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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 郭明良 | |
dc.contributor.author | Ling-Hui Chen | en |
dc.contributor.author | 陳鈴慧 | zh_TW |
dc.date.accessioned | 2021-06-16T03:44:13Z | - |
dc.date.available | 2025-12-31 | |
dc.date.copyright | 2015-03-12 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-02-09 | |
dc.identifier.citation | 1. L. M. DeAngelis, Brain tumors. The New England journal of medicine 344, 114-123 (2001); published online EpubJan 11 (10.1056/NEJM200101113440207).
2. J. A. Schwartzbaum, J. L. Fisher, K. D. Aldape, M. Wrensch, Epidemiology and molecular pathology of glioma. Nature clinical practice. Neurology 2, 494-503; quiz 491 p following 516 (2006); published online EpubSep (10.1038/ncpneuro0289). 3. H. Ohgaki, P. Kleihues, Epidemiology and etiology of gliomas. Acta neuropathologica 109, 93-108 (2005); published online EpubJan (10.1007/s00401-005-0991-y). 4. M. V. Relling, J. E. Rubnitz, G. K. Rivera, J. M. Boyett, M. L. Hancock, C. A. Felix, L. E. Kun, A. W. Walter, W. E. Evans, C. H. Pui, High incidence of secondary brain tumours after radiotherapy and antimetabolites. Lancet 354, 34-39 (1999); published online EpubJul 3 (10.1016/S0140-6736(98)11079-6). 5. H. Ohgaki, P. Dessen, B. Jourde, S. Horstmann, T. Nishikawa, P. L. Di Patre, C. Burkhard, D. Schuler, N. M. Probst-Hensch, P. C. Maiorka, N. Baeza, P. Pisani, Y. Yonekawa, M. G. Yasargil, U. M. Lutolf, P. Kleihues, Genetic pathways to glioblastoma: a population-based study. Cancer research 64, 6892-6899 (2004); published online EpubOct 1 (10.1158/0008-5472.CAN-04-1337). 6. H. Ohgaki, P. Kleihues, Genetic pathways to primary and secondary glioblastoma. The American journal of pathology 170, 1445-1453 (2007); published online EpubMay (10.2353/ajpath.2007.070011). 7. P. Kleihues, D. N. Louis, B. W. Scheithauer, L. B. Rorke, G. Reifenberger, P. C. Burger, W. K. Cavenee, The WHO classification of tumors of the nervous system. Journal of neuropathology and experimental neurology 61, 215-225; discussion 226-219 (2002); published online EpubMar ( 8. C. R. Miller, A. Perry, Glioblastoma. Archives of pathology & laboratory medicine 131, 397-406 (2007); published online EpubMar (10.1043/1543-2165(2007)131[397:G]2.0.CO;2). 9. P. Y. Wen, S. Kesari, Malignant gliomas in adults. The New England journal of medicine 359, 492-507 (2008); published online EpubJul 31 (10.1056/NEJMra0708126). 10. N. R. Smoll, O. P. Gautschi, B. Schatlo, K. Schaller, D. C. Weber, Relative survival of patients with supratentorial low-grade gliomas. Neuro-oncology 14, 1062-1069 (2012); published online EpubAug (10.1093/neuonc/nos144). 11. J. D. Olson, E. Riedel, L. M. DeAngelis, Long-term outcome of low-grade oligodendroglioma and mixed glioma. Neurology 54, 1442-1448 (2000); published online EpubApr 11 ( 12. J. Perry, N. Laperriere, L. Zuraw, A. Chambers, K. Spithoff, J. G. Cairncross, G. Neuro-oncology Disease Site, C. Cancer Care Ontario Program in Evidence-Based, Adjuvant chemotherapy for adults with malignant glioma: a systematic review. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 34, 402-410 (2007); published online EpubNov ( 13. E. S. Newlands, M. F. Stevens, S. R. Wedge, R. T. Wheelhouse, C. Brock, Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer treatment reviews 23, 35-61 (1997); published online EpubJan ( 14. R. Stupp, M. E. Hegi, W. P. Mason, M. J. van den Bent, M. J. Taphoorn, R. C. Janzer, S. K. Ludwin, A. Allgeier, B. Fisher, K. Belanger, P. Hau, A. A. Brandes, J. Gijtenbeek, C. Marosi, C. J. Vecht, K. Mokhtari, P. Wesseling, S. Villa, E. Eisenhauer, T. Gorlia, M. Weller, D. Lacombe, J. G. Cairncross, R. O. Mirimanoff, R. European Organisation for, T. Treatment of Cancer Brain, G. Radiation Oncology, G. National Cancer Institute of Canada Clinical Trials, Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. The Lancet. Oncology 10, 459-466 (2009); published online EpubMay (10.1016/S1470-2045(09)70025-7). 