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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 阮雪芬(Hsueh-Fen Juan) | |
dc.contributor.author | Xiang-Jun Chen | en |
dc.contributor.author | 陳湘鈞 | zh_TW |
dc.date.accessioned | 2021-06-08T01:48:23Z | - |
dc.date.copyright | 2016-08-24 | |
dc.date.issued | 2016 | |
dc.date.submitted | 2016-08-02 | |
dc.identifier.citation | 1. Siegel, R. L., Miller, K. D., and Jemal, A. (2015) Cancer statistics, 2015. CA Cancer J Clin 65, 5-29
2. Nawaz, K., and Webster, R. M. (2016) The non-small-cell lung cancer drug market. Nat Rev Drug Discov 15, 229-230 3. Lemjabbar-Alaoui, H., Hassan, O. U., Yang, Y. W., and Buchanan, P. (2015) Lung cancer: Biology and treatment options. Biochim Biophys Acta 1856, 189-210 4. Li, J., Deng, H., Hu, M., Fang, Y., Vaughn, A., Cai, X., Xu, L., Wan, W., Li, Z., Chen, S., Yang, X., Wu, S., and Xiao, J. (2015) Inhibition of non-small cell lung cancer (NSCLC) growth by a novel small molecular inhibitor of EGFR. Oncotarget 6, 6749-6761 5. Bordi, P., Del Re, M., Danesi, R., and Tiseo, M. (2015) Circulating DNA in diagnosis and monitoring EGFR gene mutations in advanced non-small cell lung cancer. Transl Lung Cancer Res 4, 584-597 6. Zhang, X., Gureasko, J., Shen, K., Cole, P. A., and Kuriyan, J. (2006) An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 125, 1137-1149 7. Cao, W., Liu, Y., Zhang, R., Zhang, B., Wang, T., Zhu, X., Mei, L., Chen, H., Zhang, H., Ming, P., and Huang, L. (2015) Homoharringtonine induces apoptosis and inhibits STAT3 via IL-6/JAK1/STAT3 signal pathway in Gefitinib-resistant lung cancer cells. Sci Rep 5, 8477 8. Sun, Z., Li, Q., Zhang, S., Chen, J., Huang, L., Ren, J., Chang, Y., Liang, Y., and Wu, G. (2015) NVP-BEZ235 overcomes gefitinib-acquired resistance by down-regulating PI3K/AKT/mTOR phosphorylation. Onco Targets Ther 8, 269-277 9. von Ballmoos, C., Wiedenmann, A., and Dimroth, P. (2009) Essentials for ATP synthesis by F1F0 ATP synthases. Annu Rev Biochem 78, 649-672 10. Weber, J., and Senior, A. E. (1997) Catalytic mechanism of F1-ATPase. Biochim Biophys Acta 1319, 19-58 11. Pedersen, P. L., and Amzel, L. M. (1993) ATP synthases. Structure, reaction center, mechanism, and regulation of one of nature's most unique machines. J Biol Chem 268, 9937-9940 12. Pedersen, P. L., Ko, Y. H., and Hong, S. (2000) ATP synthases in the year 2000: evolving views about the structures of these remarkable enzyme complexes. J Bioenerg Biomembr 32, 325-332 13. Das, B., Mondragon, M. O., Sadeghian, M., Hatcher, V. B., and Norin, A. J. (1994) A novel ligand in lymphocyte-mediated cytotoxicity: expression of the beta subunit of H+ transporting ATP synthase on the surface of tumor cell lines. J Exp Med 180, 273-281 14. Johnson, J. A., and Ogbi, M. (2011) Targeting the F1Fo ATP Synthase: modulation of the body's powerhouse and its implications for human disease. Curr Med Chem 18, 4684-4714 15. Burrell, H. E., Wlodarski, B., Foster, B. J., Buckley, K. A., Sharpe, G. R., Quayle, J. M., Simpson, A. W., and Gallagher, J. A. (2005) Human keratinocytes release ATP and utilize three mechanisms for nucleotide interconversion at the cell