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研究生:吳驊卿
研究生(外文):WU,HUA-QING
論文名稱:MicroRNA122對於肝細胞致癌現象的代謝通量分析
論文名稱(外文):Analysis of metabolic flux in hepatocyte: the influence of microRNA122 on carcinogenesis
指導教授:王逢盛
指導教授(外文):WANG, FENG-SHENG
口試委員:黃奇英鄒安平王逢盛
口試委員(外文):HUANG,QI-YINGZOU,AN-PINGWANG, FENG-SHENG
口試日期:2015-07-14
學位類別:碩士
校院名稱:國立中正大學
系所名稱:化學工程研究所
學門:工程學門
學類:化學工程學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:中文
論文頁數:80
中文關鍵詞:肝臟癌化Mir122aRecon2 liver model
外文關鍵詞:livercarcinogenesisRecon2 liver modelMir122a
相關次數:
  • 被引用被引用:0
  • 點閱點閱:179
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  • 下載下載:2
  • 收藏至我的研究室書目清單書目收藏:0
肝臟是人體最重要的代謝中心(人體的化工廠),許多物質和營養素都是在肝這個代謝中心進行代謝作用、轉化作用、解毒功能、合成蛋白質、排泄功能,因此肝在我們人體中扮演很重要的角色。在正常細胞的代謝活化主要依賴於粒線體氧化磷酸化(Oxidative phosphorylation)生成的三磷酸腺苷(Adenosine triphosphate,ATP)來提供能量,但在細胞趨向癌化的狀態,糖酵解(glycolysis) 路徑效能會增強,且比較傾向走產生乳酸(lactate)的路徑,而比較不走進入檸檬酸循環(TCA cycle)的路徑,符合這種現象的狀態稱做沃伯格效應(Warburg Effect)。本研究利用肝細胞代謝網路模型Recon2 liver model,在三磷酸腺苷(Adenosine triphosphate,ATP)最大化且內部通量最小化狀態下,進行通量均衡分析方法(Flux balance analysis, FBA)的計算。接著以陽明大學鄒安平教授團隊提供的老鼠 miR-122a target genes對應到Recon 2 liver model 共有20個target genes所表現的酵素,進行模擬突變通量均衡分析方法(Mutant Flux balance analysis, mFBA)的計算。FBA得到的穩態通量分佈,在與mFBA的穩態通量分布結果做比對,結果發現調控這20個miR-122a target genes中,有一半以上的酵素模擬結果與Warburg Effect 及實驗數據現象類似率達到50%以上。且我們也發現調控Ddc酵素模擬結果與Warburg effect的類似率高達到95%,所以在肝細胞癌化中扮演很重要的角色。
The liver was the the most important metabolic center in the human body (or the chemical plant of human body). Many substances and nutrients were processed by transformation, detoxification, protein synthesis and excretion in liver. Therefore, the liver played a critical role in our body .Ordinary cells depend on the metabolic activation of mitochondrial oxidative phosphorylation generating ATP to provide energy. But when it tended to become cancerous cell, the flux of glycolysis enhances and the reaction prefered to produce lactate rather than to participate the series reaction of tricarboxylic acid cycle (TCA cycle). In this study, the metabolic network model of liver cells Recon2 liver model, the analysis method (Flux balance analysis, FBA) was calculated optimal flux balance. Then the tumor suppressor gene Mir122a shave target gene, the method for analysis (Mutant Flux balance analysis, mFBA) mutant analog flux balance calculation. Steady-state flux distribution obtained FBA, in steady-state flux distribution with mFBA results do compare .The results indicated that over a half of these miR-122a target genes had fifty percent similarity to the analysis experimental data of Warburg effect & LC-MS And we also found that Ddc enzyme similar with Warburg effect to up to 95%.In conclusion ,Ddc played a critical role in the liver cell.