15. A. Malmstrom, B. H. Gronberg, C. Marosi, R. Stupp, D. Frappaz, H. Schultz, U. Abacioglu, B. Tavelin, B. Lhermitte, M. E. Hegi, J. Rosell, R. Henriksson, G. Nordic Clinical Brain Tumour Study, Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. The Lancet. Oncology 13, 916-926 (2012); published online EpubSep (10.1016/S1470-2045(12)70265-6). 16. N. Cancer Genome Atlas Research, Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061-1068 (2008); published online EpubOct 23 (10.1038/nature07385). 17. J. Li, C. Yen, D. Liaw, K. Podsypanina, S. Bose, S. I. Wang, J. Puc, C. Miliaresis, L. Rodgers, R. McCombie, S. H. Bigner, B. C. Giovanella, M. Ittmann, B. Tycko, H. Hibshoosh, M. H. Wigler, R. Parsons, PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943-1947 (1997); published online EpubMar 28 ( 18. J. M. Nigro, S. J. Baker, A. C. Preisinger, J. M. Jessup, R. Hostetter, K. Cleary, S. H. Bigner, N. Davidson, S. Baylin, P. Devilee, et al., Mutations in the p53 gene occur in diverse human tumour types. Nature 342, 705-708 (1989); published online EpubDec 7 (10.1038/342705a0). 19. A. J. Wong, S. H. Bigner, D. D. Bigner, K. W. Kinzler, S. R. Hamilton, B. Vogelstein, Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proceedings of the National Academy of Sciences of the United States of America 84, 6899-6903 (1987); published online EpubOct ( 20. D. W. Parsons, S. Jones, X. Zhang, J. C. Lin, R. J. Leary, P. Angenendt, P. Mankoo, H. Carter, I. M. Siu, G. L. Gallia, A. Olivi, R. McLendon, B. A. Rasheed, S. Keir, T. Nikolskaya, Y. Nikolsky, D. A. Busam, H. Tekleab, L. A. Diaz, Jr., J. Hartigan, D. R. Smith, R. L. Strausberg, S. K. Marie, S. M. Shinjo, H. Yan, G. J. Riggins, D. D. Bigner, R. Karchin, N. Papadopoulos, G. Parmigiani, B. Vogelstein, V. E. Velculescu, K. W. Kinzler, An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807-1812 (2008); published online EpubSep 26 (10.1126/science.1164382). 21. H. Yan, D. W. Parsons, G. Jin, R. McLendon, B. A. Rasheed, W. Yuan, I. Kos, I. Batinic-Haberle, S. Jones, G. J. Riggins, H. Friedman, A. Friedman, D. Reardon, J. Herndon, K. W. Kinzler, V. E. Velculescu, B. Vogelstein, D. D. Bigner, IDH1 and IDH2 mutations in gliomas. The New England journal of medicine 360, 765-773 (2009); published online EpubFeb 19 (10.1056/NEJMoa0808710). 22. B. V. Geisbrecht, S. J. Gould, The human PICD gene encodes a cytoplasmic and peroxisomal NADP(+)-dependent isocitrate dehydrogenase. The Journal of biological chemistry 274, 30527-30533 (1999); published online EpubOct 22 ( 23. T. Yoshihara, T. Hamamoto, R. Munakata, R. Tajiri, M. Ohsumi, S. Yokota, Localization of cytosolic NADP-dependent isocitrate dehydrogenase in the peroxisomes of rat liver cells: biochemical and immunocytochemical studies. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 49, 1123-1131 (2001); published online EpubSep ( 24. C. Ceccarelli, N. B. Grodsky, N. Ariyaratne, R. F. Colman, B. J. Bahnson, Crystal structure of porcine mitochondrial NADP+-dependent isocitrate dehydrogenase complexed with Mn2+ and isocitrate. Insights into the enzyme mechanism. The Journal of biological chemistry 277, 43454-43462 (2002); published online EpubNov 8 (10.1074/jbc.M207306200). 