請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/71877
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林能裕(Neng-Yu Lin) | |
dc.contributor.author | Chia-Yeh Hsieh | en |
dc.contributor.author | 謝佳燁 | zh_TW |
dc.date.accessioned | 2021-06-17T06:13:10Z | - |
dc.date.available | 2024-03-05 | |
dc.date.copyright | 2019-03-05 | |
dc.date.issued | 2018 | |
dc.date.submitted | 2018-10-04 | |
dc.identifier.citation | 1. Maris, J.M., et al., Neuroblastoma. The Lancet, 2007. 369(9579): p. 2106-2120.
2. Kamijo, T. and A. Nakagawara, Molecular and genetic bases of neuroblastoma. Int J Clin Oncol, 2012. 17(3): p. 190-5. 3. Park, J.R., A. Eggert, and H. Caron, Neuroblastoma: biology, prognosis, and treatment. Hematol Oncol Clin North Am, 2010. 24(1): p. 65-86. 4. W.B. London, R.P.C., K.K. Matthay, A.T. Look, R.C. Seeger, H. Shimada, P. Thorner, G. Brodeur, J.M. Maris, C.P. Reynolds, and S.L. Cohn Evidence for an Age Cutoff Greater Than 365 Days for Neuroblastoma Risk Group Stratification in the Children's Oncology Group. JOURNAL OF CLINICAL ONCOLOGY, 2005. 23. 5. Hsu, W.-M., The study of biologic prognostic factors of neuroblastoma-clinical significance and impact on surgical decision, in Graduate institute of Clinical Medicine College of Medicine. 2004, National Taiwan University. 6. Ho, W.L., et al., B3GNT3 expression suppresses cell migration and invasion and predicts favorable outcomes in neuroblastoma. Cancer Sci, 2013. 104(12): p. 1600-8. 7. Brian H. Kushner, M., Neuroblastoma: A Disease Requiring a Multitude of Imaging Studies. THE JOURNAL OF NUCLEAR MEDICINE, 2004. 45. 8. Colon, N.C. and D.H. Chung, Neuroblastoma. Adv Pediatr, 2011. 58(1): p. 297-311. 9. N D L George, G.G., C S Hoyt Does Horner’s syndrome in infancy require investigation? British Journal of Ophthalmology, 1998. 82: p. 51-54. 10. Louis, C.U. and J.M. Shohet, Neuroblastoma: molecular pathogenesis and therapy. Annu Rev Med, 2015. 66: p. 49-63. 11. Jason M Shohet, M., PhD, Jed G Nuchtern, MD, FACS, FAAP <Epidemiology, pathogenesis, and pathology of neuroblastoma>. 2016. 12. Brodeur, G.M., NEUROBLASTOMA: BIOLOGICAL INSIGHTS INTO A CLINICAL ENIGMA NATURE REVIEWS |CANCER, 2003. 3: p. 203-216. 13. <MYCN_gene.pdf>. [cited 2017 12/26]; Available from: https://ghr.nlm.nih.gov/gene/MYCN. 14. GM Brodeur, R.S., M Schwab, HE Varmus, JM Bishop, Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science, 1984. 224. 15. Bresler, S.C., et al., ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. Cancer Cell, 2014. 26(5): p. 682-94. 16. Matthay, K.K., et al., Neuroblastoma. Nat Rev Dis Primers, 2016. 2: p. 16078. 17. Berry, T., et al., The ALK(F1174L) mutation potentiates the oncogenic activity of MYCN in neuroblastoma. Cancer Cell, 2012. 22(1): p. 117-30. 18. Zhu, S., et al., Activated ALK collaborates with MYCN in neuroblastoma pathogenesis. Cancer Cell, 2012. 21(3): p. 362-73. 19. Thomas F Eleveld1, Derek A Oldridge2–4,29, Virginie Bernard5,29, Jan Koster1, Leo Colmet Daage5,6,, et al., Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. Nature GeNetics, 2015. 