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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 高嘉宏 | zh_TW |
| dc.contributor.advisor | Jia-Horng Kao | en |
| dc.contributor.author | 胡名宏 | zh_TW |
| dc.contributor.author | Ming-Hung Hu | en |
| dc.date.accessioned | 2024-08-16T17:46:04Z | - |
| dc.date.available | 2024-08-20 | - |
| dc.date.copyright | 2024-08-16 | - |
| dc.date.issued | 2024 | - |
| dc.date.submitted | 2024-08-13 | - |
| dc.identifier.citation | 1. Welzel TM, McGlynn KA, Hsing AW, O'Brien TR, Pfeiffer RM. Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States. J Natl Cancer Inst. 2006;98(12):873-875.
2. Brindley PJ, Bachini M, Ilyas SI, et al. Cholangiocarcinoma. Nat Rev Dis Primers. 2021;7(1):65. 3. Taylor-Robinson SD, Toledano MB, Arora S, et al. Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968-1998. Gut. 2001;48(6):816-820. 4. Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020;17(9):557-588. 5. Valle JW, Kelley RK, Nervi B, Oh DY, Zhu AX. Biliary tract cancer. Lancet. 2021;397(10272):428-444. 6. Goyal L, Meric-Bernstam F, Hollebecque A, et al. Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma. N Engl J Med. 2023;388(3):228-239. 7. Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):271-282. 8. Marabelle A, Le DT, Ascierto PA, et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2020;38(1):1-10. 9. Kelley RK, Ueno M, Yoo C, et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023;401(10391):1853-1865. 10. Oh DY, He AR, Bouattour M, et al. Durvalumab or placebo plus gemcitabine and cisplatin in participants with advanced biliary tract cancer (TOPAZ-1): updated overall survival from a randomised phase 3 study. Lancet Gastroenterol Hepatol. 2024;9(8):694-704. 11. Everhart JE, Ruhl CE. Burden of digestive diseases in the United States Part III: Liver, biliary tract, and pancreas. Gastroenterology. 2009;136(4):1134-1144. 12. Izquierdo-Sanchez L, Lamarca A, La Casta A, et al. Cholangiocarcinoma landscape in Europe: Diagnostic, prognostic and therapeutic insights from the ENSCCA Registry. J Hepatol. 2022;76(5):1109-1121. 13. Honjo S, Srivatanakul P, Sriplung H, et al. Genetic and environmental determinants of risk for cholangiocarcinoma via Opisthorchis viverrini in a densely infested area in Nakhon Phanom, northeast Thailand. Int J Cancer. 2005;117(5):854-860. 14. Sripa B, Mairiang E, Thinkhamrop B, et al. Advanced periductal fibrosis from infection with the carcinogenic human liver fluke Opisthorchis viverrini correlates with elevated levels of interleukin-6. Hepatology. 2009;50(4):1273-1281. 15. Li H, Lan T, Liu H, et al. IL-6-induced cGGNBP2 encodes a protein to promote cell growth and metastasis in intrahepatic cholangiocarcinoma. Hepatology. 2022;75(6):1402-1419. 16. Schuringa JJ, Wierenga AT, Kruijer W, Vellenga E. Constitutive Stat3, Tyr705, and Ser727 phosphorylation in acute myeloid leukemia cells caused by the autocrine secretion of interleukin-6. Blood. 2000;95(12):3765-3770. 17. Meng F, Wehbe-Janek H, Henson R, Smith H, Patel T. Epigenetic regulation of microRNA-370 by interleukin-6 in malignant human cholangiocytes. Oncogene. 2008;27(3):378-386. 18. Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumor microenvironment. Journal of immunology research. 2014;2014:149185. 19. Rodrigues PM, Olaizola P, Paiva NA, et al. Pathogenesis of Cholangiocarcinoma. Annu Rev Pathol. 2021;16:433-463. 