請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/59667
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 鄭安理(Ann-Lii Cheng) | |
dc.contributor.author | Hsiao-Hui Lin | en |
dc.contributor.author | 林曉慧 | zh_TW |
dc.date.accessioned | 2021-06-16T09:32:18Z | - |
dc.date.available | 2017-03-01 | |
dc.date.copyright | 2017-03-01 | |
dc.date.issued | 2017 | |
dc.date.submitted | 2017-02-15 | |
dc.identifier.citation | 1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet][cited 2016 Feb 4] Available from: http://globocan.iarc.fr
2. Mittal S, El-Serag HB. Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol 47 (2013) Suppl: S2–6 3. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 142 (2012) 1264–1273. 4. Kew MC. Epidemiology of hepatocellular carcinoma in sub-Saharan Africa. Ann Hepatol 2 (2013)173–182. 5. Lim X, Nusse R. Wnt signaling in skin development, homeostasis, and disease. Cold Spring Harb Perspect Biol e-pub ahead of print (2013) a008029 6. Health Promotion Administration Ministry of Health and Welfare Taiwan: Taiwan Cancer Registry [Internet][cited 2016 Feb 4] Available from: https://cris.hpa. gov.tw/pagepub/Home.aspx?itemNo=cr.m.10 7. Chang MH, Chen CJ, Lai MS, Hsu HM, Wu TC, Kong MS, Liang DC, Shau WY, Chen DS. Universal Hepatitis B Vaccination in Taiwan and the Incidence of Hepatocellular Carcinoma in Children. N Engl J Med 336 (1997) 1855–1859. 8. Chen HL, Chang MH, Ni YH, Hsu HY, Lee PI, Lee CY, Chen DS. Seroepidemiology of hepatitis B virus infection in children: Ten years of mass vaccination in Taiwan. JAMA 276 (1996) 906-908. 9. Chang MH. Cancer prevention by vaccination against hepatitis B. Recent Results Cancer Res. 191 (2009) 85-94. Review. 10. Taiwan Cancer Registry (TCR) http://tcr.cph.ntu.edu.tw 11. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 7 (2007) 2557-2576. Review. 12. Poon D, Anderson BO, Chen LT, Tanaka K, Lau WY, Van Cutsem E, Singh H, Chow WC, Ooi LL, Chow P, Khin MW, Koo WH; Asian Oncology Summit. Management of hepatocellular carcinoma in Asia: consensus statement from the Asian Oncology. Lancet Oncol. 11 (2009) 1111-1118. 13. WHO | Hepatitis B http://www.who.int/ mediacentre/factsheets/fs204/en/ 14. Zampino R, Boemio A, Sagnelli C, Alessio L, Adinolfi LE, Sagnelli E, Coppola N. Hepatitis B virus burden in developing countries. World J Gastroenterol. 21 (2015) 11941-11953. 15. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 127 (2004) S35–50. 16. WHO | Hepatitis C http://www.who.int/mediacentre/factsheets/fs164/en/ 17. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 9822 (2012) 1245-1255. 18. Davis GL, Dempster J, Meler JD, Orr DW, Walberg MW, Brown B, Berger BD, O’Connor JK, Goldstein RM. Hepatocellular carcinoma: management of an increasingly common problem. Proc (Bayl Univ Med Cent). 21 (2008) 266-280. 19. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B,Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 64 (2004) 7099-7109. 20. Chang YS, Adane J, Trial PA, Levy J, Henderson A, Xue D, Bortolon E, Ichetovkin M, Chen C, McNabola A, Wilkie D, Carter CA, Taylor IC, Lynch M,Wilhelm S. Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol. 59 (2007) 561-574. 21. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 5 (2011) 646-674. 22. Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 27 (2015) 450-461. 23. Postow MA, Callahan MK, Wolchok JD. Immune Checkpoint Blockade in Cancer Therapy. J Clin Oncol. 33 (2015) 1974-1982. 24. Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 348 (2015) 56-61. 