47. 20. Edward F. Attiyeh, M.D., Wendy B. London, Ph.D., Yael P. Mossé, M.D., Qun Wang, M.D., Ph.D., Cynthia Winter, B.A., Deepa Khazi, M.S., Patrick W. McGrady, M.S., Robert C. Seeger, M.D., A. Thomas Look, M.D., Hiroyuki Shimada, M.D., Garrett M. Brodeur, M.D., Susan L. Cohn, M.D., Katherine K. Matthay, M.D., and John M. Maris, M.D.,, Chromosome 1p and 11q Deletions and Outcome in Neuroblastoma. The new england journal of medicine, 2005. 21. Krona, C., et al., Screening for gene mutations in a 500 kb neuroblastoma tumor suppressor candidate region in chromosome 1p; mutation and stage-specific expression in UBE4B/UFD2. Oncogene, 2003. 22(15): p. 2343-51. 22. NICK BOWN, M.S., SIMON COTTERILL, B.A., MARIA ASTOWSKA, M.D., PH.D., SEAMUS O’NEILL, PH.D., ANDREW D.J. PEARSON, M.D., DOMINIQUE PLANTAZ, M.D., MOUNIRA MEDDEB, M.D., PH.D., GISELE DANGLOT, M.D., CHRISTIAN BRINKSCHMIDT, M.D., HOLGER CHRISTIANSEN, M.D., GENEVIEVE LAUREYS, M.D., PH.D., and P.D. AND FRANK SPELEMAN, GAIN OF CHROMOSOME ARM 17q AND ADVERSE OUTCOME IN PATIENTS WITH NEUROBLASTOMA. The New England Journal of Medicine, 1999. 23. Nadine Van Roy, K.D.P., Jasmien Hoebeeck, Tom Van Maerken, Filip Pattyn, Pieter Mestdagh, Joëlle Vermeulen, Jo Vandesompele and Frank Speleman, The emerging molecular pathogenesis of neuroblastoma:implications for improved risk assessment and targeted therapy. Genome Medicine, 2009. 24. J. Bourhis, F.D., G. D. Wilson, O. Hartmann, M. J. Terrier-Lacombe, L. Boccon-Gibod, N. J. McNally, J. Lemerle, G. Riou, and J. Benard, Combined Analysis of DNA Ploidy Index and N-myc Genomic Content in Neuroblastoma. CANCER RESEARCH, 1991. 51: p. 33-36. 25. Nakagawara A, A.-N.M., Scavarda NJ, Azar CG, Cantor AB, Brodeur GM Association between high levels of expression of the TRK gene and favorable outcome in human neuroblastoma. N Engl J Med, 1993. 26. Akira Nakagawara, M.A., Christopher G. Azar, Nancy J. Scavarda, and Garrett M. Brodeur, Inverse Relationship between trk Expression and N-myc Amplification in Human Neuroblastomas. CANCER RESEARCH, 1992. 52. 27. Shih, Y.-Y., The Roles of Glucose-Regulated Protein 75 and Calreticulin in Neuronal Differentiation of Neuroblastoma, in Institute of Zoology College of Life Science. 2012, National Taiwan University. 28. Cheung NK, Z.J., Lu C, Parker M, Bahrami A, Tickoo SK, Heguy A, Pappo AS, Federico S, Dalton J, Cheung IY, Ding L, Fulton R, Wang J, Chen X, Becksfort J, Wu J, Billups CA, Ellison D, Mardis ER, Wilson RK, Downing JR, Dyer MA; St Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project., Association of Age at Diagnosis and Genetic Mutations in Patients With Neuroblastoma. JAMA, 2012. 307: p. 1062-1071. 29. Goto, S., et al., Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors. Cancer, 2001. 92(10): p. 2699-2708. 30. Shimada H, A.I., Dehner LP, Hata J, Joshi VV, Roald B, Stram DO, Gerbing RB, Lukens JN, Matthay KK, Castleberry RP., The International Neuroblastoma Pathology Classification (the Shimada System). Cancer, 1999. 