20. Sun L, Wang Y, Cen J, et al. Modelling liver cancer initiation with organoids derived from directly reprogrammed human hepatocytes. Nat Cell Biol. 2019;21(8):1015-1026. 21. Wang S, Yadav AK, Han JY, Ahn KS, Jang BC. Anti-Growth, Anti-Angiogenic, and Pro-Apoptotic Effects by CX-4945, an Inhibitor of Casein Kinase 2, on HuCCT-1 Human Cholangiocarcinoma Cells via Control of Caspase-9/3, DR-4, STAT-3/STAT-5, Mcl-1, eIF-2alpha, and HIF-1alpha. Int J Mol Sci. 2022;23(11). 22. Zou S, Tong Q, Liu B, Huang W, Tian Y, Fu X. Targeting STAT3 in Cancer Immunotherapy. Mol Cancer. 2020;19(1):145. 23. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. 24. Moon SY, Lee H, Kim S, et al. Inhibition of STAT3 enhances sensitivity to tamoxifen in tamoxifen-resistant breast cancer cells. BMC Cancer. 2021;21(1):931. 25. Xu J, Lin H, Wu G, Zhu M, Li M. IL-6/STAT3 Is a Promising Therapeutic Target for Hepatocellular Carcinoma. Front Oncol. 2021;11:760971. 26. Di JX, Zhang HY. C188-9, a small-molecule STAT3 inhibitor, exerts an antitumor effect on head and neck squamous cell carcinoma. Anticancer Drugs. 2019;30(8):846-853. 27. Jung KH, Yoo W, Stevenson HL, et al. Multifunctional Effects of a Small-Molecule STAT3 Inhibitor on NASH and Hepatocellular Carcinoma in Mice. Clin Cancer Res. 2017;23(18):5537-5546. 28. Blechacz BR, Smoot RL, Bronk SF, Werneburg NW, Sirica AE, Gores GJ. Sorafenib inhibits signal transducer and activator of transcription-3 signaling in cholangiocarcinoma cells by activating the phosphatase shatterproof 2. Hepatology. 2009;50(6):1861-1870. 29. Tai WT, Shiau CW, Chen PJ, et al. Discovery of novel Src homology region 2 domain-containing phosphatase 1 agonists from sorafenib for the treatment of hepatocellular carcinoma. Hepatology. 2014;59(1):190-201. 30. Tai WT, Cheng AL, Shiau CW, et al. Signal transducer and activator of transcription 3 is a major kinase-independent target of sorafenib in hepatocellular carcinoma. Journal of hepatology. 2011;55(5):1041-1048. 31. Graves JD, Krebs EG. Protein phosphorylation and signal transduction. Pharmacol Ther. 1999;82(2-3):111-121. 32. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science. 2002;298(5600):1912-1934. 33. Turdo A, D'Accardo C, Glaviano A, et al. Targeting Phosphatases and Kinases: How to Checkmate Cancer. Front Cell Dev Biol. 2021;9:690306. 34. Liu J, Ren G, Li K, et al. The Smad4-MYO18A-PP1A complex regulates beta-catenin phosphorylation and pemigatinib resistance by inhibiting PAK1 in cholangiocarcinoma. Cell Death Differ. 2022;29(4):818-831. 35. Jiang TY, Shi YY, Cui XW, et al. PTEN Deficiency Facilitates Exosome Secretion and Metastasis in Cholangiocarcinoma by Impairing TFEB-mediated Lysosome Biogenesis. Gastroenterology. 2023;164(3):424-438. 36. Chida K, Kawazoe A, Kawazu M, et al. A Low Tumor Mutational Burden and PTEN Mutations Are Predictors of a Negative Response to PD-1 Blockade in MSI-H/dMMR Gastrointestinal Tumors. Clin Cancer Res. 2021;27(13):3714-3724. 37. Swingle MR, Honkanen RE, Ciszak EM. Structural basis for the catalytic activity of human serine/threonine protein phosphatase-5. J Biol Chem. 2004;279(32):33992-33999. 38. Yang J, Roe SM, Cliff MJ, et al. Molecular basis for TPR domain-mediated regulation of protein phosphatase 5. EMBO J. 2005;24(1):1-10. 39. Golden T, Swingle M, Honkanen RE. The role of serine/threonine protein phosphatase type 5 (PP5) in the regulation of stress-induced signaling networks and cancer. Cancer Metastasis Rev. 2008;27(2):169-178. 