目錄
誌謝 2
摘要 1
ABSTRACT 3
表目錄 6
圖目錄 8
第一章 緒論 10
1.1前言 10
1.2文獻回顧 13
1.3 研究動機 15
1.4 組織章節 17
第二章 代謝網路生物資料庫及工具程式簡介 18
2.1生物資料庫簡介 18
2.1.1 BRaunschweig ENzyme Database (BRENDA ) 18
2.1.2 KEGG 20
2.2工具程式簡介 23
2.2.1 Model Transformation Program (MTP) 23
2.2.2 General Algebraic Modeling System (GAMS) 27
第三章 代謝網路模型與分析方法 29
3.1前言 29
3.2 肝細胞代謝網路模型 29
3.3 基本設定及計算方法介紹 33
3.3.1最佳化目標函數 33
3.3.2 計算方法介紹 34
第四章 結果與討論 43
4.1前言 43
4.2 MIR-122A TARGET GENES 所表現的酵素 43
4.2.1 Ddc酵素表現量上升模擬結果 50
4.2.2 其他target genes表現量上升模擬結果 62
第五章 結論與未來展望 67
5.1 結論 67
5.2 未來展望與建議 68
第六章 參考文獻 69
附錄A 72
附錄B 78

[1]H. Kitano, Foundations of systems biology: MIT press Cambridge, 2001.
[2]K. J. Kauffman, P. Prakash, and J. S. Edwards, "Advances in flux balance analysis," Current opinion in biotechnology, vol. 14, pp. 491-496, 2003.
[3]S. Schuster, T. Dandekar, and D. A. Fell, "Detection of elementary flux modes in biochemical networks: a promising tool for pathway analysis and metabolic engineering," Trends in biotechnology, vol. 17, pp. 53-60, 1999.
[4]C. H. Schilling, D. Letscher, and B. Ø. Palsson, "Theory for the systemic definition of metabolic pathways and their use in interpreting metabolic function from a pathway-oriented perspective," Journal of theoretical biology, vol. 203, pp. 229-248, 2000.
[5]W. H. Koppenol, P. L. Bounds, and C. V. Dang, "Otto Warburg's contributions to current concepts of cancer metabolism," Nature Reviews Cancer, vol. 11, pp. 325-337, 2011.
[6]G. Kroemer and J. Pouyssegur, "Tumor cell metabolism: cancer's Achilles' heel," Cancer cell, vol. 13, pp. 472-482, 2008.
[7]V. R. Fantin, J. St-Pierre, and P. Leder, "Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance," Cancer cell, vol. 9, pp. 425-434, 2006.
[8]P. P. Hsu and D. M. Sabatini, "Cancer cell metabolism: Warburg and beyond," Cell, vol. 134, pp. 703-707, 2008.
[9]H. Y. Lim, Q. S. Ho, J. Low, M. Choolani, and K. P. Wong, "Respiratory competent mitochondria in human ovarian and peritoneal cancer," Mitochondrion, vol. 11, pp. 437-443, 2011.
[10]X. L. Zu and M. Guppy, "Cancer metabolism: facts, fantasy, and fiction," Biochemical and biophysical research communications, vol. 313, pp. 459-465, 2004.
[11]H. Kitano, "Systems biology: a brief overview," Science, vol. 295, pp. 1662-1664, 2002.
[12]N. Wiener, Cybernetics or Control and Communication in the Animal and the Machine vol. 25: MIT press, 1965.
[13]L. Von Bertalanffy, "General system theory: Foundations, development, applications," 1968.
[14]I. Thiele, N. Swainston, R. M. Fleming, A. Hoppe, S. Sahoo, M. K. Aurich, et al., "A community-driven global reconstruction of human metabolism," Nature biotechnology, vol. 31, pp. 419-425, 2013.
[15]W.-C. Tsai, S.-D. Hsu, C.-S. Hsu, T.-C. Lai, S.-J. Chen, R. Shen, et al., "MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis," The Journal of clinical investigation, vol. 122, p. 2884, 2012.
[16]J. Fan, J. Ye, J. J. Kamphorst, T. Shlomi, C. B. Thompson, and J. D. Rabinowitz, "Quantitative flux analysis reveals folate-dependent NADPH production," Nature, vol. 510, pp. 298-302, 2014.
[17]I. Schomburg, A. Chang, C. Ebeling, M. Gremse, C. Heldt, G. Huhn, et al., "BRENDA, the enzyme database: updates and major new developments," Nucleic acids research, vol. 32, pp. D431-D433, 2004.
[18]M. Kanehisa, S. Goto, Y. Sato, M. Furumichi, and M. Tanabe, "KEGG for integration and interpretation of large-scale molecular data sets," Nucleic acids research, p. gkr988, 2011.