86: p. 364-372. 31. Hiroyuki Shimada, M.D., Ph.D.1 Shunsuke Umehara, M.D.1 Yasumasa Monobe, M.D.1 Yoichi Hachitanda, M.D.1 Atsuko Nakagawa, M.D.1 Shoko Goto, M.D.1 and M.A.D.O.S. Robert B. Gerbing, Ph.D.3 John N. Lukens, M.D.4 Katherine K. Matthay, M.D, <The International Neuroblastoma Pathology Classification.pdf>. American Cancer Society, 2001. 32. Brodeur, G.M., et al., Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol, 1993. 11(8): p. 1466-77. 33. Cohn, S.L., et al., The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol, 2009. 27(2): p. 289-97. 34. JOANNA L. WEINSTEIN, H.M.K., SUSAN L. COHN., Advances in the Diagnosis and Treatment of Neuroblastoma. The Oncologist, 2003. 8: p. 278-292. 35. McCann, N.B.a.B., Statistical Estimation of Prognosis for Children with Neuroblastoma. Cnacer Research, 1971. 31(12): p. 2098-2013. 36. Brodeur, G.M.M.D.M., John M. M.D.; Yamashiro, Darrell J. M.D., Ph.D.; Hogarty, Michael D. M.D.; White, Peter S. Ph.D., <Biology and Genetics of Human Neuroblastomas.pdf>. Journal of Pediatric Hematology/Oncology, 1997. 19: p. 93-101. 37. Perez, C.A., et al., Biologic variables in the outcome of stages I and II neuroblastoma treated with surgery as primary therapy: a children's cancer group study. J Clin Oncol, 2000. 18(1): p. 18-26. 38. Nickerson, H.J., et al., Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or minimal therapy: a Children's Cancer Group study. J Clin Oncol, 2000. 18(3): p. 477-86. 39. Castel, V. and A. Canete, A comparison of current neuroblastoma chemotherapeutics. Expert Opin Pharmacother, 2004. 5(1): p. 71-80. 40. Laprie, A., et al., High-dose chemotherapy followed by locoregional irradiation improves the outcome of patients with international neuroblastoma staging system Stage II and III neuroblastoma with MYCN amplification. Cancer, 2004. 101(5): p. 1081-9. 41. Berthold, F., et al., Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial. The Lancet Oncology, 2005. 6(9): p. 649-658. 42. Maris, J.M., Medical Progress: Recent Advances in Neuroblastoma. New England Journal of Medicine, 2010. 362(23): p. 2202-2211. 43. London, W.B., et al., Clinical and biologic features predictive of survival after relapse of neuroblastoma: a report from the International Neuroblastoma Risk Group project. J Clin Oncol, 2011. 29(24): p. 3286-92. 44. Jason M Shohet, M., PhD, Jed G Nuchtern, MD, FACS, FAAP <Treatment and prognosis of neuroblastoma >. 2017. 45. Reynolds, C.P., et al., Retinoid therapy of high-risk neuroblastoma. Cancer Letters, 2003. 197(1-2): p. 185-192. 46. J. M. Wu, A.M.D.a.T.-C.H., Mechanism of fenretinide (4-HPR)-induced cell death. Apoptosis, 2001. 6(5): p. 377-388. 47. Saxton, R.A. and D.M. Sabatini, mTOR Signaling in Growth, Metabolism, and Disease. Cell, 2017. 168(6): p. 960-976. 48. Vaughan, L., et al., Inhibition of mTOR-kinase destabilizes MYCN and is a potential therapy for MYCN-dependent tumors. Oncotarget, 2016. 7(36): p. 57525-57544. 49. Gustafson, W.C. and W.A. Weiss, Myc proteins as therapeutic targets. Oncogene, 2010. 