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系統識別號 U0026-0812200915134771
論文名稱(中文) 以系統化方法從抗藥性與DNA損害反應建構差異表現網路 - 以卵巢癌與非小型細胞肺癌為例
論文名稱(英文) A Systematic Approach to Construct Differential Expression Network during Drug Resistance and DNA Damage Response
校院名稱 成功大學
系所名稱(中) 醫學資訊研究所
系所名稱(英) Institute of Medical Informatics
學年度 97
學期 2
出版年 98
研究生(中文) 張菀珊
研究生(英文) Woan-Shan Chang
學號 q5696401
學位類別 碩士
語文別 中文
論文頁數 114頁
口試委員 指導教授-蔣榮先
口試委員-辛致煒
口試委員-黃阿梅
口試委員-趙士儀
中文關鍵字 子網路  K條最短路徑  DNA損害修補  化療  抗藥性 
英文關鍵字 chemotherapy  drug resistance  sub-network  K-shortest paths  DNA damage repair 
學科別分類
中文摘要 癌症,是目前國人十大死因的第一位。治療癌症最常用的是化學療法,然而影響化療效果即為抗藥性的產生,一旦抗藥性在治療癌症過程中發生,治療癌症的效果將大打折扣。因此,癌症與藥物的抗藥性是這幾年治療癌症的首要課題之一。化療抗藥性的種類有很多種,以鉑類藥物為例,是為DNA烷化劑,所產生的抗藥性包含降低細胞內藥物累積量、改變細胞訊號傳遞路徑與增加DNA損害修補等。目前有許多化療抗藥性研究,大多僅止於從抗藥性基因表現量差異找出可能具有抗藥性的基因,但是對於抗藥性的機制仍然是未知。然而,如果我們越了解抗藥性的作用機轉,則可以研發出更多有效治療癌症的方法。因此,如果能夠考慮基因所參與跟抗藥性有關的生物反應途徑,並且合併多個反應途徑加以觀察分析,更能夠從中識別出抗藥性的機轉,挑出的抗藥性基因也較為準確且可信。本論文以DNA損害修補相關抗藥性的生物反應途徑,保留原始的方向,建構出DNA損害修補的大型網路,利用K條最短路徑演算法,透過抗藥性之microarray的基因表現差異值,識別出以方向性為導向的抗藥性子網路。提供化療抗藥性的機制和參與的基因是否具有引起抗藥性反應的可能。最後,本論文以系統化的方式識別出與抗藥性相關的機轉和與抗藥性相關之基因,同時也利用文獻證實。最後,透過本論文之方法,期許未來能夠找出在化療抗藥性中關鍵的機轉與基因,以發展更多治療癌症的方法。
英文摘要 Chemotherapy (CT) resistance is a common clinical problem in cancer patients; therefore, new strategies and therapeutic drugs are needed to tackle this problem. Platinum-based chemotherapy drugs have been used clinically for the treatment of many types of cancers. Resistance of the drugs could be caused by different mechanisms, including reduced intracellular drug accumulation, increased detoxification of drug by thiol-containing molecules, increased DNA damage repair, and altered cell signaling pathways and apoptosis mediators. Few systematic approaches have been developed to analyze and study the related biological pathways associated with drug resistance in CT. However, those studies play important roles in explaining the unknown resistance mechanism through known biological pathways. Our method is based on the construction of large network given DNA damage repair of resistance mechanism. We can identify the direction-oriented sub-networks related drug resistance using the K-shortest loopless paths algorithm from the large network. Through the gene expression data in drug response, we filter and score the sub-networks. Researchers are able to gain information of gene mechanisms in response to drug treatment in CT and identify important genes related CT resistance from the sub-networks. Finally, we explore gene mechanisms and the gene list associated with CT resistance. Those results are partially validated by literature reports. We anticipate this approach will be able to accelerate target identification and drug development for CT resistance in the future.