40. Urban G, Golden T, Aragon IV, Scammell JG, Dean NM, Honkanen RE. Identification of an estrogen-inducible phosphatase (PP5) that converts MCF-7 human breast carcinoma cells into an estrogen-independent phenotype when expressed constitutively. J Biol Chem. 2001;276(29):27638-27646. 41. Shao J, Hartson SD, Matts RL. Evidence that protein phosphatase 5 functions to negatively modulate the maturation of the Hsp90-dependent heme-regulated eIF2alpha kinase. Biochemistry. 2002;41(21):6770-6779. 42. Shah BH, Catt KJ. Protein phosphatase 5 as a negative key regulator of Raf-1 activation. Trends Endocrinol Metab. 2006;17(10):382-384. 43. Zhou G, Golden T, Aragon IV, Honkanen RE. Ser/Thr protein phosphatase 5 inactivates hypoxia-induced activation of an apoptosis signal-regulating kinase 1/MKK-4/JNK signaling cascade. J Biol Chem. 2004;279(45):46595-46605. 44. Zuo Z, Urban G, Scammell JG, et al. Ser/Thr protein phosphatase type 5 (PP5) is a negative regulator of glucocorticoid receptor-mediated growth arrest. Biochemistry. 1999;38(28):8849-8857. 45. Zhi X, Zhang H, He C, Wei Y, Bian L, Li G. Serine/Threonine Protein Phosphatase-5 Accelerates Cell Growth and Migration in Human Glioma. Cell Mol Neurobiol. 2015;35(5):669-677. 46. Feng L, Sun P, Li Z, Liu M, Sun S. Knockdown of PPP5C inhibits growth of hepatocellular carcinoma cells in vitro. Appl Biochem Biotechnol. 2015;175(1):526-534. 47. Zheng X, Zhang L, Jin B, Zhang F, Zhang D, Cui L. Knockdown of protein phosphatase 5 inhibits ovarian cancer growth in vitro. Oncol Lett. 2016;11(1):168-172. 48. Carrel JE, Doom JP, McCormick JP. Identification of cantharidin in false blister beetles (Coleoptera, Oedemeridae) from florida. J Chem Ecol. 1986;12(3):741-747. 49. Li YM, Casida JE. Cantharidin-binding protein: identification as protein phosphatase 2A. Proc Natl Acad Sci U S A. 1992;89(24):11867-11870. 50. Wang GS. Medical uses of mylabris in ancient China and recent studies. J Ethnopharmacol. 1989;26(2):147-162. 51. Dorn DC, Kou CA, Png KJ, Moore MA. The effect of cantharidins on leukemic stem cells. Int J Cancer. 2009;124(9):2186-2199. 52. Karras DJ, Farrell SE, Harrigan RA, Henretig FM, Gealt L. Poisoning from "Spanish fly" (cantharidin). Am J Emerg Med. 1996;14(5):478-483. 53. Miyagiwa M, Ichida T, Tokiwa T, Sato J, Sasaki H. A new human cholangiocellular carcinoma cell line (HuCC-T1) producing carbohydrate antigen 19/9 in serum-free medium. In Vitro Cell Dev Biol. 1989;25(6):503-510. 54. Sripa B, Leungwattanawanit S, Nitta T, et al. Establishment and characterization of an opisthorchiasis-associated cholangiocarcinoma cell line (KKU-100). World J Gastroenterol. 2005;11(22):3392-3397. 55. Chen MH, Chiang KC, Cheng CT, et al. Antitumor activity of the combination of an HSP90 inhibitor and a PI3K/mTOR dual inhibitor against cholangiocarcinoma. Oncotarget. 2014;5(9):2372-2389. 56. Yeh CN, Chiang KC, Juang HH, et al. Reappraisal of the therapeutic role of celecoxib in cholangiocarcinoma. PLoS One. 2013;8(7):e69928. 57. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436-444. 58. Catlett-Falcone R, Landowski TH, Oshiro MM, et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity. 1999;10(1):105-115. 59. Matsumoto K, Fujii H, Michalopoulos G, Fung JJ, Demetris AJ. Human biliary epithelial cells secrete and respond to cytokines and hepatocyte growth factors in vitro: interleukin-6, hepatocyte growth factor and epidermal growth factor promote DNA synthesis in vitro. Hepatology. 1994;20(2):376-382. 