29(9): p. 1249-59. 50. Moore, A.S., et al., Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias. Leukemia, 2010. 24(4): p. 671-8. 51. Gorgun, G., et al., A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma. Blood, 2010. 115(25): p. 5202-13. 52. I. George Fantus, M., Howard J. Goldberg, MD, Catharine. I. Whiteside, MD, PhD, and Delilah Topic,MD., The Hexosamine Biosynthesis Pathway-Contribution to the Pathogenesis of Diabetic Nephropathy. Contemporary Diabetes: The Diabetic Kidney, 2006: p. 120-133. 53. Akimoto., G.W.H.a.Y., The O-GlcNAc Modification in Essentials of Glycobiology, C.R. Varki A, Esko JD,, Editor. 2009: Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press. 54. Gao, Y., et al., Dynamic O-glycosylation of nuclear and cytosolic proteins: cloning and characterization of a neutral, cytosolic beta-N-acetylglucosaminidase from human brain. J Biol Chem, 2001. 276(13): p. 9838-45. 55. Butkinaree, C., K. Park, and G.W. Hart, O-linked beta-N-acetylglucosamine (O-GlcNAc): Extensive crosstalk with phosphorylation to regulate signaling and transcription in response to nutrients and stress. Biochim Biophys Acta, 2010. 1800(2): p. 96-106. 56. Ande, S.R., S. Moulik, and S. Mishra, Interaction between O-GlcNAc modification and tyrosine phosphorylation of prohibitin: implication for a novel binary switch. PLoS One, 2009. 4(2): p. e4586. 57. Vaidyanathan, K., S. Durning, and L. Wells, Functional O-GlcNAc modifications: implications in molecular regulation and pathophysiology. Crit Rev Biochem Mol Biol, 2014. 49(2): p. 140-163. 58. Sakabe, K. and G.W. Hart, O-GlcNAc transferase regulates mitotic chromatin dynamics. J Biol Chem, 2010. 285(45): p. 34460-8. 59. Sakabe, K., Z. Wang, and G.W. Hart, Beta-N-acetylglucosamine (O-GlcNAc) is part of the histone code. Proc Natl Acad Sci U S A, 2010. 107(46): p. 19915-20. 60. William G. Kelly, M.E.D., and Gerald W. Hart, RNA Polymerase I1 Is a Glycoprotein. The Journal of Biological Chemistry, 1993. 268(14): p. 10416-10424. 61. Ranuncolo, S.M., et al., Evidence of the involvement of O-GlcNAc-modified human RNA polymerase II CTD in transcription in vitro and in vivo. J Biol Chem, 2012. 287(28): p. 23549-61. 62. Yang, X., F. Zhang, and J.E. Kudlow, Recruitment of O-GlcNAc Transferase to Promoters by Corepressor mSin3A. Cell, 2002. 110(1): p. 69-80. 63. Fujiki R, H.W., Sekine H, Yokoyama A, Chikanishi T, Ito S, Imai Y, Kim J, He HH, Igarashi K, Kanno J, Ohtake F, Kitagawa H, Roeder RG, Brown M, Kato S., GlcNAcylation of histone H2B facilitates its monoubiquitination. Nature, 2011. 480: p. 557-560. 64. Waterland, R.A. and C. Garza, Early postnatal nutrition determines adult pancreatic glucose-responsive insulin secretion and islet gene expression in rats. J Nutr, 2002. 132(3): p. 357-64. 65. Shafi, R., et al., The O-GlcNAc transferase gene resides on the X chromosome and is essential for embryonic stem cell viability and mouse ontogeny. Proc Natl Acad Sci U S A, 2000. 97(11): p. 5735-9. 