surface. J Biol Chem 280, 29667-29676 16. Huang, T. C., Chang, H. Y., Hsu, C. H., Kuo, W. H., Chang, K. J., and Juan, H. F. (2008) Targeting therapy for breast carcinoma by ATP synthase inhibitor aurovertin B. J Proteome Res 7, 1433-1444 17. Martinez, L. O., Jacquet, S., Esteve, J. P., Rolland, C., Cabezon, E., Champagne, E., Pineau, T., Georgeaud, V., Walker, J. E., Terce, F., Collet, X., Perret, B., and Barbaras, R. (2003) Ectopic beta-chain of ATP synthase is an apolipoprotein A-I receptor in hepatic HDL endocytosis. Nature 421, 75-79 18. Moser, T. L., Kenan, D. J., Ashley, T. A., Roy, J. A., Goodman, M. D., Misra, U. K., Cheek, D. J., and Pizzo, S. V. (2001) Endothelial cell surface F1-F0 ATP synthase is active in ATP synthesis and is inhibited by angiostatin. Proc Natl Acad Sci U S A 98, 6656-6661 19. Yamamoto, K., Shimizu, N., Obi, S., Kumagaya, S., Taketani, Y., Kamiya, A., and Ando, J. (2007) Involvement of cell surface ATP synthase in flow-induced ATP release by vascular endothelial cells. Am J Physiol Heart Circ Physiol 293, H1646-1653 20. Xing, S. L., Yan, J., Yu, Z. H., and Zhu, C. Q. (2011) Neuronal cell surface ATP synthase mediates synthesis of extracellular ATP and regulation of intracellular pH. Cell Biol Int 35, 81-86 21. Schmidt, C., Lepsverdize, E., Chi, S. L., Das, A. M., Pizzo, S. V., Dityatev, A., and Schachner, M. (2008) Amyloid precursor protein and amyloid beta-peptide bind to ATP synthase and regulate its activity at the surface of neural cells. Mol Psychiatry 13, 953-969 22. Mowery, Y. M., and Pizzo, S. V. (2008) Targeting cell surface F1F0 ATP synthase in cancer therapy. Cancer Biol Ther 7, 1836-1838 23. Wang, W. J., Ma, Z., Liu, Y. W., He, Y. Q., Wang, Y. Z., Yang, C. X., Du, Y., Zhou, M. Q., and Gao, F. (2012) A monoclonal antibody (Mc178-Ab) targeted to the ecto-ATP synthase beta-subunit-induced cell apoptosis via a mechanism involving the MAPKase and Akt pathways. Clin Exp Med 12, 3-12 24. Chi, S. L., and Pizzo, S. V. (2006) Angiostatin is directly cytotoxic to tumor cells at low extracellular pH: a mechanism dependent on cell surface-associated ATP synthase. Cancer Res 66, 875-882 25. Chang, H. Y., Huang, T. C., Chen, N. N., Huang, H. C., and Juan, H. F. (2014) Combination therapy targeting ectopic ATP synthase and 26S proteasome induces ER stress in breast cancer cells. Cell Death Dis 5, e1540 26. Chang, H. Y., Huang, H. C., Huang, T. C., Yang, P. C., Wang, Y. C., and Juan, H. F. (2012) Ectopic ATP synthase blockade suppresses lung adenocarcinoma growth by activating the unfolded protein response. Cancer Res 72, 4696-4706 27. Linnett, P. E., Mitchell, A. D., Osselton, M. D., Mulheirn, L. J., and Beechey, R. B. (1978) Citreoviridin, a specific inhibitor of the mitochondiral adenosine triphosphatase. Biochem J 170, 503-510 28. Gause, E. M., Buck, M. A., and Douglas, M. G. (1981) Binding of citreoviridin to the beta subunit of the yeast F1-ATPase. J Biol Chem 256, 557-559 29. Nishie, K., Cole, R. J., and Dorner, J. W. (1988) Toxicity of citreoviridin. Res Commun Chem Pathol Pharmacol 59, 31-52 30. Sun, S. (2010) Chronic exposure to cereal mycotoxin likely citreoviridin may