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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 | 李明學(MING-SYUE LI) | |
dc.contributor.author | Chen-An Huang | en |
dc.contributor.author | 黃晨銨 | zh_TW |
dc.date.accessioned | 2021-06-17T08:06:45Z | - |
dc.date.available | 2024-08-27 | |
dc.date.copyright | 2019-08-27 | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019-08-19 | |
dc.identifier.citation | 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019;69:7-
2. Flaig TW, Potluri RC, Ng Y, Todd MB, Mehra M. Treatment evolution for metastatic castration-resistant prostate cancer with recent introduction of novel agents: retrospective analysis of real-world data. Cancer Med 2016;5:182-91. 3. Harris WP, Mostaghel EA, Nelson PS, Montgomery B. Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion. Nat Clin Pract Urol 2009;6:76-85. 4. Tsao CK, Galsky MD, Small AC, Yee T, Oh WK. Targeting the androgen receptor signalling axis in castration-resistant prostate cancer (CRPC). BJU Int 2012;110:1580-8 5. Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 1996;14:1756-64. 6. Thoma C. Prostate cancer: Targeting apoptosis resistance in CRPC. Nat Rev Urol 2016;13:631. 7. Perlmutter MA, Lepor H. Androgen deprivation therapy in the treatment of advanced prostate cancer. Rev Urol 2007;9 Suppl 1:S3-8. 8. Lin TH, Lee SO, Niu Y, et al. Differential androgen deprivation therapies with anti-androgens casodex/bicalutamide or MDV3100/Enzalutamide versus anti-androgen receptor ASC-J9(R) Lead to promotion versus suppression of prostate cancer metastasis. J Biol Chem 2013;288:19359-69. 9. Goes RM, Zanetoni C, Tomiosso TC, Ribeiro DL, Taboga SR. Surgical and chemical castration induce differential histological response in prostate lobes of Mongolian gerbil. Micron 2007;38:231-6. 10. Lehmusvaara S, Erkkila T, Urbanucci A, et al. Chemical castration and anti-androgens induce differential gene expression in prostate cancer. J Pathol 2012;227:336-45. 11. Van Asseldonk B, Black P, Elterman DS. Chemical vs Surgical ADT in Metastatic Prostate Cancer: A Comparison of Side Effects. Commentary on Comparison of Gonadotropin-releasing Hormone Agonists and Orchiectomy: Effects of Androgen Deprivation Therapy. Urology 2016;93:3-4. 12. Singla N, Ghandour RA, Raj GV. Investigational luteinizing hormone releasing hormone (LHRH) agonists and other hormonal agents in early stage clinical trials for prostate cancer. Expert Opin Investig Drugs 2019;28:249-59. 13. Visapaa H. Switching from an LHRH Antagonist to an LHRH Agonist: A Case Report of 10 Finnish Patients with Advanced Prostate Cancer. Oncol Ther 2017;5:119- 14. Mostaghel EA, Zhang A, Hernandez S, et al. Contribution of Adrenal Glands to Intratumor Androgens and Growth of Castration-Resistant Prostate Cancer. Clin Cancer Res 2019;25:426-39. 15. Siemens DR, Klotz L, Heidenreich A, et al. Efficacy and Safety of Enzalutamide vs Bicalutamide in Younger and Older Patients with Metastatic Castration Resistant Prostate Cancer in the TERRAIN Trial. J Urol 2018;199:147-54. 16. Ferrari AC, Alumkal JJ, Stein MN, et al. Correction: Epigenetic Therapy with Panobinostat Combined with Bicalutamide Rechallenge in Castration-Resistant Prostate Cancer. Clin Cancer Res 2019;25:2672. 17. Brower V. Bicalutamide with radiotherapy for prostate cancer. Lancet Oncol 2017;18:e141. 18. Bryk DJ, Angermeier KW, Klein EA. A Case of Metastatic Prostate Cancer to the Urethra That Resolved After Androgen Deprivation Therapy. Urology 2019;129:e4-e5. 19. Ito Y, Sadar MD. Enzalutamide and blocking androgen receptor in advanced prostate cancer: lessons learnt from the history of drug development of antiandrogens. Res Rep Urol 2018;10:23-32. 