66. Pantaleon, M., et al., Toxic effects of hyperglycemia are mediated by the hexosamine signaling pathway and o-linked glycosylation in early mouse embryos. Biol Reprod, 2010. 82(4): p. 751-8. 67. Yang, Y.R., et al., O-GlcNAcase is essential for embryonic development and maintenance of genomic stability. Aging Cell, 2012. 11(3): p. 439-48. 68. Webster, D.M., et al., O-GlcNAc modifications regulate cell survival and epiboly during zebrafish development. BMC Dev Biol, 2009. 9: p. 28. 69. Hsieh, T.J., et al., Suppression of Glutamine:fructose-6-phosphate amidotransferase-1 inhibits adipogenesis in 3T3-L1 adipocytes. J Cell Physiol, 2012. 227(1): p. 108-15. 70. Ishihara, K., et al., Characteristic increase in nucleocytoplasmic protein glycosylation by O-GlcNAc in 3T3-L1 adipocyte differentiation. Biochem Biophys Res Commun, 2010. 398(3): p. 489-94. 71. Li, X., et al., O-linked N-acetylglucosamine modification on CCAAT enhancer-binding protein beta: role during adipocyte differentiation. J Biol Chem, 2009. 284(29): p. 19248-54. 72. Andres-Bergos, J., et al., The increase in O-linked N-acetylglucosamine protein modification stimulates chondrogenic differentiation both in vitro and in vivo. J Biol Chem, 2012. 287(40): p. 33615-28. 73. Nagel, A.K., et al., Identification of O-linked N-acetylglucosamine (O-GlcNAc)-modified osteoblast proteins by electron transfer dissociation tandem mass spectrometry reveals proteins critical for bone formation. Mol Cell Proteomics, 2013. 12(4): p. 945-55. 74. Fehm, H.L., W. Kern, and A. Peters, The selfish brain: competition for energy resources. Progress in Brain Research, 2006. 153: p. 129-140. 75. Alfaro, J.F., et al., Tandem mass spectrometry identifies many mouse brain O-GlcNAcylated proteins including EGF domain-specific O-GlcNAc transferase targets. Proc Natl Acad Sci U S A, 2012. 109(19): p. 7280-5. 76. Kang, M.J., et al., Synapsin-1 and tau reciprocal O-GlcNAcylation and phosphorylation sites in mouse brain synaptosomes. Exp Mol Med, 2013. 45: p. e29. 77. Trinidad, J.C., et al., Global identification and characterization of both O-GlcNAcylation and phosphorylation at the murine synapse. Mol Cell Proteomics, 2012. 11(8): p. 215-29. 78. Akan, I., et al., Nutrient-driven O-GlcNAc in proteostasis and neurodegeneration. J Neurochem, 2018. 144(1): p. 7-34. 79. Alonso, A., et al., Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci U S A, 2001. 98(12): p. 6923-8. 80. Hastings, N.B., et al., Inhibition of O-GlcNAcase leads to elevation of O-GlcNAc tau and reduction of tauopathy and cerebrospinal fluid tau in rTg4510 mice. Mol Neurodegener, 2017. 12(1): p. 39. 81. Yuzwa, S.A., et al., A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo. Nat Chem Biol, 2008. 4(8): p. 483-90. 82. Kim, C., et al., O-linked beta-N-acetylglucosaminidase inhibitor attenuates beta-amyloid plaque and rescues memory impairment. Neurobiol Aging, 2013. 34(1): p. 275-85. 83. Jozwiak, P., et al., O-GlcNAcylation and Metabolic Reprograming in Cancer. Front Endocrinol (Lausanne), 2014. 5: p. 145. 