25. X. Xu, J. Zhao, Z. Xu, B. Peng, Q. Huang, E. Arnold, J. Ding, Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity. The Journal of biological chemistry 279, 33946-33957 (2004); published online EpubAug 6 (10.1074/jbc.M404298200). 26. E. R. Mardis, L. Ding, D. J. Dooling, D. E. Larson, M. D. McLellan, K. Chen, D. C. Koboldt, R. S. Fulton, K. D. Delehaunty, S. D. McGrath, L. A. Fulton, D. P. Locke, V. J. Magrini, R. M. Abbott, T. L. Vickery, J. S. Reed, J. S. Robinson, T. Wylie, S. M. Smith, L. Carmichael, J. M. Eldred, C. C. Harris, J. Walker, J. B. Peck, F. Du, A. F. Dukes, G. E. Sanderson, A. M. Brummett, E. Clark, J. F. McMichael, R. J. Meyer, J. K. Schindler, C. S. Pohl, J. W. Wallis, X. Shi, L. Lin, H. Schmidt, Y. Tang, C. Haipek, M. E. Wiechert, J. V. Ivy, J. Kalicki, G. Elliott, R. E. Ries, J. E. Payton, P. Westervelt, M. H. Tomasson, M. A. Watson, J. Baty, S. Heath, W. D. Shannon, R. Nagarajan, D. C. Link, M. J. Walter, T. A. Graubert, J. F. DiPersio, R. K. Wilson, T. J. Ley, Recurring mutations found by sequencing an acute myeloid leukemia genome. The New England journal of medicine 361, 1058-1066 (2009); published online EpubSep 10 (10.1056/NEJMoa0903840). 27. M. F. Amary, K. Bacsi, F. Maggiani, S. Damato, D. Halai, F. Berisha, R. Pollock, P. O'Donnell, A. Grigoriadis, T. Diss, M. Eskandarpour, N. Presneau, P. C. Hogendoorn, A. Futreal, R. Tirabosco, A. M. Flanagan, IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. The Journal of pathology 224, 334-343 (2011); published online EpubJul (10.1002/path.2913). 28. M. F. Amary, S. Damato, D. Halai, M. Eskandarpour, F. Berisha, F. Bonar, S. McCarthy, V. R. Fantin, K. S. Straley, S. Lobo, W. Aston, C. L. Green, R. E. Gale, R. Tirabosco, A. Futreal, P. Campbell, N. Presneau, A. M. Flanagan, Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2. Nature genetics 43, 1262-1265 (2011); published online EpubDec (10.1038/ng.994). 29. D. R. Borger, K. K. Tanabe, K. C. Fan, H. U. Lopez, V. R. Fantin, K. S. Straley, D. P. Schenkein, A. F. Hezel, M. Ancukiewicz, H. M. Liebman, E. L. Kwak, J. W. Clark, D. P. Ryan, V. Deshpande, D. Dias-Santagata, L. W. Ellisen, A. X. Zhu, A. J. Iafrate, Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. The oncologist 17, 72-79 (2012)10.1634/theoncologist.2011-0386). 30. L. Dang, D. W. White, S. Gross, B. D. Bennett, M. A. Bittinger, E. M. Driggers, V. R. Fantin, H. G. Jang, S. Jin, M. C. Keenan, K. M. Marks, R. M. Prins, P. S. Ward, K. E. Yen, L. M. Liau, J. D. Rabinowitz, L. C. Cantley, C. B. Thompson, M. G. Vander Heiden, S. M. Su, Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739-744 (2009); published online EpubDec 10 (10.1038/nature08617). 31. S. Zhao, Y. Lin, W. Xu, W. Jiang, Z. Zha, P. Wang, W. Yu, Z. Li, L. Gong, Y. Peng, J. Ding, Q. Lei, K. L. Guan, Y. Xiong, Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science 324, 261-265 (2009); published online EpubApr 10 (10.1126/science.1170944). 32. Z. J. Reitman, D. W. Parsons, H. Yan, IDH1 and IDH2: not your typical oncogenes. Cancer cell 17, 215-216 (2010); published online EpubMar 16 (10.1016/j.ccr.2010.02.024). 33. W. Xu, H. Yang, Y. Liu, Y. Yang, P. Wang, S. H. Kim, S. Ito, C. Yang, P. Wang, M. T. Xiao, L. X. Liu, W. Q. Jiang, J. Liu, J. Y. Zhang, B. Wang, S. Frye, Y. Zhang, Y. H. Xu, Q. Y. Lei, K. L. Guan, S. M. Zhao, Y. Xiong, Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer cell 19, 17-30 (2011); published online EpubJan 18 (10.1016/j.ccr.2010.12.014). 