20. Mateo J, Smith A, Ong M, de Bono JS. Novel drugs targeting the androgen receptor pathway in prostate cancer. Cancer Metastasis Rev 2014;33:567-79. 21. Jimenez-Panizo A, Perez P, Rojas A, Fuentes-Prior P, Estebanez-Perpina E. Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease. Endocr Relat Cancer 2019. 22. Hsieh T, Chen SS, Wang X, Wu JM. Regulation of androgen receptor (AR) and prostate specific antigen (PSA) expression in the androgen-responsive human prostate LNCaP cells by ethanolic extracts of the Chinese herbal preparation, PC-SPES. Biochem Mol Biol Int 1997;42:535-44. 23. Cumming AP, Hopmans SN, Vukmirovic-Popovic S, Duivenvoorden WC. PSA affects prostate cancer cell invasion in vitro and induces an osteoblastic phenotype in bone in vivo. Prostate Cancer Prostatic Dis 2011;14:286-94. 24. Tsaur I, Hennenlotter J, Oppermann E, et al. PCA3 and PSA gene activity correlates with the true tumor cell burden in prostate cancer lymph node metastases. Cancer Biomark 2015;15:311-6. 25. He Y, Korboukh I, Jin J, Huang J. Targeting protein lysine methylation and demethylation in cancers. Acta Biochim Biophys Sin (Shanghai) 2012;44:70-9. 26. Huang J, Perez-Burgos L, Placek BJ, et al. Repression of p53 activity by Smyd2-mediated methylation. Nature 2006;444:629-32. 27. Saddic LA, West LE, Aslanian A, et al. Methylation of the retinoblastoma tumor suppressor by SMYD2. J Biol Chem 2010;285:37733-40. 28. Kogure M, Takawa M, Saloura V, et al. The oncogenic polycomb histone methyltransferase EZH2 methylates lysine 120 on histone H2B and competes ubiquitination. Neoplasia 2013;15:1251-61. 29. Li LX, Zhou JX, Calvet JP, Godwin AK, Jensen RA, Li X. Lysine methyltransferase SMYD2 promotes triple negative breast cancer progression. Cell Death Dis 2018;9:326. 30. Patel KR, Patel HD. p53: An Attractive Therapeutic Target for Cancer. Curr Med Chem 2019. 31. Mazur PK, Reynoird N, Khatri P, et al. SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer. Nature 2014;510:283-7. 32. Pang CN, Gasteiger E, Wilkins MR. Identification of arginine- and lysine-methylation in the proteome of Saccharomyces cerevisiae and its functional implications. BMC Genomics 2010;11:92. 33. Hamamoto R, Saloura V, Nakamura Y. Critical roles of non-histone protein lysine methylation in human tumorigenesis. Nat Rev Cancer 2015;15:110-24. 34. Taylor AP, Szewczyk MM, Kennedy S, et al. Selective, small molecule co-factor binding site inhibition of a Su(var)3-9, Enhancer of Zeste, Trithorax (SET) domain containing lysine methyltransferase. J Med Chem 2019. 35. Komatsu S, Imoto I, Tsuda H, et al. Overexpression of SMYD2 relates to tumor cell proliferation and malignant outcome of esophageal squamous cell carcinoma. Carcinogenesis 2009;30:1139-46. 36. Brown MA, Sims RJ, 3rd, Gottlieb PD, Tucker PW. Identification and characterization of Smyd2: a split SET/MYND domain-containing histone H3 lysine 36-specific methyltransferase that interacts with the Sin3 histone deacetylase complex. Mol Cancer 2006;5:26. 37. Abu-Farha M, Lambert JP, Al-Madhoun AS, Elisma F, Skerjanc IS, Figeys D. The tale of two domains: proteomics and genomics analysis of SMYD2, a new histone methyltransferase. Mol Cell Proteomics 2008;7:560-72. 38. Ren H, Wang Z, Chen Y, et al. SMYD2-OE promotes oxaliplatin resistance in colon cancer through MDR1/P-glycoprotein via MEK/ERK/AP1 pathway. Onco Targets Ther 2019;12:2585-94. 39. Xu W, Chen F, Fei X, Yang X, Lu X. Overexpression of SET and MYND Domain-Containing Protein 2 (SMYD2) Is Associated with Tumor Progression and Poor Prognosis in Patients with Papillary Thyroid Carcinoma. Med Sci Monit 2018;24:7357- 40. Shang L, Wei M. Inhibition of SMYD2 Sensitized Cisplatin to Resistant Cells in NSCLC Through Activating p53 Pathway. Front Oncol 2019;9:306. 