25. Sangro B, Melero I, Yau TC, Hsu C, Kudo M, Crocenzi TS, Kim TY, Choo SP, Trojan J, Meyer T, Kang YK, Anderson J, Cruz CMD, Lang L, Neely J, El-Khoueiry AB. Safety and antitumor activity of nivolumab (nivo) in patients (pts) with advanced hepatocellular carcinoma (HCC): Interim analysis of dose-expansion cohorts from the phase 1/2 CheckMate-040 study. J Clin Oncol 34 (2016) (suppl; abstr 4078) 26. Sangro B, Yau TC, Crocenzi TS, Welling TH, Yeo W, Chopra A, Anderson J, Cruz CMD, Lang L, Neely J, Melero I. Phase I/II safety and antitumor activity of nivolumab (nivo) in patients (pts) with advanced hepatocellular carcinoma (HCC): Interim analysis of the CheckMate-040 dose escalation study. J Clin Oncol 34 (2016) (suppl; abstr 4012) 27. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L,Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 59 (2008) 378–390. 28. Cheng AL, Guan Z, Chen Z, Tsao CJ, Qin S, Kim JS, Yang TS, Tak WY, Pan H, Yu S, Xu J, Fang F, Zou J, Lentini G, Voliotis D, Kang YK. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 10 (2009) 25–34. 29. Hsu CH, Shen YC, Shao YY, Hsu C, Cheng AL. Sorafenib in advanced hepatocellular carcinoma: current status and future perspectives. Journal of Hepatocellular Carcinoma. 1 (2014) 85-99. 30. Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M, Carter C. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 66 (2006) 11851-11858. 31. Ou DL, Shen YC, Yu SL, Chen KF, Yeh PY, Fan HH, Feng WC, Wang CT, Lin LI, Hsu C, Cheng AL. Induction of DNA damage-inducible gene GADD45beta contributes to sorafenib-induced apoptosis in hepatocellular carcinoma cells. Cancer Res. 22 (2010) 9309-9318. 32. Martin del Campo SE, Levine KM, Mundy-Bosse BL, Grignol VP, Fairchild ET, Campbell AR, Trikha P, Mace TA, Paul BK, Jaime-Ramirez AC, Markowitz J, Kondadasula SV, Guenterberg KD, McClory S, Karpa VI, Pan X, Olencki TE, Monk JP, Mortazavi A, Tridandapani S, Lesinski GB, Byrd JC, Caligiuri MA, Shah MH, Carson WE 3rd. The Raf Kinase Inhibitor Sorafenib Inhibits JAK-STAT Signal Transduction in Human Immune Cells. J Immunol. 195 (2015) 1995-2005. 33. Chen ML, Yan BS, Lu WC, Chen MH, Yu SL, Yang PC, Cheng AL. Sorafenib relieves cell-intrinsic and cell-extrinsic inhibitions of effector T cells in tumor microenvironment to augment antitumor immunity. Int J Cancer. 134 (2014) 319-331. 34. Chen KF, Tai WT, Liu TH, Huang HP, Lin YC, Shiau CW, Li PK, Chen PJ, Cheng AL. Sorafenib overcomes TRAIL resistance of hepatocellular carcinoma cells through the inhibition of STAT3. Clin Cancer Res. 21 (2010) 5189-5199. 35. Lackner MR, Wilson TR, Settleman J. Mechanisms of acquired resistance to targeted cancer therapies. Future Oncol. 8 (2012) 999–1014. 36. Bagrodia S, Smeal T, Abraham RT. Mechanisms of intrinsic and acquired resistance to kinase-targeted therapies. Pigment Cell Melanoma Res. 25 (2012) 819–831. 37. Zhai B, Sun XY. Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma. World J Hepatol. 5 (2013) 345–352. 38. Chen KF, Chen HL, Tai WT, Feng WC, Hsu CH, Chen PJ, Cheng AL. Activation of phosphatidylinositol 3-kinase/Akt signaling pathway mediates acquired resistance to sorafenib in hepatocellular carcinoma cells. J Pharmacol Exp Ther. 337 (2011) 155-161. 39. Lin TH, Shao YY, Chan SY, Huang CY, Hsu CH, Cheng AL. High Serum Transforming Growth Factor-β1 Levels Predict Outcome in Hepatocellular Carcinoma Patients Treated with Sorafenib. Clin Cancer Res. 21 (2015) 3678-3684. 40. Wei Z, Jiang X, Qiao H, Zhai B, Zhang L, Zhang Q, Wu Y, Jiang H, Sun X. STAT3 interacts with Skp2/p27/p21 pathway to regulate the motility and invasion of gastric cancer cells. Cell Signal. 25 (2013) 931–938. 41. Tai WT, Cheng AL, Shiau CW, Liu CY, Ko CH, Lin MW, Chen PJ, Chen KF. Dovitinib induces apoptosis and overcomes sorafenib resistance in hepatocellular carcinoma through SHP-1-mediated inhibition of STAT3. Mol Cancer Ther. 11 (2012) 452-463. 42. Komiya Y, Habas R. Wnt signal transduction pathways. Organogenesis. 4 (2008) 68-75. 43. Stamos JL, Weis WI. The β-catenin destruction complex. Cold Spring Harb Perspect Biol. 5 (2013) a007898. 44. Sethi JK1, Vidal-Puig A. Wnt signalling and the control of cellular metabolism. Biochem J. 427 (2010) 1-17. 45. MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 17 (2009) 9-26. 46. Giannakis M, Hodis E, Jasmine Mu X, Yamauchi M, Rosenbluh J, Cibulskis K, Saksena G, Lawrence MS, Qian ZR, Nishihara R, Van Allen EM, Hahn WC, Gabriel SB, Lander ES, Getz G, Ogino S, Fuchs CS, Garraway LA. RNF43 is frequently mutated in colorectal and endometrial cancers. Nat Genet 46 (2014) 1264–1266. 47. Delmas V, Beermann F, Martinozzi S, Carreira S, Ackermann J, Kumasaka M, Denat L, Goodall J, Luciani F, Viros A, Demirkan N, Bastian BC, Goding CR, Larue L. Beta-catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development. Genes Dev 21 (2007) 2923–2935. 48. Juan J, Muraguchi T, Iezza G, Sears RC, McMahon M. Diminished WNT ->beta -catenin->c-MYC signaling is a barrier for malignant progression of BRAFV600E-induced lung tumors. Genes Dev 28 (2014) 561–575. 49. Zhang Y, Morris JP 4th, Yan W, Schofield HK, Gurney A, Simeone DM, Millar SE, Hoey T, Hebrok M, Pasca di Magliano M. Canonical wnt signaling is required for pancreatic carcinogenesis. Cancer Res. 73 (2013) 4909-4922. 50. Lin SY, Xia W, Wang JC, Kwong KY, Spohn B, Wen Y, Pestell RG, Hung MC. Beta-catenin, a novel prognostic marker for breast cancer: its roles in cyclin D1 expression and cancer progression. Proc Natl Acad Sci USA 97 (2000) 4262–4266. 51. Kaveri D, Kastner P, Dembélé D, Nerlov C, Chan S, Kirstetter P. β-Catenin activation synergizes with Pten loss and Myc overexpression in Notch-independent T-ALL. Blood 122 (2013) 694–704. 52. Lu D, Zhao Y, Tawatao R, Cottam HB, Sen M, Leoni LM, Kipps TJ, Corr M, Carson DA. Activation of the Wnt signaling pathway in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 101 (2004) 3118–3123. 53. Villanueva A, Newell P, Chiang DY, Friedman SL, Llovet JM. Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis. 27 (2007) 55–76. 54. Lachenmayer A, Alsinet C, Savic R, Cabellos L, Toffanin S, Hoshida Y, Villanueva A, Minguez B, Newell P, Tsai HW, et al. Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib. Clin Cancer Res. 18 (2012) 4997–5007. 55. Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, Calderaro J, Bioulac-Sage P, Letexier M, Degos F, Clément B, Balabaud C, Chevet E, Laurent A, Couchy G, Letouzé E, Calvo F, Zucman-Rossi J. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nature Genetics 44 (2012) 694–698. 56. Takigawa Y, Brown AM. Wnt signaling in liver cancer. Curr Drug Targets. 11 (2008) 1013-1024. 57. Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, Zhang Z, Lin X, He X. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell. 108 (2002) 837-847. 58. Legoix P, Bluteau O, Bayer J, Perret C, Balabaud C, Belghiti J, Franco D, Thomas G, Laurent-Puig P, Zucman-Rossi J. Beta-catenin mutations in hepatocellular carcinoma correlate with a low rate of loss of heterozygosity. Oncogene. 27 (1999) 4044-4046. 59. Behrens J, Jerchow BA, Würtele M, Grimm J, Asbrand C, Wirtz R, Kühl M, Wedlich D, Birchmeier W. Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Science. 5363 (1998) 596-599. 60. Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, Kawasoe T, Ishiguro H, Fujita M, Tokino T, Sasaki Y, Imaoka S, Murata M, Shimano T, Yamaoka Y, Nakamura Y. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet. 24 (2000) 245-250. 61. Huang H, Fujii H, Sankila A, Mahler-Araujo BM, Matsuda M, Cathomas G, Ohgaki H. Beta-catenin mutations are frequent in human hepatocellular carcinomas associated with hepatitis C virus infection. Am J Pathol. 155 (1999) 1795-1801. 62. Hoshida Y, Nijman SM, Kobayashi M, Chan JA, Brunet JP, Chiang DY, Villanueva A, Newell P, Ikeda K, Hashimoto M, Watanabe G, Gabriel S, Friedman SL, Kumada H, Llovet JM, Golub TR. Integrative Transcriptome Analysis Reveals Common Molecular Subclasses of Human Hepatocellular Carcinoma. Cancer Res. 69 (2009) 7385-7392. 