84. Luanpitpong, S., et al., Hyper-O-GlcNAcylation induces cisplatin resistance via regulation of p53 and c-Myc in human lung carcinoma. Sci Rep, 2017. 7(1): p. 10607. 85. Yang, W.H., et al., Modification of p53 with O-linked N-acetylglucosamine regulates p53 activity and stability. Nat Cell Biol, 2006. 8(10): p. 1074-83. 86. Itkonen, H.M., et al., O-GlcNAc transferase integrates metabolic pathways to regulate the stability of c-MYC in human prostate cancer cells. Cancer Res, 2013. 73(16): p. 5277-87. 87. Lazarus, B.D., D.C. Love, and J.A. Hanover, Recombinant O-GlcNAc transferase isoforms: identification of O-GlcNAcase, yes tyrosine kinase, and tau as isoform-specific substrates. Glycobiology, 2006. 16(5): p. 415-21. 88. Lazarus, M.B., et al., Structure of human O-GlcNAc transferase and its complex with a peptide substrate. Nature, 2011. 469(7331): p. 564-7. 89. Zachara, N., Y. Akimoto, and G.W. Hart, The O-GlcNAc Modification, in Essentials of Glycobiology, rd, et al., Editors. 2015: Cold Spring Harbor (NY). p. 239-251. 90. Singh, A., et al., Retinoic acid induces REST degradation and neuronal differentiation by modulating the expression of SCF(beta-TRCP) in neuroblastoma cells. Cancer, 2011. 117(22): p. 5189-202. 91. Weng, W.C., et al., VEGF expression correlates with neuronal differentiation and predicts a favorable prognosis in patients with neuroblastoma. Sci Rep, 2017. 7(1): p. 11212. 92. Guglielmi, L., et al., MYCN gene expression is required for the onset of the differentiation programme in neuroblastoma cells. Cell Death Dis, 2014. 5: p. e1081. 93. Liu, Y.L., J.S. Miser, and W.M. Hsu, Risk-directed therapy and research in neuroblastoma. J Formos Med Assoc, 2014. 113(12): p. 887-9. 94. Carpentieri, A., et al., Differentiation of human neuroblastoma cells toward the osteogenic lineage by mTOR inhibitor. Cell Death Dis, 2015. 6: p. e1974. 95. Wang, A.C., et al., Loss of O-GlcNAc glycosylation in forebrain excitatory neurons induces neurodegeneration. Proc Natl Acad Sci U S A, 2016. 113(52): p. 15120-15125. 96. Lagerlof, O., et al., The nutrient sensor OGT in PVN neurons regulates feeding. Science, 2016. 351(6279): p. 1293-6. 97. Su, C. and T.L. Schwarz, O-GlcNAc Transferase Is Essential for Sensory Neuron Survival and Maintenance. J Neurosci, 2017. 37(8): p. 2125-2136. 98. Ruan, H.B., et al., O-GlcNAc transferase enables AgRP neurons to suppress browning of white fat. Cell, 2014. 159(2): p. 306-17. 99. Stevenson, R.E. and C.E. Schwartz, X-linked intellectual disability: unique vulnerability of the male genome. Dev Disabil Res Rev, 2009. 15(4): p. 361-8. 100. Richards, M.W., et al., Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors. Proc Natl Acad Sci U S A, 2016. 113(48): p. 13726-13731. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/71877 | - |