41. Hamamoto R, Toyokawa G, Nakakido M, Ueda K, Nakamura Y. SMYD2-dependent HSP90 methylation promotes cancer cell proliferation by regulating the chaperone complex formation. Cancer Lett 2014;351:126-33. 42. Zhang X, Tanaka K, Yan J, et al. Regulation of estrogen receptor alpha by histone methyltransferase SMYD2-mediated protein methylation. Proc Natl Acad Sci U S A 2013;110:17284-9. 43. Chandramouli B, Chillemi G. Conformational Dynamics of Lysine Methyltransferase Smyd2. Insights into the Different Substrate Crevice Characteristics of Smyd2 and Smyd3. J Chem Inf Model 2016;56:2467-75. 44. Xu S, Zhong C, Zhang T, Ding J. Structure of human lysine methyltransferase Smyd2 reveals insights into the substrate divergence in Smyd proteins. J Mol Cell Biol 2011;3:293-300. 45. Chen X, Lu J, Xia L, Li G. Drug Resistance of Enzalutamide in CRPC. Curr Drug Targets 2018;19:613-20. 46. Igawa T, Lin FF, Lee MS, Karan D, Batra SK, Lin MF. Establishment and characterization of androgen-independent human prostate cancer LNCaP cell model. The Prostate 2002;50:222-35. 47. Lee MS, Igawa T, Lin MF. Tyrosine-317 of p52(Shc) mediates androgen-stimulated proliferation signals in human prostate cancer cells. Oncogene 2004;23:3048-58. 48. Lee MS, Igawa T, Yuan TC, Zhang XQ, Lin FF, Lin MF. ErbB-2 signaling is involved in regulating PSA secretion in androgen-independent human prostate cancer LNCaP C-81 cells. Oncogene 2003;22:781-96. 49. Tyson MD, Bryce A. The Effect of Enzalutamide and Bicalutamide on Patient-reported Quality of Life Outcomes: Results from the TERRAIN Study. Eur Urol 2017;71:543-4. 50. Penson DF, Armstrong AJ, Concepcion R, et al. Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial. J Clin Oncol 2016;34:2098-106. 51. Tonry C, Armstrong J, Pennington S. Probing the prostate tumour microenvironment II: Impact of hypoxia on a cell model of prostate cancer progression. Oncotarget 2017;8:15307-37. 52. Andersen MK, Rise K, Giskeodegard GF, et al. Integrative metabolic and transcriptomic profiling of prostate cancer tissue containing reactive stroma. Sci Rep 2018;8:14269. 53. Ferguson AD, Larsen NA, Howard T, et al. Structural basis of substrate methylation and inhibition of SMYD2. Structure 2011;19:1262-73. 54. Paller C, Pu H, Begemann DE, Wade CA, Hensley PJ, Kyprianou N. TGF-beta receptor I inhibitor enhances response to enzalutamide in a pre-clinical model of advanced prostate cancer. Prostate 2019;79:31-43. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/73610 | - |
dc.description.abstract | 前列腺癌在初期治療上是透過賀爾蒙剝奪式治療,因為其在生理上需要賀爾蒙的供應來維持生存。但是賀爾蒙剝奪式療法沒辦法讓病人痊癒,甚至前列腺癌在經過一段時間治療後反而產生更嚴重的復發叫做去勢抗藥性前列腺癌,並伴隨著差勁的預後以及高度的轉移風險。在前列腺癌的進程中,其分子機制在目前還沒有非常全面的了解。根據我們實驗室先前的研究中,發現甲基化轉移酶MTx在叫惡性的前列腺癌細胞當中有更高的表現量相較於初期的前列腺癌細胞。在本篇研究中,我更進一步的測試人類前列腺癌細胞對於賀爾蒙的敏感度以及前列腺癌細胞的惡化進程。研究結果顯示,惡性前列腺癌細胞c-81 LNCaP 細胞相較於對於賀爾蒙較敏感的初期前列腺癌細胞有更高的MTx表現量。實驗中我將MTx做下調控處理,會讓惡性前列腺癌細胞c-81 LNCaP 恢復對於雄性激素的敏感度,且恢復了對於賀爾蒙治療的反應。而且我們發現,MTx會透過非直接性的方式使AR的活性增加,導致下游的目標基因被開啟。在我們的動物實驗中,我們發現使用賀爾蒙藥物與下調控MTx的惡性前列腺癌細胞能降低轉移的風險。結果合併顯示MTx在前列腺癌細胞的進程與抗藥性中扮演著重要的角色。因此,在對抗惡性前列腺癌細胞時,MTx可能成為一個新的治療性目標物。 | zh_TW |