63. Fischer AN, Fuchs E, Mikula M, Huber H, Beug H, Mikulits W. PDGF essentially links TGF-β signaling to nuclear β-catenin accumulation in hepatocellular carcinoma progression. Oncogene 26 (2007) 3395–3405. 64. Jian H, Shen X, Liu I, Semenov M, He X, Wang XF. SMAD3-dependent nuclear translocation of β-catenin is required for TGF-β1-induced proliferation of bone marrow-derived adult human mesenchymal stem cells. Genes Dev 20 (2006) 666–74. 65. Anastas JN, Kulikauskas RM, Tamir T, Rizos H, Long GV, von Euw EM, Yang PT, Chen HW, Haydu L, Toroni RA, Lucero OM, Chien AJ, Moon RT. Wnt5a enhances resistance of melanoma cells to targeted Braf inhibitors. J Clin Invest 124 (2014) 2877–2890. 66. Peng C, Zhang X, Yu H, Wu D, Zheng J. Wnt5a as a predictor in poor clinical outcome of patients and a mediator in chemoresistance of ovarian cancer. Int J Gynecol Cancer 21 (2011) 280–288. 67. Chikazawa N, Tanaka H, Tasaka T, Nakamura M, Tanaka M, Onishi H, Katano M. Inhibition of Wnt signaling pathway decreases chemotherapy-resistant side- population colon cancer cells. Anticancer Res. 30 (2010) 2041-2048. 68. Wang B, Zou Q, Sun M, Chen J, Wang T, Bai Y, Chen Z, Chen B, Zhou M. Reversion of trichostatin A resistance via inhibition of the Wnt signaling pathway in human pancreatic cancer cells. Oncol Rep. 32 (2014) 2015-2022. 69. Yu C, Bruzek LM, Meng XW, Gores GJ, Carter CA, Kaufmann SH, Adjei AA. The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006. Oncogene. 24 (2005) 6861-6869. 70. Rahmani M, Davis EM, Bauer C, Dent P, Grant S. Apoptosis induced by the kinase inhibitor BAY 43-9006 in human leukemia cells involves down-regulation of Mcl-1 through inhibition of translation. J Biol Chem. 280 (2005) 35217-3527. 71. Yang L, Perez AA, Fujie S, Warden C, Li J, Wang Y, Yung B, Chen YR, Liu X, Zhang H, Zheng S, Liu Z, Ann D, Yen Y. Wnt modulates MCL1 to control cell survival in triple negative breast cancer. BMC Cancer. 14 (2014) 124. 72. Iqbal S, Zhang S, Driss A, Liu ZR, Kim HR, Wang Y, Ritenour C, Zhau HE, Kucuk O, Chung LW, Wu D. PDGF upregulates Mcl-1 through activation of β-catenin and HIF-1α-dependent signaling in human prostate cancer cells. PLoS One. 7 (2012) e30764. 73. Wei Y, Shen N, Wang Z, Yang G, Yi B, Yang N, Qiu Y, Lu J. Sorafenib sensitizes hepatocellular carcinoma cell to cisplatin via suppression of Wnt/β-catenin signaling. Mol Cell Biochem. 381 (2013):139-144. 74. Lin YT, Chao CC. Identification of the β-catenin/JNK/prothymosin-alpha axis as a novel target of sorafenib in hepatocellular carcinoma cells. Oncotarget. 6 (2015):38999-9017. 75. Muche S, Kirschnick M, Schwarz M, Braeuning A. Synergistic effects of β-catenin inhibitors and sorafenib in hepatoma cells. Anticancer Res. 34 (2014) 4677-4683. 76. Galuppo R, Maynard E, Shah M, Daily MF, Chen C, Spear BT, et al. Synergistic inhibition of HCC and liver cancer stem cell proliferation by targeting RAS/RAF/MAPK and Wnt/β-catenin pathways. Anticancer Res. 34 (2014) 1709-1713. 77. Boyault S, Rickman DS, de Reyniès A, Balabaud C, Rebouissou S, Jeannot E, Hérault A, Saric J, Belghiti J, Franco D, Bioulac-Sage P, Laurent-Puig P, Zucman-Rossi J. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology. 45 (2007) 42-52. 78. Kan Z, Zheng H, Liu X, Li S, Barber TD, Gong Z, Gao H, Hao K, Willard MD, Xu J, Hauptschein R, Rejto PA, Fernandez J, Wang G, Zhang Q, Wang B, Chen R, Wang J, Lee NP, Zhou W, Lin Z, Peng Z, Yi K, Chen S, Li L, Fan X, Yang J, Ye R, Ju J, Wang K, Estrella H, Deng S, Wei P, Qiu M, Wulur IH, Liu J, Ehsani ME, Zhang C, Loboda A, Sung WK, Aggarwal A, Poon RT, Fan ST, Wang J, Hardwick J, Reinhard C, Dai H, Li Y, Luk JM, Mao M. Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma. Genome Res. 23 (2013) 1422-1433. 79. Rebouissou S, Franconi A, Calderaro J, Letouzé E, Imbeaud S, Pilati C, Nault JC, Couchy G, Laurent A, Balabaud C, Bioulac-Sage P, Zucman-Rossi J. Genotype- phenotype correlation of CTNNB1 mutations reveals different β-catenin activity associated with liver tumor progression. Hepatology. 