dc.description.abstract | 神經母細胞瘤為兒童最常見的顱外固態腫瘤,佔總體兒童癌症死亡率達15%。神經母細胞瘤起源於交感神經系統,為神經脊前驅細胞發育受阻所致,因具有高度異質性而難以根治。神經母細胞瘤高風險群病患的長期存活率不佳,即使切除或接受高強度治療後仍無法改善病況且有復發的風險存在。提出更多預後因子幫助臨床分析是目前研究的趨勢。我們的研究發現,較不分化、較惡性的神經母細胞瘤病患的腫瘤,其表現較少的O-GlcNAc。另外,我們的小鼠模型,TH-MYCN誘發的神經母細胞瘤腫瘤中胞內蛋白O-GlcNAcylation也較正常小鼠腎上腺胞內少,此趨勢與病患腫瘤分析一致。結合臨床統計分析發現158位病患中,總體O-GlcNAc陽性的病患存活率較高外;而從臨床早、晚期與MYCN無擴增病患的存活率分析,O-GlcNAc陽性者存活率也較高,且O-GlcNAc是除了年齡外的獨立預後因子,O-GlcNAcylation將有機會提供臨床上新的治療方向。O-GlcNAc(乙醯葡萄醣胺)為修飾細胞內蛋白質的醣類結構,目前發現受到兩種酵素專一性的調控胞內蛋白質的加醣與去醣作用(乙醯葡萄醣胺轉移酶(OGT)負責加醣;乙醯葡萄醣胺水解酶(OGA)負責去醣)。O-GlcNAcylation作用於胞內蛋白的絲胺酸和蘇胺酸上氫氧基。O-GlcNAcylation涉及細胞內眾多生理機制,失調後會引起許多疾病產生。我們想調查O-GlcNAcylation在神經母細胞瘤的角色。我們的研究發現,以13-cis Retinoic Acid(13-cis RA)治療神經母細胞瘤細胞株後,胞內O-GlcNAc的表現隨分化而提升;以藥物Thiamet G抑制OGA蛋白活性使胞內O-GlcNAcylation蛋白累積後也能改善神經母細胞瘤惡性行為與刺激細胞分化並同時降低致癌因子N-myc蛋白表現。在裸鼠異種移植實驗中發現用sh-OGT lentivirus敲除神經母細胞瘤ogt基因後會使腫瘤生長惡化。綜合以上結論,我們的研究結果指出,以藥物促使細胞內O-GlcNAc上升將能幫助神經母細胞瘤分化並減緩神經母細胞瘤的惡性行為及抑制致癌因子N-myc表現。臨床上分析顯示O-GlcNAc陽性能夠作為獨立預後因子,提供未來治療新方向。O-GlcNAcylation是如何調控神經母細胞瘤相關分化基因的表現,並且抑制致癌基因表現是我們未來的研究重點。 | zh_TW |
dc.description.abstract | Neuroblastoma is the most common malignant extracranial solid tumor of childhood and accounts for 15% cancer death in children. Neuroblastoma arises from sympathetic nervous system due to the aberrant developmental differentiation of early neural crest precursor cells. The disease is remarkable for its broad spectrum of heterogeneous behaviour. Further identify novel prognosis factors is the aim of clinical research. Here we present evidence that hypo-O-GlcNAc expression in undifferentiation, malignant NB patient tumors similar to the result of TH-MYCN mice tumor IHC experiments. According to clinical statistical analyses, NB patients with positive O-GlcNAc expression has higher long-term survival than those O-GlcNAc negative. Moreover, based on Survival-rate analyses, patients with O-GlcNAc-positive in early or late stage as well as MYCN-nonamplification has higher long-term survival. Multivariate analyses revealed that positive O-GlcNAc expression in tumor tissues predicted a favorable prognosis in NB patients independent of other prognostic markers except age. Intracellular O-GlcNAcylation could proivde new clinical strategy.O-GlcNAcylation is a dynamic modification of serine or threonine hydroxyl moieties nucleocytoplasmic proteins by UDP-GlcNAc. The dynamic and inducible cycling of the modification is governed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which add and remove the O-GlcNAc moiety respectively. The O-GlcNAcylation involes in many important cellular pathways and unbalance of O-GlcNAcylation has implicated in many kinds of diseases. We are going to investigate the role of O-GlcNAcylation in Neuroblatoma.The differentiation of NB cell induced by 13 cis-Retinoic Acid caused O-GlcNAc accumulation and N-myc decreased in NB cell, simultaneously. Furthermore, using Thiamet G to inhibit OGA activity result in cellular O-GlcNAc level increased, also ameliorates malignant phenotypes, induces differentiation and decreases N-myc protein expression in NB cells.Above all, our findings suggest that O-GlcNAcylation regulates malignant phenotypes of NB cells through the differentiation. Moreover, clinical analysis also indicates that O-GlcNAc-positive could be an independent prognosis factor. These results regarding O-GlcNAcylation may also provide an alternative approach for cancer therapy by means of modulating oncogene-specific O-GlcNAcylation. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T06:13:10Z (GMT). No. of bitstreams: 1 ntu-107-R05446012-1.pdf: 22242845 bytes, checksum: 08c93a8d76905fcad8a438e86e61cb7e (MD5) Previous issue date: 2018 | en |
