期調控者週期素A2互動所增加之活體外肝癌提升及精氨基琥珀酸裂解酶過度表現所增加之活體外肝癌進展攸關抗藥性。我們探得於醯基輔酶A硫酯酶8所增加之活體外肝癌發展部分，生物資訊分析顯示醯基輔酶A硫酯酶8之基因拷貝數與RNA表現於肝癌檢體中相較於非癌肝組織有增加之情形，而活體外實驗顯示醯基輔酶A硫酯酶8基因靜默降低肝癌發展而可被其過度表現及下游脂質代謝產物肉荳蔻酸所恢復；於醯基輔酶A硫酯酶7所增加之活體外乳癌發展部分，系統化生物資訊分析顯示醯基輔酶A硫酯酶7於乳癌中展現醯基輔酶A硫酯酶家族成員所相關之癌症預後中最強關聯性，且可進一步與脂質代謝改變連結，而可被芳香酶抑制劑及磷脂醯肌醇-3激酶抑制劑所壓抑，而活體外實驗顯示醯基輔酶A硫酯酶7基因靜默降低乳癌發展，而可被其下游脂質代謝產物棕櫚酸所恢復，而其過度表現則提升乳癌發展，而可被芳香酶抑制劑及磷脂醯肌醇-3激酶抑制劑所壓抑；於精氨基琥珀酸裂解酶-週期素A2互動所增加之活體外肝癌提升及精氨基琥珀酸裂解酶過度表現所增加之活體外肝癌進展攸關抗藥性部分，活體外實驗顯示精氨基琥珀酸裂解酶與週期素A2共同存在且互動於肝癌細胞質中，且該互動無須兩者之分子功能並亦可恢復精氨基琥珀酸裂解酶基因靜默所降低之肝癌發展，而精氨基琥珀酸裂解酶過度表現提高肝癌對精氨酸抽離療法之抗藥性，而生物資訊分析顯示精氨基琥珀酸裂解酶所調控之肝癌發展與細胞週期進展等途徑相關，且可被預測得之藥物康肯、希樂葆、益撲喘所壓抑。上述研究進而顯示代謝失衡於多種癌症之重要性，以脂質分解於肝癌及乳癌發展，及精氨酸代謝於肝癌發展為例。

Dysregulated cancer metabolism is an emerging hallmark in cancer formation, and disturbed macromolecule metabolism including those of glucose, lipid, and amino acid regulates cancer formation. In the part of lipid, in addition to lipogenesis, lipolysis modulates tumor development by controlling free fatty acid availability supporting neoplastic energetics. In the part of amino acid, in addition to glutamine, serine and glycine, arginine metabolism regulates cancer formation by controlling arginine availability supporting neoplastic growth. In the present study, we analyzed the importance of dysregulated metabolism in cancer formation, by giving examples of lipolytic enzyme acyl-CoA thioesterase 8 (ACOT8)-increased HCC formation in vitro, lipolytic enzyme ACOT7-increased breast cancer formation in vitro, and arginine producing enzyme argininosuccinate lyase (ASL)-cell cycle regulator cyclin A2 (CCNA2) interaction-increased HCC promotion and ASL-increased HCC progression regarding drug resistance in vitro. We found that in the part of ACOT8-increased HCC formation in vitro, ACOT8 gene copy number and mRNA expression are increased in HCC compared to those of non-tumor liver tissues with bioinformatic analysis, and ACOT8 knockdown decreased HCC formation which could be compensated with ACOT8 overexpression and downstream lipid metabolite myristic acid with in vitro assays; in the part of ACOT7-increased breast cancer formation in vitro, ACOT7 in breast cancer displays strongest association in ACOT member-connected cancer prognosis which further links to altered lipid metabolism and can be counteracted with aromatase- and PI3K-antagonists with systematically bioinformatic analysis, and ACOT7 knockdown decreased breast cancer formation which could be compensated with downstream lipid metabolite palmitic acid, while ACOT7 overexpression increased breast cancer formation which could be counteracted with aromatase- and PI3K-antagonists with in vitro assays; in the part of ASL-CCNA2 interaction-increased HCC promotion and ASL-increased HCC progression regarding drug resistance in vitro, ASL colocalized and interacted with CCNA2 in the cytosol of HCC cells requiring no their molecular functions, and their interaction compensated ASL knockdown-decreased HCC formation, as well as ASL overexpression increased drug resistance against arginine deprivation therapy ADI-PEG with in vitro assays, with ASL-regulated HCC involves pathways including cell cycle progression and can be counteracted with predicted therapeutics bisoprolol, celecoxib, and ipratropium bromide with bioinformatic analysis. Above studies thus suggest the importance of dysregulated metabolism in cancer formation of multiple origins, taking lipolysis in HCC and breast cancer formation as well as arginine metabolism in HCC formation as examples.