64 (2016) 2047-2061. 80. Wong CM, Fan ST, Ng IO. beta-Catenin mutation and overexpression in hepatocellular carcinoma: clinicopathologic and prognostic significance. Cancer. 92 (2001) 136-145. 81. Kim YD, Park CH, Kim HS, Choi SK, Rew JS, Kim DY, Koh YS, Jeung KW, Lee KH, Lee JS, Juhng SW, Lee JH. Genetic alterations of Wnt signaling pathway-associated genes in hepatocellular carcinoma. J Gastroenterol Hepatol. 23 (2008) 110-118. 82. Fujie H, Moriya K, Shintani Y, Tsutsumi T, Takayama T, Makuuchi M, Kimura S, Koike K. Frequent beta-catenin aberration in human hepatocellular carcinoma. Hepatol Res. 20 (2001) 39-51. 83. Li M, Zhao H, Zhang X, Wood LD, Anders RA, Choti MA, Pawlik TM, Daniel HD, Kannangai R, Offerhaus GJ, Velculescu VE, Wang L, Zhou S, Vogelstein B, Hruban RH, Papadopoulos N, Cai J, Torbenson MS, Kinzler KW. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat Genet. 43 (2011) 828-829. 84. Fujimoto A, Totoki Y, Abe T, Boroevich KA, Hosoda F, Nguyen HH, Aoki M, Hosono N, Kubo M, Miya F, Arai Y, Takahashi H, Shirakihara T, Nagasaki M, Shibuya T, Nakano K, Watanabe-Makino K, Tanaka H, Nakamura H, Kusuda J, Ojima H, Shimada K, Okusaka T, Ueno M, Shigekawa Y, Kawakami Y, Arihiro K, Ohdan H, Gotoh K, Ishikawa O, Ariizumi S, Yamamoto M, Yamada T, Chayama K, Kosuge T, Yamaue H, Kamatani N, Miyano S, Nakagama H, Nakamura Y, Tsunoda T, Shibata T, Nakagawa H. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet. 44 (2012) 760-764. 85. Lu LC, Shao YY, Lee YH, Hsieh MS, Hsiao CH, Lin HH, Kao HF, Ma YY, Yen FC, Cheng AL, Hsu CH. β-catenin (CTNNB1) mutations are not associated with prognosis in advanced hepatocellular carcinoma. Oncology 87 (2014) 159-166. 86. Hsu HC, Jeng YM, Mao TL, Chu JS, Lai PL, Peng SY. Beta-catenin mutations are associated with a subset of low-stage hepatocellular carcinoma negative for hepatitis B virus and with favorable prognosis. Am J Pathol. 157 (2000) 763-770. 87. Takahashi-Yanaga F, Kahn M. Targeting Wnt signaling: can we safely eradicate cancer stem cells? Clin Cancer Res. 16 (2010) 3153-3162. 88. Chen B, Dodge ME, Tang W, Lu J, Ma Z, Fan CW, Wei S, Hao W, Kilgore J, Williams NS, Roth MG, Amatruda JF, Chen C, Lum L. Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat Chem Biol 5 (2009) 100–107. 89. Liu J, Pan S, Hsieh MH, Ng N, Sun F, Wang T, Kasibhatla S, Schuller AG, Li AG, Cheng D, Li J, Tompkins C, Pferdekamper A, Steffy A, Cheng J, Kowal C, Phung V, Guo G, Wang Y, Graham MP, Flynn S, Brenner JC, Li C, Villarroel MC, Schultz PG, Wu X, McNamara P, Sellers WR, Petruzzelli L, Boral AL, Seidel HM, McLaughlin ME, Che J, Carey TE, Vanasse G, Harris JL. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc Natl Acad Sci USA 110 (2013) 20224–20229. 90. Huang SM, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA, Charlat O, Wiellette E, Zhang Y, Wiessner S, Hild M, Shi X, Wilson CJ, Mickanin C, Myer V, Fazal A, Tomlinson R, Serluca F, Shao W, Cheng H, Shultz M, Rau C, Schirle M, Schlegl J, Ghidelli S, Fawell S, Lu C, Curtis D, Kirschner MW, Lengauer C, Finan PM, Tallarico JA, Bouwmeester T, Porter JA, Bauer A, Cong F. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461 (2009) 614–620. 91. Emami KH, Nguyen C, Ma H, Kim DH, Jeong KW, Eguchi M, Moon RT, Teo JL, Kim HY, Moon SH, Ha JR, Kahn M. A small molecule inhibitor of beta-catenin/CREB-binding protein transcription. Proc Natl Acad Sci USA 101 (2004) 12682–12687. 92. Gang EJ, Hsieh YT, Pham J, Zhao Y, Nguyen C, Huantes S, Park E, Naing K, Klemm L, Swaminathan S, Conway EM, Pelus LM, Crispino J, Mullighan CG, McMillan M, Muschen M, Kahn M, Kim YM. Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia. Oncogene 33 (2014) 2169–2178. 93. Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, Kawasoe T, Ishiguro H, Fujita M, Tokino T, Sasaki Y, Imaoka S, Murata M, Shimano T, Yamaoka Y, Nakamura Y. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet. 24 (2000) 245-250. 94. Laurent-Puig P, Legoix P, Bluteau O, Belghiti J, Franco D, Binot F, Monges G, Thomas G, Bioulac-Sage P, Zucman-Rossi J. Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis. Gastroenterology. 120 (2001) 1763-1773. 95. Delgado E, Okabe H, Preziosi M, Russell JO, Alvarado TF, Oertel M, Nejak-Bowen KN, Zhang Y, Monga SP. Complete response of Ctnnb1-mutated tumours to β-catenin suppression by locked nucleic acid antisense in a mouse hepatocarcinogenesis model. J Hepatol. 62 (2015) 380-387. 96. Kim YM, Kahn M. The role of the Wnt signaling pathway in cancer stem cells: prospects for drug development. Res Rep Biochem. 4 (2014) 1-12. 97. McMillan M, Kahn M. Investigating Wnt signaling: a chemogenomic safari. Drug Discov Today. 21 (2005) 1467-1474. 98. Arensman MD, Telesca D, Lay AR, Kershaw KM, Wu N, Donahue TR, et al. The CREB-binding protein inhibitor ICG-001 suppresses pancreatic cancer growth. Mol Cancer Ther. 13 (2014) 2303-2314. 99. Jiang X, Hao HX, Growney JD, Woolfenden S, Bottiglio C, Ng N, Lu B, Hsieh MH, Bagdasarian L, Meyer R, Smith TR, Avello M, Charlat O, Xie Y, Porter JA, Pan S, Liu J, McLaughlin ME, Cong F. Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. Proc Natl Acad Sci U S A. 110 (2013) 12649-12654. 100. Novellasdemunt L, Antas P, Li VS. Targeting Wnt signaling in colorectal cancer. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms. Am J Physiol Cell Physiol. 309 (2015) C511-C521. 101. Gurney A, Axelrod F, Bond CJ, Cain J, Chartier C, Donigan L, Fischer M, Chaudhari A, Ji M, Kapoun AM, Lam A, Lazetic S, Ma S, Mitra S, Park IK, Pickell K, Sato A, Satyal S, Stroud M, Tran H, Yen WC, Lewicki J, Hoey T. Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc Natl Acad Sci USA 109 (2012) 11717–11722. 102. DeAlmeida VI, Miao L, Ernst JA, Koeppen H, Polakis P, Rubinfeld B. The soluble Wnt receptor Frizzled8CRD-hFc inhibits the growth of teratocarcinomas in vivo. Cancer Res 67 (2007) 5371–5379. 103. Le PN McDermott JD, Jimeno A. Targeting the Wnt pathway in human cancers: therapeutic targeting with a focus on OMP-54F28. Pharmacol Ther. 146 (2015) 1-11. 104. Jimeno A, Gordon MS, Chugh R, Messersmith WA, Mendelson DS, Dupont J, Stagg RJ, Kapoun A, Xu L, Brachmann RK, Smith DC. A first-in-human phase 1 study of anticancer stem cell agent OMP-54F28 (FZD8-Fc), decoy receptor for WNT ligands, in patients with advanced solid tumors. J. Clin. Oncol. 32 (Suppl.) (2014) Abstract 2505 105. Shultz MD, Cheung AK, Kirby CA, Firestone B, Fan J, Chen CH, Chen Z, Chin DN, Dipietro L, Fazal A, Feng Y, Fortin PD, Gould T, Lagu B, Lei H, Lenoir F, Majumdar D, Ochala E, Palermo MG, Pham L, Pu M, Smith T, Stams T, Tomlinson RC, Touré BB, Visser M, Wang RM, Waters NJ, Shao W. Identification of NVP-TNKS656: the use of structure-efficiency relationships to generate a highly potent, selective, and orally active tankyrase inhibitor. J Med Chem. 56 (2013) 6495-6511. 106. Masuda M, Sawa M, Yamada T. Therapeutic targets in the Wnt signaling pathway: Feasibility of targeting TNIK in colorectal cancer. Pharmacol Ther. 156 (2015) 1-9. 107. Tian W, Han X, Yan M, Xu Y, Duggineni S, Lin N, Luo G, Li YM, Han X, Huang Z, An J. Structure-based discovery of a novel inhibitor targeting the beta-catenin/Tcf4 interaction. Biochemistry 51 (2012) 724–731. 108. Ma H, Nguyen C, Lee KS, Kahn M. Differential roles for the coactivators CBP and p300 on TCF/beta-catenin-mediated survivin gene expression. Oncogene. 24 (2005) 3619-3631. 109. El-Khoueiry AB, Ning Y, Yang DY, Cole S, Kahn M, Zoghbi M, Berg J, Fujimori M, Inada T, Kouji H, Lenz HJ. A phase I first-in-human study of PRI-724 in patients (pts) with advanced solid tumors. Journal of Clinical Oncology. (2013) 31. 110. Lenz HJ, Kahn M. Safely targeting cancer stem cells via selective catenin coactivator antagonism. Cancer Sci. 105 (2014) 1087-1092. 