dc.description.abstract | Prostate cancer (PCa) often receive androgen-deprivation therapy (ADT) due to its physiological needs of androgens to survive. However, ADT is not curable. Prostate cancer frequently relapses in a certain period after ADT and acquires castration-resistant prostate cancer (CRPC) with poor prognosis and a high potential of metastasis. The molecular mechanism of how PCa progresses to CRPC is still elusive. Based on the previous finding in our laboratory that a methyltransferase MTx was up-regulated in CRPC, in this study, I further investigated the role of MTx in the androgen sensitivity of human prostate cancer cells and prostate cancer cell progression. The results showed that castration-resistant C-81 LNCaP cells expressed a high level of MTx, compared to androgen-sensitive C-33 LNCaP cells. Silencing of MTx restored the sensitivity of castration-resistant C-81 LNCaP cells to androgens. Moreover, the treatment of MTx inhibitor could re-sensitize the effectiveness of anti-androgen drugs. In addition, MTx-induced androgen receptor (AR) activity may promote AR turning on its target gene expression through an indirect pathway. In our animal study, data have shown with significant reduction of tumor volume with knockdown of MTx in castration resistant c-81 LNCaP cells with anti-androgen drug treatment. The results together may suggest that MTx plays an critical role in the progression and drug resistance of human prostate cancer. Thus, MTx may serve as an novel therapeutic target for drug development against advanced prostate cancer. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T08:06:45Z (GMT). No. of bitstreams: 1 ntu-108-R06442006-1.pdf: 8159673 bytes, checksum: b33cb90189c9a721ac88cc76ddf81959 (MD5) Previous issue date: 2019 | en |
dc.description.tableofcontents | 致謝 i
中文摘要 ii Abstract iii Content A Chapter 1. Introduction 1 1-1 Human Prostate Cancer and Castration Resistance Prostate cancer (CRPC) 2 1-2 Androgen Deprivation Therapy (ADT) 3 1-3 Androgen Receptor (AR) signal pathway 4 1-4 Roles of non-histone protein lysine methylation in human tumorigenesis 5 1-5 Methyltransferase SMYD2 7 1-6 Research motivation 10 Chapter 2. Materials and Methods 11 Chapter 3. Results 26 3-1 Androgen sensitivity of C-33 and C-81 LNCaP cells. 27 3-2 Characterization of the androgen-resistance of C-33 and C-81 LNCaP cells 28 3-3 Up-regulation of methyltransferase SMYD2 in castration-resistant prostate cancer. 29 3-4 Overexpression of SMYD2 increased LNCaP cell growth and invasion 30 3-5 Knockdown of SMYD2 reduced the cell growth and invasive ability of castration-resistance C-81 LNCaP cells. 31 3-6 Knockdown of SMYD2 restored the sensitivity to androgen or anti-androgen treatment of Casodex-resistant LNCaP cells. 32 3-7 Investigation of the relationship between SMYD2 and androgen receptor (AR) 33 3-8 Combination treatment of a SMYD2 inhibitor with anti-androgen drugs on the cell growth of castration-resistant prostate cancer. 35 3-9 Examination of the SMYD2 role in the tumor growth of castration-resistant C-81 LNCaP cells in a xenograft tumor model. 36 Chapter 4. Figures 38 Chapter. 5 Discussion 59 Chapter 6. Reference 65 | |
dc.language.iso | en | |
dc.title | 甲基轉移酶MTx在前列腺癌細胞惡化以及對賀爾蒙療法產生抗性中所扮演的角色 | zh_TW |
dc.title | The role of methyltransferase MTx in prostate cancer cells progression and resistant to anti-androgen drugs treatment | en |
dc.type | Thesis | |
dc.date.schoolyear | 107-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 蕭培文(PEI-WEN HSIAO),鄧述諄(SHU-JHUN DENG),華國泰(GUO-TAI HUA) | |
dc.subject.keyword | 抗去勢惡性前列腺癌,甲基化轉移?,抗藥性,雄性激素受體,抗雄性激素藥物, | zh_TW |
dc.subject.keyword | castration-resistant prostate cancer,methyltransferase,drug resistance,androgen receptor,anti-androgen drugs, | en |
dc.relation.page | 70 | |
dc.identifier.doi | 10.6342/NTU201902351 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2019-08-19 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
顯示於系所單位: | 生物化學暨分子生物學科研究所 |
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