34. P. Koivunen, S. Lee, C. G. Duncan, G. Lopez, G. Lu, S. Ramkissoon, J. A. Losman, P. Joensuu, U. Bergmann, S. Gross, J. Travins, S. Weiss, R. Looper, K. L. Ligon, R. G. Verhaak, H. Yan, W. G. Kaelin, Jr., Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 483, 484-488 (2012); published online EpubMar 22 (10.1038/nature10898). 35. D. S. Aaronson, C. M. Horvath, A road map for those who don't know JAK-STAT. Science 296, 1653-1655 (2002); published online EpubMay 31 (10.1126/science.1071545). 36. D. E. Levy, J. E. Darnell, Jr., Stats: transcriptional control and biological impact. Nature reviews. Molecular cell biology 3, 651-662 (2002); published online EpubSep (10.1038/nrm909). 37. S. Akira, Roles of STAT3 defined by tissue-specific gene targeting. Oncogene 19, 2607-2611 (2000); published online EpubMay 15 (10.1038/sj.onc.1203478). 38. J. Bromberg, J. E. Darnell, Jr., The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19, 2468-2473 (2000); published online EpubMay 15 (10.1038/sj.onc.1203476). 39. P. C. Heinrich, I. Behrmann, S. Haan, H. M. Hermanns, G. Muller-Newen, F. Schaper, Principles of interleukin (IL)-6-type cytokine signalling and its regulation. The Biochemical journal 374, 1-20 (2003); published online EpubAug 15 (10.1042/BJ20030407). 40. Z. Wen, Z. Zhong, J. E. Darnell, Jr., Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82, 241-250 (1995); published online EpubJul 28 ( 41. J. Bromberg, Stat proteins and oncogenesis. The Journal of clinical investigation 109, 1139-1142 (2002); published online EpubMay (10.1172/JCI15617). 42. Z. Q. Ning, J. Li, M. McGuinness, R. J. Arceci, STAT3 activation is required for Asp(816) mutant c-Kit induced tumorigenicity. Oncogene 20, 4528-4536 (2001); published online EpubJul 27 (10.1038/sj.onc.1204590). 43. N. de la Iglesia, S. V. Puram, A. Bonni, STAT3 regulation of glioblastoma pathogenesis. Current molecular medicine 9, 580-590 (2009); published online EpubJun ( 44. M. Liu, K. Inoue, T. Leng, S. Guo, Z. G. Xiong, TRPM7 channels regulate glioma stem cell through STAT3 and Notch signaling pathways. Cellular signalling 26, 2773-2781 (2014); published online EpubDec (10.1016/j.cellsig.2014.08.020). 45. L. Gao, F. Li, B. Dong, J. Zhang, Y. Rao, Y. Cong, B. Mao, X. Chen, Inhibition of STAT3 and ErbB2 suppresses tumor growth, enhances radiosensitivity, and induces mitochondria-dependent apoptosis in glioma cells. International journal of radiation oncology, biology, physics 77, 1223-1231 (2010); published online EpubJul 15 (10.1016/j.ijrobp.2009.12.036). 46. P. A. Agudelo-Garcia, J. K. De Jesus, S. P. Williams, M. O. Nowicki, E. A. Chiocca, S. Liyanarachchi, P. K. Li, J. J. Lannutti, J. K. Johnson, S. E. Lawler, M. S. Viapiano, Glioma cell migration on three-dimensional nanofiber scaffolds is regulated by substrate topography and abolished by inhibition of STAT3 signaling. Neoplasia 13, 831-840 (2011); published online EpubSep ( 47. G. P. Atkinson, S. E. Nozell, E. T. Benveniste, NF-kappaB and STAT3 signaling in glioma: targets for future therapies. Expert review of neurotherapeutics 10, 575-586 (2010); published online EpubApr (10.1586/ern.10.21). 48. H. M. Smilowitz, J. Weissenberger, J. Weis, J. D. Brown, R. J. O'Neill, J. A. Laissue, Orthotopic transplantation of v-src-expressing glioma cell lines into immunocompetent mice: establishment of a new transplantable in vivo model for malignant glioma. Journal of neurosurgery 106, 652-659 (2007); published online EpubApr (10.3171/jns.2007.106.4.652). 49. N. Farhat, A. M. Mamarbachi, E. Thorin, B. G. Allen, Cloning, expression and purification of functionally active human angiopoietin-like protein 2. SpringerPlus 3, 337 (2014)10.1186/2193-1801-3-337). 