be a trigger for Keshan disease mainly through oxidative stress mechanism. Med Hypotheses 74, 841-842 31. Hu, C. W., Hsu, C. L., Wang, Y. C., Ishihama, Y., Ku, W. C., Huang, H. C., and Juan, H. F. (2015) Temporal Phosphoproteome Dynamics Induced by an ATP Synthase Inhibitor Citreoviridin. Mol Cell Proteomics 14, 3284-3298 32. Wang, Y., Liu, Y., Liu, X., Jiang, L., Yang, G., Sun, X., Geng, C., Li, Q., Yao, X., and Chen, M. (2015) Citreoviridin Induces Autophagy-Dependent Apoptosis through Lysosomal-Mitochondrial Axis in Human Liver HepG2 Cells. Toxins (Basel) 7, 3030-3044 33. Liu, Y. N., Wang, Y. X., Liu, X. F., Jiang, L. P., Yang, G., Sun, X. C., Geng, C. Y., Li, Q. J., Chen, M., and Yao, X. F. (2015) Citreoviridin induces ROS-dependent autophagic cell death in human liver HepG2 cells. Toxicon 95, 30-37 34. Bai, Y., Jiang, L. P., Liu, X. F., Wang, D., Yang, G., Geng, C. Y., Li, Q., Zhong, L. F., Sun, Q., and Chen, M. (2015) The role of oxidative stress in citreoviridin-induced DNA damage in human liver-derived HepG2 cells. Environ Toxicol 30, 530-537 35. Humphrey, S. J., James, D. E., and Mann, M. (2015) Protein Phosphorylation: A Major Switch Mechanism for Metabolic Regulation. Trends Endocrinol Metab 26, 676-687 36. Macek, B., Mann, M., and Olsen, J. V. (2009) Global and site-specific quantitative phosphoproteomics: principles and applications. Annu Rev Pharmacol Toxicol 49, 199-221 37. Sharma, K., D'Souza, R. C., Tyanova, S., Schaab, C., Wisniewski, J. R., Cox, J., and Mann, M. (2014) Ultradeep human phosphoproteome reveals a distinct regulatory nature of Tyr and Ser/Thr-based signaling. Cell Rep 8, 1583-1594 38. Ku, W.-C., Sugiyama, N., and Ishihama, Y. (2012) Large-Scale Protein Phosphorylation Analysis by Mass Spectrometry-Based Phosphoproteomics. In: Mukai, H., ed. Protein Kinase Technologies, pp. 35-46, Humana Press, Totowa, NJ 39. Chikamori, K., Grabowski, D. R., Kinter, M., Willard, B. B., Yadav, S., Aebersold, R. H., Bukowski, R. M., Hickson, I. D., Andersen, A. H., Ganapathi, R., and Ganapathi, M. K. (2003) Phosphorylation of serine 1106 in the catalytic domain of topoisomerase II alpha regulates enzymatic activity and drug sensitivity. J Biol Chem 278, 12696-12702 40. de Campos-Nebel, M., Larripa, I., and Gonzalez-Cid, M. (2010) Topoisomerase II-mediated DNA damage is differently repaired during the cell cycle by non-homologous end joining and homologous recombination. PLoS One 5 41. Wartlick, F., Bopp, A., Henninger, C., and Fritz, G. (2013) DNA damage response (DDR) induced by topoisomerase II poisons requires nuclear function of the small GTPase Rac. Biochim Biophys Acta 1833, 3093-3103 42. Wells, N. J., Addison, C. M., Fry, A. M., Ganapathi, R., and Hickson, I. D. (1994) Serine 1524 is a major site of phosphorylation on human topoisomerase II alpha protein in vivo and is a substrate for casein kinase II in vitro. J Biol Chem 269, 29746-29751 43. Qi, X., Hou, S., Lepp, A., Li, R., Basir, Z., Lou, Z., and Chen, G. (2011) Phosphorylation and stabilization of topoisomerase IIalpha protein by p38gamma mitogen-activated protein kinase sensitize breast cancer cells to its poisons. J Biol Chem 286, 