論文目次 第一章 導論 1
1.1 背景 1
1.2 動機 3
1.3 預期貢獻 5
第二章 文獻回顧與相關研究 7
2.1 生物反應路徑、轉錄因子與蛋白質交互作用資料庫 7
2.1.1 KEGG (Kyoto Encyclopedia of Genes and Genomes) 7
2.1.2 PID (Pathway Interaction Database) 8
2.1.3 TRANSFAC 9
2.1.4 Reactome 10
2.2 化療藥物抗藥性相關研究 10
2.2.1 抗藥性的文獻探勘 11
2.2.2 轉錄因子及其相關黏合序列 11
2.2.3 化療抗藥性與microarray之相關研究 12
2.3 生物反應路徑建構方法 13
2.4 K條最短非循環式路徑 15
第三章 識別DNA損害相關之抗藥性子網路 18
3.1 識別抗藥性子網路之流程概述 18
3.2 大型網路的建構 19
3.2.1 基因關係合併 20
3.2.2 循環式節點合併 23
3.3 Seed nodes的選取條件 25
3.4 識別、記分與過濾抗藥性子網路 26
3.5 差別子網路分析 28
第四章 實驗設計與結果分析 31
4.1 大型生物網路之資料來源 31
4.1.1 卵巢癌 32
4.1.2 非小型細胞肺癌 33
4.1.3 膀胱癌 33
4.2 實驗用seed nodes選取 35
4.3 抗藥性子網路符號說明 35
4.4 抗藥性子網路實驗設計 37
4.4.1 單一實驗之抗藥性子網路實驗設計 38
4.4.2 不同實驗之交集抗藥性子網路實驗設計 38
4.5 抗藥性子網路結果分析 40
4.5.1 單一實驗之抗藥性子網路結果分析 41
4.5.2 不同實驗之交集抗藥性子網路結果分析 45
第五章 結論與未來研究方向 77
5.1 結論 77
5.2 未來研究方向 78
參考文獻 80
附錄一 生物反應途徑(KEGG和PID) 85
附錄二 交集抗藥性子網路 98
參考文獻 [1] BioCarta. Available from: http://www.biocarta.com/.
[2] Almeida, G.M., et al., Multiple end-point analysis reveals cisplatin damage tolerance to be a chemoresistance mechanism in a NSCLC model: Implications for predictive testing. International Journal of Cancer, 2008. 122(8): p. 1810-1819.
[3] Auner, V., et al., KRAS mutation analysis in ovarian samples using a high sensitivity biochip assay. BMC Cancer, 2009. 9(1): p. 111.
[4] Boatright, K.M. and G.S. Salvesen, Mechanisms of caspase activation. Current Opinion in Cell Biology, 2003. 15(6): p. 725-731.
[5] Brozovic, A. and M. Osmak, Activation of mitogen-activated protein kinases by cisplatin and their role in cisplatin-resistance. Cancer Letters, 2007. 251(1): p. 1-16.
[6] Cabusora, L., et al., Differential network expression during drug and stress response. Bioinformatics, 2005. 21(12): p. 2898-2905.
[7] Casciato, D.A. and M.C. Territo, Manual of Clinical Oncology. 6 ed. 2008.
[8] Chen, Y.-J., J. Sims-Mourtada, and J.I.a.K.S.C. Chao, Targeting the Hedgehog Pathway to Mitigate Treatment Resistance. Cell Cycle 2007. 6(15): p. 1826-1830.
[9] Corn, P.G. and W.S. El-Deiry, Microarray Analysis of p53-Dependent Gene Expression in Response to Hypoxia and DNA Damage Cancer Biology & Therapy 2007. 6(12): p. 1858-1866.
[10] Dijkstra, E.W., A note on two problems in connexion with graphs. Numerische Mathematik, 1959. 1.
[11] Dummler, B. and B.A. Hemmings, Physiological roles of PKB/Akt isoforms in development and disease. Biochemical Society Transactions, 2007. 035(2): p. 231-235.
[12] Fraser, M., et al., Chemoresistance in human ovarian cancer: the role of apoptotic regulators. Reproductive Biology and Endocrinology, 2003. 1(1): p. 66.
[13] Gagnon, V., et al., AKT involvement in cisplatin chemoresistance of human uterine cancer cells. Gynecologic Oncology, 2004. 94(3): p. 785-795.
[14] Hennessy, B.T., et al., Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery. Nat Rev Drug Discov, 2005. 4(12): p. 988-1004.
[15] Hershberger, J., M. Maxel, and S. Suri, Finding the k shortest simple paths: A new algorithm and its implementation. ACM Trans. Algorithms, 2007. 3(4): p. 45.
[16] Hintze, A. and C. Adami, Evolution of Complex Modular Biological Networks. PLoS Comput Biol, 2008. 4(2): p. e23.