50. E. Nkansah, R. Shah, G. W. Collie, G. N. Parkinson, J. Palmer, K. M. Rahman, T. T. Bui, A. F. Drake, J. Husby, S. Neidle, G. Zinzalla, D. E. Thurston, A. F. Wilderspin, Observation of unphosphorylated STAT3 core protein binding to target dsDNA by PEMSA and X-ray crystallography. FEBS letters 587, 833-839 (2013); published online EpubApr 2 (10.1016/j.febslet.2013.01.065). 51. E. Cerami, J. Gao, U. Dogrusoz, B. E. Gross, S. O. Sumer, B. A. Aksoy, A. Jacobsen, C. J. Byrne, M. L. Heuer, E. Larsson, Y. Antipin, B. Reva, A. P. Goldberg, C. Sander, N. Schultz, The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer discovery 2, 401-404 (2012); published online EpubMay (10.1158/2159-8290.CD-12-0095). 52. J. Gao, B. A. Aksoy, U. Dogrusoz, G. Dresdner, B. Gross, S. O. Sumer, Y. Sun, A. Jacobsen, R. Sinha, E. Larsson, E. Cerami, C. Sander, N. Schultz, Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Science signaling 6, pl1 (2013); published online EpubApr 2 (10.1126/scisignal.2004088). 53. D. Kesanakurti, C. Chetty, D. H. Dinh, M. Gujrati, J. S. Rao, Role of MMP-2 in the regulation of IL-6/Stat3 survival signaling via interaction with alpha5beta1 integrin in glioma. Oncogene 32, 327-340 (2013); published online EpubJan 17 (10.1038/onc.2012.52). 54. B. A. Orr, M. C. Haffner, W. G. Nelson, S. Yegnasubramanian, C. G. Eberhart, Decreased 5-hydroxymethylcytosine is associated with neural progenitor phenotype in normal brain and shorter survival in malignant glioma. PloS one 7, e41036 (2012)10.1371/journal.pone.0041036). 55. E. H. Shim, C. B. Livi, D. Rakheja, J. Tan, D. Benson, V. Parekh, E. Y. Kho, A. P. Ghosh, R. Kirkman, S. Velu, S. Dutta, B. Chenna, S. L. Rea, R. J. Mishur, Q. Li, T. L. Johnson-Pais, L. Guo, S. Bae, S. Wei, K. Block, S. Sudarshan, L-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer. Cancer discovery 4, 1290-1298 (2014); published online EpubNov (10.1158/2159-8290.CD-13-0696). | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/55009 | - |
dc.description.abstract | Gliomas (神經膠質瘤) 為常見的原發性腦瘤,常使用的分類方法有藉由不同的細胞特性分為星細胞瘤、 寡樹突膠質瘤及室管膜瘤,或是用組織病理程度將神經膠質瘤分為一到四級以區分惡性和良性程度,良性腦瘤有分化良好、生長緩慢, 能治癒或不易復發的特性,而惡性腦瘤生長快速且治癒率低。目前對於腦神經膠質瘤的治療仍以手術為主,並輔以放射線治療及化療藥物,如: temozolomide (TMZ,帝盟多膠囊)。研究發現,神經膠質瘤中的某些基因突變 (mutation)或變異 (alteration)會影響腫瘤的發展過程進而影響到病人的復原情形;其中,Isocitrate dehydrogenases (IDH,異檸檬酸脫氫酶)為檸檬酸循環中催化isocitrate (異檸檬酸)進行氧化脫羧反應成為α-ketoglutarate (α-KG,α-酮戊二酸),並產生NADPH的酵素,已知IDH1最常見的突變為IDH1 R132H,會改變IDH1原本的催化反應,轉而將α-KG轉化為2-hydroxyglutarate (2-HG,2-羥基戊二酸),且在某些分類的神經膠質瘤中有高於50%的突變機率。在近年來的研究中發現2-HG具有使細胞趨於癌化的能力,被視為oncometabolite (癌代謝物),目前已知會對α-KG相關的酵素進行競爭型抑制,影響α-KG相關酵素 (組蛋白去甲基酶)的活性進而影響組蛋白的甲基化,進而影響相關的基因表現及表觀遺傳 (epigenetic regulation)相關調控;但對於2-HG在細胞及癌症中是否有其他功能,以及其所扮演的角色和機制目前尚未完全了解。在我們的研究中,首先利用串聯親合疏水層析法 (AETHIC)篩選小鼠腦組織細胞內2-HG可能的標的蛋白,進一步去探討2-HG在小鼠腦癌的發生及進展中扮演的角色。在經過西方點墨法及和腫瘤發展相關的細胞實驗確認後我們發現Signal transducer and activator of transcription 3 (STAT-3) 蛋白量會隨著2-HG的產生而明顯減少,加上過去研究顯示STAT-3的表現量和腦神經膠質瘤的預後有極密切的關係,我們選定STAT-3作為研究2-HG的標的蛋白,並進一步以胞外實驗證實2-HG和STAT-3 之間為直接的影響關係。臨床資料顯示在表現IDH1突變基因的病人中,其預後會顯著優於表現正常IDH1基因的病人,且在表現突變IDH1基因的病人中,STAT-3的下游基因會有明顯降低的情形。綜合以上,IDH1透過突變後提升2-HG表現量,並透過降低STAT-3蛋白質表現量及下游訊息傳遞來影響神經膠質瘤的發展過程及病人的預後。 | zh_TW |