111. Park CH, Hahm ER, Park S, Kim HK, Yang CH. The inhibitory mechanism of curcumin and its derivative against beta-catenin/Tcf signaling. FEBS Lett. 579 (2005) 2965-2971. 112. Zhang X, Hao J. Development of anticancer agents targeting the Wnt/β-catenin signaling. Am J Cancer Res. 5 (2015) 2344-2360. 113. Pilati C, Letouzé E, Nault JC, Imbeaud S, Boulai A, Calderaro J, Poussin K, Franconi A, Couchy G, Morcrette G, Mallet M, Taouji S, Balabaud C, Terris B, Canal F, Paradis V, Scoazec JY, de Muret A, Guettier C, Bioulac-Sage P, Chevet E, Calvo F, Zucman-Rossi J. Genomic profiling of hepatocellular adenomas reveals recurrent FRK-activating mutations and the mechanisms of malignant transformation. Cancer Cell 25 (2014) 428-441. 114. Luke JJ, Bao R, Spranger S, Sweis RF, Gajewski T. Correlation of WNT/β-catenin pathway activation with immune exclusion across most human cancers. J Clin Oncol 34 (2016) suppl; abstr 3004. 115. Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature. 523 (2015) 231-235. 116. Spranger S, Sivan A, Corrales L, Gajewski TF. Tumor and Host Factors Controlling Antitumor Immunity and Efficacy of Cancer Immunotherapy. Adv Immunol. 130 (2016) 75-93. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/59667 | - |
dc.description.abstract | 肝細胞癌(Hepatocellular Carcinoma,簡稱HCC)為十分致命且預後非常差的癌症之一。過去幾十年來,在肝細胞癌的篩檢、早期診斷、以及局部治療上,雖然已有長足的進步;但大多數的肝細胞癌病人仍終將發展至晚期(advanced stage),而必須考慮接受全身性藥物治療。目前晚期肝細胞癌的標準治療,也是唯一經衛生主管機關核可的藥物是sorafenib (商品名為Nexavar【蕾莎瓦】)。Sorafenib是一種多重激酶抑制劑,可抑制Raf激酶及對抗血管內皮生長因子受體。整體而言,sorafenib在肝癌的治療上,腫瘤縮小的機率不高,腫瘤控制時間短暫,其治療效果仍有相當進步的空間。
本論文研究鎖定「Wnt/β-catenin訊息傳遞路徑」做為肝細胞癌嶄新的治療標的。Wnt/β-catenin訊息傳遞路徑在胚胎發育、組織結構的恆定、以及肝細胞癌癌化的過程上,都扮演十分重要的角色。本論文研究嘗試驗證以下兩個假說:一、抑制Wnt/β-catenin訊息傳遞路徑的活性可促進sorafenib對於肝細胞癌的治療療效;二、肝細胞癌β-catenin 基因上特殊的活化性突變,可能導致該癌細胞對特定的Wnt/β-catenin訊息傳遞路徑抑制劑特別敏感。 在本論文的第一部分中,我們證實了無論於細胞培養上或活體內,抑制Wnt/ β-catenin訊息傳遞路徑的活性可促進sorafenib對於肝細胞癌的治療效果。ICG-001是Wnt/β-catenin訊息傳遞路徑的小分子抑制劑,它經由阻斷的β-catenin與轉譯共同激活因子CBP之間的交互作用而達到抑制效果。在多株肝細胞癌的體外培養實驗中,我們發現伴隨著ICG-001使用的濃度提高,肝細胞癌細胞株生長受到sorafenib治療後生長抑制的情況及走向細胞凋亡的細胞比例隨之增加。進一步以RNA干擾的技術抑制β-catenin後,我們亦發現肝細胞癌細胞株Huh7對sorafenib作用的敏感度明顯提升;反之將β-catenin過度表現,則可降低Huh7對sorafenib作用的敏感度。此外,我們發現經短髮夾RNA(shRNA)處理導致β-catenin表現低下之Huh7對sorafenib作用的敏感度提升,再將該細胞的β-catenin過度表現之後,其敏感度則再度降低。就機制上而言,合併使用sorafenib與ICG-001可促使更多肝細胞癌細胞株走向細胞凋亡,並導致Mcl-1表現的更顯著下降。在Huh7肝細胞癌細胞小鼠皮下腫瘤的動物模式,合併使用sorafenib與ICG-001的組別相較於單獨使用sorafenib亦或ICG-001的組別,更能顯著地抑制腫瘤的生長。 在本論文的第二部分中,我們則闡明了CTNNB1基因之第三外顯子具有錯義突變(missense mutation)之肝細胞癌細胞株,對特定的Wnt/β-catenin訊息傳遞路徑抑制劑的抑制作用有較高的敏感度。我們使用SNU398與Huh6(分別於CTNNB1基因的第三外顯子的S37C及G34V有錯義突變)、Huh7及HepG2(在CTNNB1基因第三外顯子處有缺失的片段[interstitial deletion])、及PLC5、Hep3B、HLE及SK-Hep1 (在第三外顯子的位置無基因異常)等肝細胞癌細胞株;並分別處理包括ICG-001、XAV939 (為tankyrase的抑制劑,可藉此達到AXIN-1的穩定,以抑制β-catenin的訊息傳遞活性)、以及LGK974 (為porcupine的抑制劑;porcupine可促使Wnt ligands的成熟與分泌)等Wnt/β-catenin訊息傳遞路徑抑制劑。在XAV939及LGK974的處理下,不同肝細胞癌細胞株生長受到抑制的程度差異並不顯著;然而在ICG-001的處理下,我們發現SNU398的生長抑制作用最為顯著,緊追其後為Huh6。除此之外, ICG-001對於SNU398的細胞聚落形成的抑制力、經ICG-001處理後誘發sub-G1波峰提升的程度,皆高於其他肝細胞癌細胞株。最後,不同的化學治療藥物,包含doxorubicin、cisplatin、及5-fluorouracil對不同肝細胞癌細胞株的抑癌效果,並無發現顯著的差異。 我們的實驗研究結果顯示抑制Wnt/β-catenin訊息傳遞路徑的活性可促進sorafenib對於肝細胞癌的治療療效,而具有β-catenin第三外顯子有錯義突變的肝細胞癌細胞株對ICG-001的抑癌效果最為敏感。本論文研究的發現支持持續鎖定Wnt/β-catenin訊息傳遞路徑研發抑制劑(無論是與sorafenib合併使用,或針對特定分子標記族群做單一治療)以治療肝細胞癌。 | zh_TW |
dc.description.abstract | Hepatocellular carcinoma (HCC) is one of the most lethal cancers in the world. Although a lot of advances in screening, early diagnosis, and loco-regional therapies for HCC have been made over the past decades, most HCC patients would eventually develop advanced diseases that need systemic therapy. Currently, sorafenib, a multikinase inhibitor targeting Raf kinase and vascular endothelial growth factor receptor, is the only approved drug for HCC. However, its efficacy is limited, with low tumor response rate and short tumor control duration.