[17] Huang, Y. and W. Sadée, Drug sensitivity and resistance genes in cancer chemotherapy: a chemogenomics approach. Drug Discovery Today, 2003. 8(8): p. 356-363.
[18] Institute, N.C. Non-Small Cell Lung Cancer Treatment 2008; Available from: http://www.cancer.gov/CANCERTOPICS/PDQ/TREATMENT/NON-SMALL-CELL-LUNG/PATIENT#Keypoint1.
[19] J.H. Hong, E.L., J. Hong, Y.J. Shin, H. Ahn,, Antisense Bcl2 oligonucleotide in cisplatin-resistant bladder cancer cell lines. BJU International, 2002. 90(1): p. 113-117.
[20] Ji-Youn Han, G.K.L., Dae Ho Jang, Sung Young Lee, Jin Soo Lee,, Association of p53 codon 72 polymorphism and MDM2 SNP309 with clinical outcome of advanced nonsmall cell lung cancer. Cancer, 2008. 113(4): p. 799-807.
[21] Kajta, M., et al., Aryl hydrocarbon receptor-mediated apoptosis of neuronal cells: A possible interaction with estrogen receptor signaling. Neuroscience, 2009. 158(2): p. 811-822.
[22] Kanehisa, M., et al., KEGG for linking genomes to life and the environment. Nucl. Acids Res., 2008. 36(suppl_1): p. D480-484.
[23] Karlebach, G. and R. Shamir, Modelling and analysis of gene regulatory networks. Nat Rev Mol Cell Biol, 2008. 9(10): p. 770-780.
[24] Kohno, K., et al., Transcription factors and drug resistance. European Journal of Cancer, 2005. 41(16): p. 2577-2586.
[25] L'Espérance, S., et al., Gene expression profiling of paired ovarian tumors obtained prior to and following adjuvant chemotherapy: Molecular signatures of chemoresistant tumors. International Journal of Oncology, 2006. 29: p. 5-24.
[26] Lee, S., et al., Activation of PI3K/Akt pathway by PTEN reduction and PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cell line. Gynecologic Oncology, 2005. 97(1): p. 26-34.
[27] Li, F., et al., Reversing chemoresistance in cisplatin-resistant human ovarian cancer cells: A role of c-Jun NH2-terminal kinase 1. Biochemical and Biophysical Research Communications, 2005. 335(4): p. 1070-1077.
[28] Li, M., et al., Enriched transcription factor binding sites in hypermethylated gene promoters in drug resistant cancer cells. Bioinformatics, 2008. 24(16): p. 1745-1748.
[29] Lipinski, R.J., et al., Unique and complimentary activities of the Gli transcription factors in Hedgehog signaling. Experimental Cell Research, 2006. 312(11): p. 1925-1938.
[30] Matthews, L., et al., Reactome knowledgebase of human biological pathways and processes. Nucl. Acids Res., 2009. 37(suppl_1): p. D619-622.
[31] Matys, V., et al., TRANSFAC(R): transcriptional regulation, from patterns to profiles. Nucl. Acids Res., 2003. 31(1): p. 374-378.
[32] Moriyama, M., et al., Relevance Network between Chemosensitivity and Transcriptome in Human Hepatoma Cells1. Molecular Cancer Therapeutics, 2003. 2(2): p. 199-205.
[33] Moulay, A.A.-J., D. Isabelle, and Q. He, Prediction of drug sensitivity and drug resistance in cancer by transcriptional and proteomic profiling. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy, 2004. 7(4): p. 245-255.
[34] Myoung Woo Lee, D.S.K., Na Young Min, Heung Tae Kim,, Akt1 inhibition by RNA interference sensitizes human non-small cell lung cancer cells to cisplatin. International Journal of Cancer, 2008. 122(10): p. 2380-2384.
[35] Nagata, S., Apoptosis by Death Factor. Cell, 1997. 88(3): p. 355-365.
[36] Nakatsu, N., et al., Chemosensitivity profile of cancer cell lines and identification of genes determining chemosensitivity by an integrated bioinformatical approach using cDNA arrays. Molecular Cancer Therapeutics, 2005. 4(3): p. 399-412.
[37] Nikolsky, Y., T. Nikolskaya, and A. Bugrim, Biological networks and analysis of experimental data in drug discovery. Drug Discovery Today, 2005. 10(9): p. 653-662.
[38] O'Shea, J.J., M. Gadina, and R.D. Schreiber, Cytokine Signaling in 2002: New Surprises in the Jak/Stat Pathway. 2002. 109(2): p. S121-S131.