dc.description.abstract | Glioma are tumors that often arise from glial cells and mostly start in the brain. It can be classified by the specific cell types including astrocytomas and oligodendrogliomas or by histopathological and clinical criteria from WHO grade I to grade IV gliomas. Low-grade gliomas tended to exhibit benign tendencies and portend a better prognosis for the patients while high grade gliomas are mostly malignant and cause worse prognosis. The current treatment is combination of the radiation therapy and oral administration of chemotherapy drug temozolomide (TMZ). It has been reported that several gene mutations can influence glioma progression. Among them, isocitrate dehydrogenases (IDH) mutation lost the normal function of α-ketoglutarate (α-KG) production and convert to 2-hydroxyglutarate (2-HG) and was reported to prolong the gliomas survival rate. The neo-enzyme 2HG is regarded as an oncometabolite through the inhibition of α-KG dependent enzymes and induction of cell transformation in tumor initiation. However, the role of D-2HG in tumor progression is still controversial and need to be further investigated. In our study, we presented the novel target proteins of 2-HG by using AETHIC, which can dissect the interaction of small molecules and proteins. We identified Signal transducer and activator of transcription 3 (STAT-3) as the target protein by screening the functional outcomes and protein changes in the overexpressed mutant IDH1 glioma cells. Furthermore, we used the in vitro binding assay to investigate the interaction between STAT-3 and 2-HG, the results confirmed that 2-HG can directly bind to STAT-3. Clinically, the survival rate and the expression level of STAT-3 downstream target genes also validated the importance of 2-HG affects prognosis through STAT-3. We hope to provide a new point of view on the better therapeutic target of glioma patients. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T03:44:13Z (GMT). No. of bitstreams: 1 ntu-104-R01447008-1.pdf: 7403368 bytes, checksum: b9bbe44386840cbdd315932083632e8f (MD5) Previous issue date: 2015 | en |
dc.description.tableofcontents | 口試委員會審定書 …………………………………………………………………………………………… I
摘要 ………………………………………………………………………………………………………………….. II Abstract ……………………………………………………………………………………………………………… IV Chapter 1. INTRODUCTION .............................1 1.1 Gliomas .....................................2 1.2 Prognosis and therapy of gliomas ............2 1.3 Mutant genes in gliomas .....................3 1.4 Isocitrate dehydrogenase (IDH) and cancers ..4 1.5 IDH1 mutations ..............................5 1.6 2-HG and glioma cancer metabolism ...........6 1.7 Signal transducer and activator of transcription (STAT) family .......................................8 1.8 STAT-3 and glioma tumor progression .........9 1.9 Motivation and purpose ......................9 Chapter 2. MATERIALS AND METHOEDS ...................11 2.1 Cell culture ................................12 2.2 Transfection and lentivirus infection .......12 2.3 Cell viability assay ........................13 2.4 RNA isolation and reverse transcription-polymerase chain reaction ...........................13 2.5 Western blotting analysis ...................14 2.6 Migration and invasion assays ...............14 2.7 Soft agar ...................................15 2.8 Sphere formation ............................15 2.9 Immunohistochemistry staining ...............16 2.10 Orthotropic brain injection animal model ...17 2.11 Affinity elution from tandem hydrophobic interaction chromatography (AETHIC) .................18 2.12 Mass spectrometry ..........................18 2.13 Construction of the STAT-3 recombinant plasmid .............................................19 2.14 Expression and purification of recombinant STAT-3 protein ...........................................19 2.15 Circular dichroism (CD) spectroscopy .......21 2.16 Site-directed mutagenesis ..................21 2.17 Statistical analysis .......................22 