35883-35890 44. Iida, M., Matsuda, M., and Komatani, H. (2008) Plk3 phosphorylates topoisomerase IIalpha at Thr(1342), a site that is not recognized by Plk1. Biochem J 411, 27-32 45. Grozav, A. G., Chikamori, K., Kozuki, T., Grabowski, D. R., Bukowski, R. M., Willard, B., Kinter, M., Andersen, A. H., Ganapathi, R., and Ganapathi, M. K. (2009) Casein kinase I delta/epsilon phosphorylates topoisomerase IIalpha at serine-1106 and modulates DNA cleavage activity. Nucleic Acids Res 37, 382-392 46. Rappsilber, J., Mann, M., and Ishihama, Y. (2007) Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat Protoc 2, 1896-1906 47. Cox, J., and Mann, M. (2008) MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol 26, 1367-1372 48. Cox, J., Neuhauser, N., Michalski, A., Scheltema, R. A., Olsen, J. V., and Mann, M. (2011) Andromeda: a peptide search engine integrated into the MaxQuant environment. J Proteome Res 10, 1794-1805 49. Hu, J., Rho, H. S., Newman, R. H., Zhang, J., Zhu, H., and Qian, J. (2014) PhosphoNetworks: a database for human phosphorylation networks. Bioinformatics 30, 141-142 50. Humphrey, S. J., Yang, G., Yang, P., Fazakerley, D. J., Stockli, J., Yang, J. Y., and James, D. E. (2013) Dynamic adipocyte phosphoproteome reveals that Akt directly regulates mTORC2. Cell Metab 17, 1009-1020 51. Newman, R. H., Hu, J., Rho, H. S., Xie, Z., Woodard, C., Neiswinger, J., Cooper, C., Shirley, M., Clark, H. M., Hu, S., Hwang, W., Jeong, J. S., Wu, G., Lin, J., Gao, X., Ni, Q., Goel, R., Xia, S., Ji, H., Dalby, K. N., Birnbaum, M. J., Cole, P. A., Knapp, S., Ryazanov, A. G., Zack, D. J., Blackshaw, S., Pawson, T., Gingras, A. C., Desiderio, S., Pandey, A., Turk, B. E., Zhang, J., Zhu, H., and Qian, J. (2013) Construction of human activity-based phosphorylation networks. Mol Syst Biol 9, 655 52. Colonna, M. (2015) DNA damage response impacts macrophage functions. Blood 126, 2440-2442 53. Yoshiyama, K. O., Sakaguchi, K., and Kimura, S. (2013) DNA damage response in plants: conserved and variable response compared to animals. Biology (Basel) 2, 1338-1356 54. Zhao, M., Ma, J., Zhu, H. Y., Zhang, X. H., Du, Z. Y., Xu, Y. J., and Yu, X. D. (2011) Apigenin inhibits proliferation and induces apoptosis in human multiple myeloma cells through targeting the trinity of CK2, Cdc37 and Hsp90. Mol Cancer 10, 104 55. Sharma, S. V., Bell, D. W., Settleman, J., and Haber, D. A. (2007) Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 7, 169-181 56. Hu, C. W., Hsu, C. L., Wang, Y. C., Ishihama, Y., Ku, W. C., Huang, H. C., and Juan, H. F. Temporal Phosphoproteome Dynamics Induced by an ATP Synthase Inhibitor Citreoviridin. 57. Wu, Y. H., Hu, C. W., Chien, C. W., Chen, Y. J., Huang, H. C., and Juan, H. F. (2013) Quantitative proteomic analysis of human lung tumor xenografts treated with the ectopic ATP synthase inhibitor citreoviridin. PLoS One 8, e70642 58. Johnson, S. A., and Hunter, T. (2004) Phosphoproteomics finds its timing. Nat Biotechnol 22, 1093-1094 59. Wang, X. A., Xiang, S. S., Li, H. F., Wu, X. S., Li, M. L., Shu, Y. J., Zhang, F., Cao, Y., Ye, Y. Y., Bao, R. F., Weng, H., Wu, W. G., Mu, J. S., Hu, Y. P., Jiang, L., Tan, Z. J., Lu, W., Wang, P., and