Contents
Abstract in Chinese…………………………………………………………..…	i
Abstract…………………………………………………………………………	iii
Acknowledgement………………………………………………………………	v
Contents…………………………………………………………………………	vi

Introduction
1.	Cancer metabolism as a target in cancer research and treatment………	1
2.	Primary liver cancer cells modulate lipid metabolism including those resulted from acyl-CoA thioesterases to support neoplasia formation……………………………………………………………………	3
3.	Primary liver cancer cells regulate amino acid metabolism including those resulted from argininosuccinate lyase to promote tumor development…………………………………………………………………	5

Research Aims………………………………………………………	7

Materials and Methods
1.	ACOT8 promotes HCC in vitro………………………………………........	8
2.	ACOT7 promotes breast cancer in vitro……………………………......…	11
3.	ASL-CCNA2 interaction promotes HCC in vitro……………...................	15

Results
1.	ACOT8 promotes HCC in vitro……………………………………………	21
2.	ACOT7 promotes breast cancer in vitro…………………………………..	23
3.	ASL-CCNA2 interaction promotes HCC in vitro…………………………	28

Discussion
1.	ACOT8 promotes HCC in vitro……………………………………………	31
2.	ACOT7 promotes breast cancer in vitro…………………………………..	33
3.	ASL-CCNA2 interaction promotes HCC in vitro…………………………	35

Conclusion…………………………………………………………..	37

References…………………………………………………………...	38

Figures and Tables
Table 1-1. GEO datasets applied in analysis of ACOT8 gene copy number and mRNA expression alteration in HCC verse non-tumor liver tissues……………………………………………………………………………	54
Figure 1-1. Gene copy number of ACOT8 is increased in HCC……………..	55
Figure 1-2. mRNA expression of ACOT8 is increased in HCC…………........	56
Figure 1-3. Knockdown of ACOT8 decreases HCC growth in vitro................	57
Figure 1-4. Silencing of ACOT8 decreases thioesterase activity………...…...	58
Figure 1-5. ACOT8 knockdown-decreased HCC proliferation in vitro is compensated by ACOT8 overexpression……………………………………	59
Figure 1-6. ACOT8 knockdown-decreased HCC growth in vitro is partially compensated by its downstream metabolite myristic acid...............................	60
Table 2-1. Systematically bioinformatic analysis with PrognoScan and GEO databases reveals altered ACOT member expression is associated with cancer overall survival (OS).......................................................................	61
Table 2-2. Systematically bioinformatic analysis with PrognoScan and GEO databases reveals altered ACOT member expression is associated with cancer disease-specific survival (DSS).......................................................	62
Table 2-3. Systematically bioinformatic analysis with PrognoScan and GEO databases reveals altered ACOT member expression is associated with cancer disease-free survival (DFS)……………………………………….	63
Table 2-4. Bioinformatic analysis with AmiGO database reveals ACOT7-high breast cancer associates with altered lipid metabolism.............	64
Table 2-5. Bioinformatic analysis with Connectivity Map database reveals ACOT7-high breast cancer can be targeted by aromatase- and PI3K-antagonists………………………………………………………………	66
Table 2-6. Bioinformatic analysis with GEO database reveals ACOT7 as a top-ranking gene in breast cancer formation....................................................	67
Table 2-7. Bioinformatic analysis with PrognoScan database reveals ACOT7 as a strong prognosis-predicting gene in breast cancer formation...	68
Figure 2-1. Diagram of overall study design......................................................	69
Figure 2-2. In vitro analysis reveals ACOT7 expression increased in malignant breast cancer cell line and its knockdown decreased breast cancer proliferation which could be compensated by downstream lipid metabolite palmitic acid………………………………………………………...	70
Figure 2-3. In vitro analysis reveals ACOT7 overexpression increased breast cancer growth which could be suppressed by predicted therapeutics……………………………………………………………………...	72
Figure 3-1. ASL interacts and colocalizes with cyclin A2 in the cytosol of HCC cells……………………………………………………………………….	74
Figure 3-2. Function-losing mutant ASL or cyclin A2 retains interaction with their wildtype interacting partner in HCC cells.......................................	76
Figure 3-3. Function-losing mutant ASL or cyclin A2 compensates ASL knockdown-decreased HCC growth in vitro…………………………….....	77
Figure 3-4. ASL overexpression increases drug resistance against arginine deprivation therapy in HCC in vitro………………………………………….	78
Table 3-1. Bioinformatic analysis with Metacore database reveals important pathways in ASL-regulated HCC proliferation…………………..	79
Figure 3-5. Diagram of bioinformatic analysis with Connectivity Map database revealing counteracting therapeutics for ASL-regulated HCC growth………………………………………………………………………........	81

                                    

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