Chapter 3. RESULTS ..................................23 3.1 Overexpress mutant IDH1 gene increases 2HG level and effects α-KG dependent enzymes ......................24 3.2 IDH1 mutation effects glioma cells through migration and invasion ability .....................24 3.3 Novel 2-HG target proteins was identified by AETHIC ..............................................26 3.4 Mutant IDH1 influence 2-HG target protein STAT-3 and play an important role in glioma tumor progression .....................................................27 3.5 2-HG decreases STAT-3 protein expression through proteasomal degradation while α-KG is a competitive inhibitor ...........................................28 3.6 IDH1 mutation lead to low cell migration through reducing STAT-3 protein stability ...................30 3.7 2-HG direct binding with STAT-3 and affect its secondary structure .................................31 3.8 Mutant IDH1 correlate with better prognosis through inhibit STAT-3 signal pathway in clinical results .....................................................32 3.9 Investigation the role of IDH1 and STAT-3 in glioma tumor progression and prognosis in animal model .....................................................34 Chapter 4. DISCUSSION ...............................35 Chapter 5. FIGURES AND FIGURE LEGENDS ...............39 Figure 1. Overexpression of mutant IDH1 increases 2HG level in cells ......................................42 Figure 2. IDH1 mutation effects cellular functions .....................................................47 Figure 3. Identification of novel 2HG target proteins by AETHIC ..............................................50 Figure 4. The influence of 2HG target proteins in IDH1 mutant cells ...................................53 Figure 5. IDH1 mutation decrease STAT3 expression through protein degradation by 2HG ..........................57 Figure 6. Decrease of STAT3 result in reduction of cell migration ability in IDH1 mutant cell ...............62 Figure 7. 2HG directly binds to STAT3 ...............65 Figure 8. IDH mutation correlate with better prognosis through STAT3 degradation by 2HG ....................68 Figure 9. Investigation the role of IDH1 and STAT-3 in glioma tumor progression and prognosis in animal model .....................................................72 Table 1. List of 2-HG target proteins ...............73 Table 2. Proportion of secondary structure analysis of STAT-3 protein plus various concentration of 2-HG .....................................................74 Table 3. Proportion of secondary structure analysis of STAT-3 protein plus various concentration of α-KG .....................................................74 Chapter 6. REFERENCES ...............................75 | |
dc.language.iso | en | |
dc.title | 神經膠質瘤發生與進程中2-羥基戊二酸新穎目標蛋白之探討 | zh_TW |
dc.title | Identification and characterization of novel 2-hydroxyglutarate target proteins involve in glioma formation and progression | en |
dc.type | Thesis | |
dc.date.schoolyear | 103-1 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 張震東,蕭宏昇,洪文俊 | |
dc.subject.keyword | 神經膠質瘤,異檸檬酸脫氫?,2-羥基戊二酸,串聯親合疏水層析法,STAT-3,病人預後, | zh_TW |
dc.subject.keyword | gliomas,isocitrate dehydrogenases (IDH),2-hydroxyglutarate (2-HG),AETHIC,Signal transducer and activator of transcription 3 (STAT-3),prognosis, | en |
dc.relation.page | 82 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2015-02-09 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 毒理學研究所 | zh_TW |
顯示於系所單位: | 毒理學研究所 |
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