Liu, Y. B. (2014) Cordycepin induces S phase arrest and apoptosis in human gallbladder cancer cells. Molecules 19, 11350-11365 60. Uchibori, K., Kasamatsu, A., Sunaga, M., Yokota, S., Sakurada, T., Kobayashi, E., Yoshikawa, M., Uzawa, K., Ueda, S., Tanzawa, H., and Sato, N. (2012) Establishment and characterization of two 5-fluorouracil-resistant hepatocellular carcinoma cell lines. Int J Oncol 40, 1005-1010 | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/19194 | - |
dc.description.abstract | 非小細胞肺癌是全世界癌症死亡的首要原因,艾瑞莎(gefitinib)是表皮生長因子受體酪氨酸激酶的抑製劑作為非小細胞癌患者的第一線治療藥物,然而,許多患者最終卻對藥物產生抗藥性。因此,有效地開發藥物去治療具抗藥性的患者正迫在眉睫。我們先前發現黃綠青黴素,從真菌物種提煉的毒素之一,可以通過抑制異位表達三磷酸腺苷合成酶的活性進而抑制肺癌細胞生長,但對正常細胞的影響有限。在老鼠模型與CL1-0 (艾瑞莎非抗性肺癌細胞株)證實黃綠青黴素會藉由降低熱休克蛋白中特定絲氨酸(S255)的磷酸化而去抑制絲裂原活化蛋白激酶所參與的訊息傳遞。我們好奇黃綠青黴素在治療具艾瑞莎獲得性抗藥性肺癌細胞的潛在信號傳遞是否不同。在這項研究中,我們發現黃綠青黴素會抑制NCI-H1975(EGFR T790M突變艾瑞莎獲得性抗藥性)細胞生長與群落形成。此外,我們藉由時間性偵測磷酸化蛋白質體學來探討動態分子反應共鑑定出738個磷酸化蛋白,1476條磷酸化胜肽鏈以及1901個磷酸化位置。其中有顯著調控的磷酸化蛋白有174條對應274個磷酸化位置。功能富集分析發現黃綠青黴素會影響染色質的組織,細胞週期和細胞凋亡。有趣的是,我們發現黃綠青黴素藉由磷酸化拓撲異構酶的特定絲氨酸1106位置進而抑制細胞生長,而黃綠青黴素誘發DNA雙股斷裂,進而造成DNA損傷反應(DNA damage response)。DNA受損會促使細胞進行細胞週期停滯在S期去進行修復或是走向細胞凋亡。而所有資料指出黃綠青黴素可能作為治療具艾瑞莎抗藥性的有效藥物。 | zh_TW |
dc.description.abstract | Non-small cell lung cancer is the leading cause of cancer death worldwide. Gefitinib, epidermal growth factor receptor tyrosine kinase inhibitor, is the first-line treatment of NSCLC, however, many patients eventually become resistant and experience progressive disease. Therefore, development of efficient therapeutic agents to overcome resistance is urgent. We previously found that citreoviridin, one of toxic mycotoxins derived from fungal species, can suppress lung cancer cell growth by inhibiting the activity of ectopic ATP synthase, but has limited effect on normal cells. Citreoviridin suppresses mitogen-activated protein kinase/extracellular signal-regulated kinase signaling by site-specific dephosphorylation of HSP90AB1 on Serine 255 in gefitinib non-resistant lung cancer CL1-0 cells and xenograft model. We are curious whether signaling pathways underlying citreoviridin-treated gefitinib-acquired resistant lung cancer cells are different. In this study, we showed that citreoviridin inhibited cell proliferation and anchorage-dependent growth of gefitinib-acquired resistance NCI-H1975 cells with EGFR T790M mutation. Furthermore, we explored the dynamic molecular response by temporal phosphoproteomic approach. We identified 1476 phosphopeptides corresponding to 738 phosphoproteins and quantified 1901 phosphorylation sites. There were 274 phosphosites corresponding to 174 phosphorylated proteins significantly differential expressed. Functional enrichment analysis demonstrated that citreoviridin treatment affected chromatin organization, cell cycle and apoptosis. Interestingly, we found that citreovirdin suppressed cell proliferation by site-specific phosphorylation of topoisomerase on serine 1106. Citreovirdin induced double strands breaks, and then leaded to DNA damage response. The DNA lesions triggered cells to cell cycle arrest at S phase for repairing or apoptosis for cell death. The results indicated that citreoviridin could potentially be a therapeutic agent against gefitinib-resistant NSCLC. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T01:48:23Z (GMT). No. of bitstreams: 1 ntu-105-R03b43023-1.pdf: 4469113 bytes, checksum: 1d41fb52884a3fefa868030bbd909d41 (MD5) Previous issue date: 2016 | en |