dc.description.tableofcontents | 誌謝 i
中文摘要 iii Abstract v 目錄(Contents) vii 圖目錄(List of Figures) x 表目錄(List of Tables) xi 一、 緒論(Introdction) 1 1 神經母細胞瘤(Neuroblastoma) 1 2 乙醯葡萄醣胺(O-GlcNAc) 15 二、 研究目的(Aim) 25 1 探討O-GlcNAc在神經母細胞瘤臨床的重要性 25 2 調控O-GlcNAc對於神經母細胞瘤的影響 25 三、 研究方法與材料(Materials & Methods) 26 1 實驗材料(Materials) 26 2 病患資料與檢體搜集(Patients and tissue samples) 28 3 免疫組織染色法(IHC) 29 4 組織石蠟包埋與切片(Paraffin embedding & paraffin section) 30 5 蘇木精-依紅染色(H&E stain) 31 6 細胞株及細胞培養(Cell line & Cell culture) 31 7 藥物處理(Drug treatment) 31 8 細胞免疫螢光染色(ICC) 32 9 蛋白質定量(Bradford protein assay) 33 10 西方點墨法(Western blot) 34 11 RNA萃取與RT-PCR(RNA Extraction & RT-PCR) 35 12 Real-time PCR 36 13 Migration、Invasion實驗(Wound healing assay & Transwell assay) 37 14 噻唑藍比色法 (MTT assay) 37 15 裸鼠的異種移植物模型(Xenograft tumor growth in nude mice) 38 16 統計分析(Statistical analyses) 38 四、 結果(Results) 39 1 O-GlcNAc在神經母細胞瘤病患腫瘤中的表現以及其與臨床病理和生物性因子的關聯性 39 2 O-GlcNAc的表現與存活分析 40 3 TH-MYCN小鼠腫瘤與對照組小鼠腎上腺比較胞內蛋白O-GlcNAcylation表現量 40 4 以Retinoic acid 刺激神經母細胞瘤細胞株,O-GlcNAc隨著分化而上升 41 5 給予Thiamet G專一性抑制OGA蛋白活性,累積胞內O-GlcNAc在蛋白質上修飾程度,N-myc蛋白質表現下降且細胞朝向分化 43 6 Thiamet G和Retinoic acid合併使用能更好的影響神經母細胞瘤細胞分化 45 7 Thiamet G降低神經母細胞瘤惡性行為 46 8 ogt基因敲落(gene knockdown)增加神經母細胞瘤腫瘤生長 48 五、 結論(Conclusion) 49 六、 討論(Discussion) 51 1 O-GlcNAc是否為獨立預後因子 51 2 O-GlcNAc為細胞分化發育所必須 51 3 O-GlcNAc在神經系統中的角色 53 4 O-GlcNAcylation的異常造成神經退化性疾病 54 5 X染色體異常造成的智能障礙(X-linked intellectual disability, XLID) 55 6 抑制神經母細胞瘤細胞OGA活性會劇烈影響OGA與OGT的表現量,反映O-GlcNAc在胞內蛋白修飾程度影響細胞的惡性行為 55 7 神經母細胞瘤O-GlcNAc與MYCN蛋白 56 七、 展望(Future work) 58 1 研究MYCN蛋白是否可以被O-GlcNAc修飾 58 2 研究PI3K/AKT/mTOR pathway以及Aurora A kinase中O-GlcNAcylation的角色 58 3 調查神經母細胞瘤中O-GlcNAcylation對p53的調控 59 八、 圖表(Tables & Figures) 61 九、 參考文獻(References) 85 | |
dc.language.iso | zh-TW | |
dc.title | 探討胞內乙醯葡萄醣胺與神經母細胞瘤病患預後因子相關性及其累積有效抑制神經母細胞瘤之惡性行為 | zh_TW |
dc.title | The pattern of O-GlcNAcylation correlates with neuroblastoma prognosis and its accumulation ameliorates malignant phenotypes in NB cells | en |
dc.type | Thesis | |
dc.date.schoolyear | 107-1 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 黃敏銓(Min-Chuan Huang),許文明(Wen-Ming Hsu) | |
dc.subject.keyword | 神經母細胞瘤,乙醯葡萄醣胺,乙醯葡萄醣胺轉移?,乙醯葡萄醣胺水解?,Thiamet G,細胞分化, | zh_TW |
dc.subject.keyword | Neuroblastoma,O-GlcNAc,O-GlcNAc transferase,O-GlcNAcase,Thiamet G,differentiation, | en |
dc.relation.page | 93 | |
dc.identifier.doi | 10.6342/NTU201804145 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2018-10-04 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 解剖學暨細胞生物學研究所 | zh_TW |
顯示於系所單位: | 解剖學暨細胞生物學科所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-107-1.pdf 目前未授權公開取用 | 21.72 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。