60. Meng F, Yamagiwa Y, Ueno Y, Patel T. Over-expression of interleukin-6 enhances cell survival and transformed cell growth in human malignant cholangiocytes. Journal of hepatology. 2006;44(6):1055-1065. 61. Yokomuro S, Tsuji H, Lunz JG, 3rd, et al. Growth control of human biliary epithelial cells by interleukin 6, hepatocyte growth factor, transforming growth factor beta1, and activin A: comparison of a cholangiocarcinoma cell line with primary cultures of non-neoplastic biliary epithelial cells. Hepatology. 2000;32(1):26-35. 62. Nehls O, Gregor M, Klump B. Serum and bile markers for cholangiocarcinoma. Seminars in liver disease. 2004;24(2):139-154. 63. Dokduang H, Techasen A, Namwat N, et al. STATs profiling reveals predominantly-activated STAT3 in cholangiocarcinoma genesis and progression. Journal of hepato-biliary-pancreatic sciences. 2014;21(10):767-776. 64. Yang J, Liang X, Niu T, Meng W, Zhao Z, Zhou GW. Crystal structure of the catalytic domain of protein-tyrosine phosphatase SHP-1. The Journal of biological chemistry. 1998;273(43):28199-28207. 65. Yang J, Liu L, He D, et al. Crystal structure of human protein-tyrosine phosphatase SHP-1. The Journal of biological chemistry. 2003;278(8):6516-6520. 66. Wang W, Liu L, Song X, et al. Crystal structure of human protein tyrosine phosphatase SHP-1 in the open conformation. Journal of cellular biochemistry. 2011;112(8):2062-2071. 67. Liu CY, Tseng LM, Su JC, et al. Novel sorafenib analogues induce apoptosis through SHP-1 dependent STAT3 inactivation in human breast cancer cells. Breast Cancer Res. 2013;15(4):R63. 68. Jackson JR, Gilmartin A, Imburgia C, Winkler JD, Marshall LA, Roshak A. An indolocarbazole inhibitor of human checkpoint kinase (Chk1) abrogates cell cycle arrest caused by DNA damage. Cancer research. 2000;60(3):566-572. 69. Hirose Y, Berger MS, Pieper RO. Abrogation of the Chk1-mediated G(2) checkpoint pathway potentiates temozolomide-induced toxicity in a p53-independent manner in human glioblastoma cells. Cancer research. 2001;61(15):5843-5849. 70. O'Connor DS, Grossman D, Plescia J, et al. Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(24):13103-13107. 71. Altieri DC. Survivin, cancer networks and pathway-directed drug discovery. Nature reviews Cancer. 2008;8(1):61-70. 72. Bollrath J, Phesse TJ, von Burstin VA, et al. gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer cell. 2009;15(2):91-102. 73. Jarnicki A, Putoczki T, Ernst M. Stat3: linking inflammation to epithelial cancer - more than a "gut" feeling? Cell division. 2010;5:14. 74. Liu T, Peng H, Zhang M, Deng Y, Wu Z. Cucurbitacin B, a small molecule inhibitor of the Stat3 signaling pathway, enhances the chemosensitivity of laryngeal squamous cell carcinoma cells to cisplatin. European journal of pharmacology. 2010;641(1):15-22. 75. Bromberg JF, Wrzeszczynska MH, Devgan G, et al. Stat3 as an oncogene. Cell. 1999;98(3):295-303. 76. Masuda M, Suzui M, Yasumatu R, et al. Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma. Cancer research. 2002;62(12):3351-3355. 77. Bowman T, Broome MA, Sinibaldi D, et al. Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(13):7319-7324. 78. Neel BG, Tonks NK. Protein tyrosine phosphatases in signal transduction. Current opinion in cell biology. 1997;9(2):193-204. 79. Barford D, Neel BG. Revealing mechanisms for SH2 domain mediated regulation of the protein tyrosine phosphatase SHP-2. Structure. 1998;6(3):249-254. 