dc.description.tableofcontents | 口試委員會審定書 i
謝辭 ii 中文摘要 iii Abstract iv Contents v List of Figures viii List of Tables ix Chapter 1 Introduction 1 1.1 Non-small cell lung cancer 1 1.2 Resistance of EGFR tyrosine kinase inhibitors 2 1.3 Ectopic ATP synthase 2 1.4 ATP synthase inhibitor 3 1.5 Phosphoproteomics 4 1.6 Topoisomerases II α 5 1.7 Motivation 6 Chapter 2 Materials and Methods 8 2.1 Cell culture 8 2.2 Drug treatment 8 2.3 Immunocytochemistry 9 2.4 Proliferation assay 9 2.5 Colony formation assay 10 2.6 Sample preparation (31) 10 2.7 Dimethyl labeling of peptides (31) 11 2.8 Stage tip preparation and Desalting with SDB-XC Stage Tips (31) 12 2.9 Phosphopeptide enrichment with HAMMOC (31) 13 2.10 NanoLC–MS/MS analysis (31) 14 2.11 Data analysis for phosphoproteomes (31) 15 2.12 Functional annotation and clustering analyses 15 2.13 Western blot analysis 16 2.14 Cell cycle analysis 17 2.15 Apoptosis using Annexin V/PI staining by flow cytometry 17 2.16 Reactive oxygen species by flow cytometry 18 Chapter 3 Results 19 3.1 ATP synthase is expressed on the surface of gefitinib-resistant lung cancer NCI-H1975 cells 19 3.2 Ectopic ATP synthase inhibitor citreoviridin suppresses the proliferation of NCI-H1975 cells 20 3.3 Dynamic phosphorylation profiles of citreoviridin-treated NCI-H1975 cells 21 3.4 Functional enrichment map and temporal clustering analysis reveal the functions of differentially regulated phosphoproteins with citreoviridin treatment 23 3.5 Motif analysis reveals the potential kinases of TOP2A at serine 1106 24 3.6 Citreoviridin triggers DNA damage response by double strand break 25 3.7 Citreoviridin induces cell cycle arrest at S phase and causes apoptosis 26 3.8 Inhibition of casein kinase 2 alpha 1 reduces S1106 phosphorylation of topoisomerase IIα and blocks TOP2A-induced DNA damage response in short time. 27 3.9 Citreoviridin induces ROS-dependent DNA damage in 48 hours 28 Chapter 4 Discussion 30 Chapter 5 Conclusion 35 References 36 Figures 41 Tables 58 Appendix. Supplementary Figures 116 | |
dc.language.iso | en | |
dc.title | 以動態磷酸化蛋白體學探討異位表達ATP合成酶抑制劑黃綠青黴素在艾瑞莎抗藥性肺癌細胞中所扮演的角色 | zh_TW |
dc.title | Temporal Phosphoproteome Dynamics Reveals the Role of ATP Synthase Inhibitor Citreoviridin in Gefitinib-resistant Lung Cancer Cells | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 黃宣誠,王憶卿,李岳倫 | |
dc.subject.keyword | 艾瑞莎獲得性抗藥性肺癌細胞,黃綠青黴素,磷酸化蛋白質體學,拓撲異構?,DNA損傷反應, | zh_TW |
dc.subject.keyword | gefitinib-acquired resistant lung cancer cell,citreoviridin,phosphoproteome,topoisomerase,DNA damage response, | en |
dc.relation.page | 118 | |
dc.identifier.doi | 10.6342/NTU201601742 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2016-08-03 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 分子與細胞生物學研究所 | zh_TW |
顯示於系所單位: | 分子與細胞生物學研究所 |
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