[19]N. C. Duarte, S. A. Becker, N. Jamshidi, I. Thiele, M. L. Mo, T. D. Vo, et al., "Global reconstruction of the human metabolic network based on genomic and bibliomic data," Proceedings of the National Academy of Sciences, vol. 104, pp. 1777-1782, 2007.
[20]H. Ma, A. Sorokin, A. Mazein, A. Selkov, E. Selkov, O. Demin, et al., "The Edinburgh human metabolic network reconstruction and its functional analysis," Molecular systems biology, vol. 3, p. 135, 2007.
[21]C. Gille, C. Bölling, A. Hoppe, S. Bulik, S. Hoffmann, K. Hübner, et al., "HepatoNet1: a comprehensive metabolic reconstruction of the human hepatocyte for the analysis of liver physiology," Molecular systems biology, vol. 6, p. 411, 2010.
[22]B. W. Trotman, S. E. Bernstein, W. F. Balistreri, G. D. Wirt, and R. A. Martin, "Hemolysis-induced gallstones in mice: increased unconjugated bilirubin in hepatic bile predisposes to gallstone formation," Gastroenterology, vol. 81, p. 6, 1981.
[23]K. Fukumoto, S. Kikuchi, N. Itoh, A. Tamura, M. Hata, H. Yamagishi, et al., "Effects of genetic backgrounds on hyperbilirubinemia in radixin-deficient mice due to different expression levels of Mrp3," Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, vol. 1772, pp. 298-306, 2007.
[24]T. Vera and D. E. Stec, "Moderate hyperbilirubinemia improves renal hemodynamics in ANG II-dependent hypertension," American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, vol. 299, pp. R1044-R1049, 2010.
[25]V. Rottiers and A. M. Näär, "MicroRNAs in metabolism and metabolic disorders," Nature reviews Molecular cell biology, vol. 13, pp. 239-250, 2012.
[26]W. C. Tsai, P. W. C. Hsu, T. C. Lai, G. Y. Chau, C. W. Lin, C. M. Chen, et al., "MicroRNA‐122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma," Hepatology, vol. 49, pp. 1571-1582, 2009.
[27]S.-h. Hsu, B. Wang, J. Kota, J. Yu, S. Costinean, H. Kutay, et al., "Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver," The Journal of clinical investigation, vol. 122, p. 2871, 2012.
[28]D. G. Mappouras, J. Stiakakis, and E. G. Fragoulis, "Purification and characterization of L-dopa decarboxylase from human kidney," Molecular and cellular biochemistry, vol. 94, pp. 147-156, 1990.
[29]M.-Z. Siaterli, D. Vassilacopoulou, and E. G. Fragoulis, "Cloning and expression of human placental L-Dopa decarboxylase," Neurochemical research, vol. 28, pp. 797-803, 2003.
[30]M. Berry, A. Juorio, X.-M. Li, and A. Boulton, "Aromaticl-amino acid decarboxylase: A neglected and misunderstood enzyme," Neurochemical research, vol. 21, pp. 1075-1087, 1996.
[31]J. G. Christenson, W. Dairman, and S. Udenfriend, "On the identity of DOPA decarboxylase and 5-hydroxytryptophan decarboxylase," Proceedings of the National Academy of Sciences, vol. 69, pp. 343-347, 1972.
[32]Y. Asgari, Z. Zabihinpour, A. Salehzadeh-Yazdi, F. Schreiber, and A. Masoudi-Nejad, "Alterations in cancer cell metabolism: The Warburg effect and metabolic adaptation," Genomics, vol. 105, pp. 275-281, 2015.
[33]M. Upadhyay, J. Samal, M. Kandpal, O. V. Singh, and P. Vivekanandan, "The Warburg effect: insights from the past decade," Pharmacology & therapeutics, vol. 137, pp. 318-330, 2013.
[34]W. L. McKeehan and K. A. McKeehan, "Changes in NAD (P)+‐dependent malic enzyme and malate dehydrogenase activities during fibroblast proliferation," Journal of cellular physiology, vol. 110, pp. 142-148, 1982.
[35]R. Moreadith, and and A. Lehninger, "The pathways of glutamate and glutamine oxidation by tumor cell mitochondria. Role of mitochondrial NAD (P)+-dependent malic enzyme," Journal of Biological Chemistry, vol. 259, pp. 6215-6221, 1984.



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