80. Hegazy SA, Wang P, Anand M, Ingham RJ, Gelebart P, Lai R. The tyrosine 343 residue of nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) is important for its interaction with SHP1, a cytoplasmic tyrosine phosphatase with tumor suppressor functions. The Journal of biological chemistry. 2010;285(26):19813-19820. 81. Witkiewicz A, Raghunath P, Wasik A, et al. Loss of SHP-1 tyrosine phosphatase expression correlates with the advanced stages of cutaneous T-cell lymphoma. Human pathology. 2007;38(3):462-467. 82. Hayslip J, Montero A. Tumor suppressor gene methylation in follicular lymphoma: a comprehensive review. Molecular cancer. 2006;5:44. 83. Chim CS, Wong KY, Loong F, Srivastava G. SOCS1 and SHP1 hypermethylation in mantle cell lymphoma and follicular lymphoma: implications for epigenetic activation of the Jak/STAT pathway. Leukemia. 2004;18(2):356-358. 84. Fan LC, Teng HW, Shiau CW, et al. SHP-1 is a target of regorafenib in colorectal cancer. Oncotarget. 2014;5(15):6243-6251. 85. Huang CY, Tai WT, Wu SY, et al. Dovitinib Acts As a Novel Radiosensitizer in Hepatocellular Carcinoma by Targeting SHP-1/STAT3 Signaling. International journal of radiation oncology, biology, physics. 2016. 86. Su JC, Tseng PH, Hsu CY, et al. RFX1-dependent activation of SHP-1 induces autophagy by a novel obatoclax derivative in hepatocellular carcinoma cells. Oncotarget. 2014;5(13):4909-4919. 87. Oberoi J, Dunn DM, Woodford MR, et al. Structural and functional basis of protein phosphatase 5 substrate specificity. Proc Natl Acad Sci U S A. 2016;113(32):9009-9014. 88. von Kriegsheim A, Pitt A, Grindlay GJ, Kolch W, Dhillon AS. Regulation of the Raf-MEK-ERK pathway by protein phosphatase 5. Nat Cell Biol. 2006;8(9):1011-1016. 89. Swingle M, Ni L, Honkanen RE. Small-molecule inhibitors of ser/thr protein phosphatases: specificity, use and common forms of abuse. Methods Mol Biol. 2007;365:23-38. 90. Puerto Galvis CE, Vargas Mendez LY, Kouznetsov VV. Cantharidin-based small molecules as potential therapeutic agents. Chem Biol Drug Des. 2013;82(5):477-499. 91. Hong TJ, Park K, Choi EW, Hahn JS. Ro 90-7501 inhibits PP5 through a novel, TPR-dependent mechanism. Biochem Biophys Res Commun. 2017;482(2):215-220. 92. Liu JY, Chen XE, Zhang YL. Insights into the key interactions between human protein phosphatase 5 and cantharidin using molecular dynamics and site-directed mutagenesis bioassays. Sci Rep. 2015;5:12359. 93. Oakhill JS, Scott JW, Kemp BE. AMPK functions as an adenylate charge-regulated protein kinase. Trends Endocrinol Metab. 2012;23(3):125-132. 94. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012;13(4):251-262. 95. Hardie DG, Ross FA, Hawley SA. AMP-activated protein kinase: a target for drugs both ancient and modern. Chem Biol. 2012;19(10):1222-1236. 96. Jeon SM. Regulation and function of AMPK in physiology and diseases. Exp Mol Med. 2016;48(7):e245. 97. Kjobsted R, Wojtaszewski JF, Treebak JT. Role of AMP-Activated Protein Kinase for Regulating Post-exercise Insulin Sensitivity. EXS. 2016;107:81-126. 98. O'Neill LA, Hardie DG. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature. 2013;493(7432):346-355. 99. Xu J, Ji J, Yan XH. Cross-talk between AMPK and mTOR in regulating energy balance. Crit Rev Food Sci Nutr. 2012;52(5):373-381. 100. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330(7503):1304-1305. 101. Cuzick J, Otto F, Baron JA, et al. Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement. Lancet Oncol. 2009;10(5):501-507. 