[39] Ohta, T., et al., Inhibition of Phosphatidylinositol 3-Kinase Increases Efficacy of Cisplatin in in Vivo Ovarian Cancer Models. Endocrinology, 2006. 147(4): p. 1761-1769.
[40] Parsons, J.T., Focal adhesion kinase: the first ten years. J Cell Sci, 2003. 116(8): p. 1409-1416.
[41] Peters, D., J. Freund, and R.L. Ochs, Genome-wide transcriptional analysis of carboplatin response in chemosensitive and chemoresistant ovarian cancer cells. Mol Cancer Ther, 2005. 4(10): p. 1605-1616.
[42] PU, Y.-S., et al., Cross-resistance and combined cytotoxic effects of paclitaxel and cisplatin in bladder cancer cells. The Journal of Urology 2001. 165(6): p. 2082-2085.
[43] Rabik, C.A. and M.E. Dolan, Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treatment Reviews, 2007. 33(1): p. 9-23.
[44] Raspollini, M.R., et al., c-KIT expression and correlation with chemotherapy resistance in ovarian carcinoma: an immunocytochemical study. Ann Oncol, 2004. 15(4): p. 594-597.
[45] Riedel, R.F., et al., A genomic approach to identify molecular pathways associated with chemotherapy resistance. Molecular Cancer Therapeutics, 2008. 7(10): p. 3141-3149.
[46] Schaefer, C.F., et al., PID: the Pathway Interaction Database. Nucl. Acids Res., 2008: p. gkn653.
[47] Scott, J.P., Social Network Analysis: A Handbook (Paperback). 2 ed. 2000.
[48] Sekine, I., et al., Genes Regulating the Sensitivity of Solid Tumor Cell Lines to Cytotoxic Agents: A Literature Review. Jpn. J. Clin. Oncol., 2007. 37(5): p. 329-336.
[49] Seth, A., Transcription factors in cancer. European Journal of Cancer, 2005. 41(16): p. 2379-2380.
[50] Siddik, Z.H., Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene, 2003. 22(47): p. 7265-7279.
[51] Stein, J.P., et al., Radical Cystectomy in the Treatment of Invasive Bladder Cancer: Long-Term Results in 1,054 Patients. J Clin Oncol, 2001. 19(3): p. 666-675.
[52] Stella Okouoyo, K.H., Esat Ucur, Jgen Mattern, Peter H. Krammer, Klaus-Michael Debatin, Ingrid Herr,, Rescue of death receptor and mitochondrial apoptosis signaling in resistant human NSCLC in vivo. International Journal of Cancer, 2004. 108(4): p. 580-587.
[53] T.A. GATCLIFFE, B.J.M., K. PLANUTIS, R.F. HOLCOMBE,, Wnt signaling in ovarian tumorigenesis. International Journal of Gynecological Cancer, 2008. 18(5): p. 954-962.
[54] Tamada, Y., et al., Identifying Drug Active Pathways from Gene Networks Estimated by Gene Expression Data. Genome Informatics, 2005. 16(1).
[55] Torigoe, T., et al., Cisplatin Resistance and Transcription Factors. Current Medicinal Chemistry - Anti-Cancer Agents, 2005. 5: p. 15-27.
[56] Wang, Z., et al., Emerging role of Notch in stem cells and cancer. Cancer Letters, 2009. 279(1): p. 8-12.
[57] Wang, Z., et al., Mitogen-Activated Protein Kinase Phosphatase-1 Is Required for Cisplatin Resistance. Cancer Res, 2006. 66(17): p. 8870-8877.
[58] Weaver, D., et al., ABCC5, ERCC2, XPA and XRCC1 transcript abundance levels correlate with cisplatin chemoresistance in non-small cell lung cancer cell lines. Molecular Cancer, 2005. 4(1): p. 18.
[59] Yen, J., Finding the K shortest loopless paths in a network. Management Science, 1971. 17(11).
[60] Yu, H.J., et al., Characterization of a newly established human bladder carcinoma cell line, NTUB1. Journal of the Formosan Medical Association 19(6): p. 608-13.
[61] 行政院衛生署. 民國96年主要死因統計. Available from: .
[62] 醫療財團法人辜公亮基金會和信治癌中心醫院. 癌症知識庫. Available from: http://www.kfsyscc.org/.
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