102. Lee KH, Hsu EC, Guh JH, et al. Targeting energy metabolic and oncogenic signaling pathways in triple-negative breast cancer by a novel adenosine monophosphate-activated protein kinase (AMPK) activator. J Biol Chem. 2011;286(45):39247-39258. 103. Zadra G, Photopoulos C, Tyekucheva S, et al. A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis. EMBO Mol Med. 2014;6(4):519-538. 104. Saengboonmee C, Seubwai W, Cha'on U, Sawanyawisuth K, Wongkham S, Wongkham C. Metformin Exerts Antiproliferative and Anti-metastatic Effects Against Cholangiocarcinoma Cells by Targeting STAT3 and NF-kB. Anticancer Res. 2017;37(1):115-123. | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/94726 | - |
| dc.description.abstract | 膽管癌是一種高惡性度之侵襲性癌症，由於缺乏明顯症狀、診斷不易以及有限的藥物治療選 擇，造成膽管癌病人預後不佳，治療上帶來一個相當大的臨床挑戰。由於目前標準治療的療 效不盡理想，開發新型膽管癌的治療藥物無疑是一項重要使命。蛋白激脢是調節多種重要細 胞功能(如增殖和細胞代謝)的酵素，並且在發炎反應中扮演關鍵角色，而膽管細胞內的發炎反應是導致各種膽管癌亞型的主要風險。包括膽管癌在內的發炎性癌細胞中，signal transducers and activators of transcription 3 (STAT3)等激脢常常被過度活化，而蛋白激脢的活 性及其上下游相關的激脢均會受到磷酸脢的負向調控，這些磷酸脢負責激脢的去磷酸化，與 激脢的活性息息相關。與蛋白激脢相同，磷酸脢在調節細胞活動中也扮演著重要的角色，對 於多種細胞的功能至關重要。Serine/ threonine protein phosphatase 5 (PP5)，屬於磷蛋白磷酸 脢(PPP)家族當中，一種參與調節壓力信號和細胞增長的獨特磷酸脢。我們的研究專注於 抑制蛋白激脢或抑制磷酸脢的調控，藉以開發新型膽管癌治療藥物。在我們的兩個概念驗證 模型當中，展示了開發膽管癌新型治療劑的潛在機制。第一個模型顯示，藉由新型 Sorafenib 衍生物調控 SHP-1，抑制磷酸化的 STAT3 可以作為潛在的治療策略。第二個模型則發現， 通過調控 AMPK 來抑制 PP5，亦是一種可能的膽管癌治療途徑。我們衷心地希望透過這些 發現，能為未來膽管癌的治療藥物的研發盡上一份微薄貢獻。 | zh_TW |
| dc.description.abstract | Cholangiocarcinoma (CCA) is an aggressive disease with a dismal prognosis due to its silent presentation, delayed diagnosis, and limited effective treatment options. The significant unmet medical need in patients with CCA presents a substantial clinical challenge. Due to the unsatisfactory therapeutic outcomes associated with the current standard treatments, the development of novel agents for CCA treatment is undeniably an essential mission. Protein kinases, enzymes that regulate numerous essential cellular functions such as proliferation and cell metabolism, play a key role in inflammation, which represents the main risk factor shared by all CCA subtypes. Kinases such as signal transducers and activators of transcription 3 (STAT3) are frequently activated in inflammatory cancer cells including CCA. The activities of protein kinases and their upstream or down-stream kinases are negatively regulated by protein phosphatase, which are responsible for the dephosphorylation of these kinases. Similar to kinases, protein phosphatases play a fundamental role in regulating cellular activities, as protein phosphorylation and dephosphorylation are essential for a wide range of cellular functions. Serine/threonine protein phosphatase 5 (PP5), belong to the phosphoprotein phosphatase (PPP) family, is a unique phosphatase that participate in regulating stress signaling and cell growth. We focus on discovering new agents for CCA treatment not only regulating kinase but also phosphatase pathway. We focus on discovering new agents for CCA treatment through
the inhibition of not only kinase but also phosphatase pathways. Our two proof-of-concept models demonstrate the potential mechanisms for developing novel therapeutic agents for CCA. The first model demonstrates that inhibiting phosphorylated STAT3 by a novel Sorafenib derivative, through the regulation of SHP-1, is a potential therapeutic strategy. The second model, on the other hand, suggests that targeting PP5A through the regulation of AMPK presents an appealing treatment pathway for CCA. We hope that our findings will pave the way for the development of new treatments for CCA in the future. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2024-08-16T17:46:04Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2024-08-16T17:46:04Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | Acknowledgement……………………………………………………………...P1-2
Chinese abstract………………………………………………………………...P3 English abstract…………………………………………………………………P4-5 Content………………………………………………………………………….P6-8 Introduction……………………………………………………………………..P9-13 Materials and Methods………………………………………………………….P14-22 Results…………………………………………………………………………..P23-29 Discussion………………………………………………………………………P30-35 Conclusion……………………………………………………………………...P36 Perspectives…………………………………………………………………….P37 References.………………………………………………………………….….P38-43 Figure 1………………………………………………………………………..P44 Figure 2………………………………………………………………………..P45 Figure 3………………………………………………………………………..P46 Figure 4………………………………………………………………………..P47 Figure 5………………………………………………………………………..P48 Figure 6………………………………………………………………………..P49 Figure 7………………………………………………………………………..P50 Figure 8………………………………………………………………………..P51 Figure 9………………………………………………………………………..P52 Figure 10………………………………………………………………………P53 Figure 11………………………………………………………………………P54 Figure 12………………………………………………………………………P55 Figure 13………………………………………………………………………P56 Figure 14………………………………………………………………………P57 Figure 15………………………………………………………………………P58 Figure 16………………………………………………………………………P59 Figure 17………………………………………………………………………P60 Figure 18………………………………………………………………………P61 Figure 19………………………………………………………………………P62-63 Figure 20………………………………………………………………………P64 Figure 21………………………………………………………………………P65 Figure 22………………………………………………………………………P66 Figure 23………………………………………………………………………P67 Figure 24………………………………………………………………………P68 Figure 25………………………………………………………………………P69 Figure 26………………………………………………………………………P70 Figure 27………………………………………………………………………P71 Figure 28………………………………………………………………………P72 Figure 29………………………………………………………………………P73 Figure 30………………………………………………………………………P74 Figure 31………………………………………………………………………P75 Figure 32………………………………………………………………………P76 Figure 33………………………………………………………………………P77 | - |
| dc.language.iso | zh_TW | - |
| dc.subject | STAT3 | zh_TW |
| dc.subject | 膽管癌 | zh_TW |
| dc.subject | AMPK | zh_TW |
| dc.subject | PP5 | zh_TW |
| dc.subject | SHP-1 | zh_TW |
| dc.subject | Cholangiocarcinoma | en |
| dc.subject | STAT3 | en |
| dc.subject | AMPK | en |
| dc.subject | PP5 | en |
| dc.subject | SHP-1 | en |
| dc.title | 新興膽管癌藥物研究 | zh_TW |
| dc.title | Novel Target Signaling Pathway for the Treatment of Cholangiocarcinoma | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 112-2 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.coadvisor | 劉俊人 | zh_TW |
| dc.contributor.coadvisor | Chun-Jen Liu | en |
| dc.contributor.oralexamcommittee | 陳立宗;林俊彥;楊宏志;蘇東弘 | zh_TW |
| dc.contributor.oralexamcommittee | Li-Tzong Chen;Chun-Yen Lin;Hung-Chih Yang;Tung-Hung Su | en |
| dc.subject.keyword | 膽管癌,STAT3,SHP-1,PP5,AMPK, | zh_TW |
| dc.subject.keyword | Cholangiocarcinoma,STAT3,SHP-1,PP5,AMPK, | en |
| dc.relation.page | 77 | - |
| dc.identifier.doi | 10.6342/NTU202404281 | - |
| dc.rights.note | 同意授權(全球公開) | - |
| dc.date.accepted | 2024-08-13 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 臨床醫學研究所 | - |
| 顯示於系所單位： | 臨床醫學研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-112-2.pdf | 3.15 MB | Adobe PDF | 檢視/開啟 |
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。