The current thesis work focuses on developing new therapeutic strategies for HCC by targeting the Wnt/β-catenin signaling pathway, which plays an important role in embryonic development and tissue homeostasis, as well as in hepatocarcinogenesis. The thesis work has tested two hypotheses: (1) inhibition of the Wnt/β-catenin signaling pathway could improve the anti-tumor effects of sorafenib in HCC; (2) activating mutations of β-catenin gene may confer sensitivity to specific Wnt/β-catenin pathway inhibitors in HCC. In the first part of the current thesis work, we demonstrated that inhibition of the Wnt/β-catenin signaling pathway could improve the anti-tumor effects of sorafenib against HCC in vitro and in vivo. ICG-001, a small molecule that blocks the interaction of β-catenin with its transcriptional coactivator CBP, dose-dependently enhanced the growth-suppressive and apoptosis- induction effects of sorafenib in multiple HCC cell lines. Downregulation of β-catenin by RNA interference increased sorafenib sensitivity, whereas overexpression of β-catenin reduced sorafenib sensitivity in Huh7 cells. The sorafenib-sensitization effect of short hairpin RNA (shRNA)-mediated β-catenin downregulation in Huh7 cells was attenuated by β-catenin overexpression. Mechanistically, sorafenib combined with ICG-001 or shRNA- mediated β-catenin downregulation augmented the induction of apoptosis, and resulted in a significant downregulation of Mcl-1 in HCC cells. In Huh7 cell mouse xenograft model, the combination of ICG-001 and sorafenib showed a more significant growth-retarding effect than single agent treatment of sorafenib or ICG-001. In the second part of the current thesis work, we demonstrated that HCC cells with point mutation at exon 3 of the CTNNB1 gene exhibited an increased sensitivity to antitumor effects of certain Wnt/β-catenin inhibitors in vitro. SNU398 and Huh6 are HCC cells harboring missense somatic mutations in exon 3 of the CTNNB1 gene, resulting in S37C and G34V mutation, respectively; Huh7 and HepG2 are HCC cells with interstitial deletion of exon 3; while other HCC cells including PLC5, Hep3B, HLE, and SK-Hep1 are HCC cells containing no mutations in exon 3. Several classes of Wnt/β-catenin pathway inhibitors were tested including ICG-001, XAV939 (an inhibitor of tankyrases which would stabilize AXIN-1 and thus β-catenin transactivation activity), and LGK974 (an inhibitor of porcupine which could help maturation and secretion of Wnt ligands). The sensitivity to growth suppressive effects of XAV939 and LGK974 did not vary significantly among all tested HCC cells. However, the growth-suppressive effect to ICG-001 was most sensitive in SNU398 cells, followed by Huh6 cells, and less sensitive in other HCC cells. ICG-001 also induced a more significant suppression of colony-formation, and a more significant increase of sub-G1 fraction by flow cytometry in SNU398 than other HCC cells. Finally, the cytotoxic effects of multiple chemotherapy drugs including doxorubicin, cisplatin, and 5-fluorouracil did not significantly differ among tested HCC cells. Our studies have demonstrated that targeting of Wnt/β-catenin signaling pathway improves the anti-tumor effects of sorafenib against HCC and the presence of a missense mutation in exon 3 of β-catenin may confer increased sensitivity to ICG-001 in certain HCC cells. These data support further investigations on developing Wnt/β-catenin inhibitors as potential cancer therapeutics for HCC by either combination with sorafenib or single-agent approach focusing on biomarker-enriched population. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T09:32:18Z (GMT). No. of bitstreams: 1 ntu-106-D98453001-1.pdf: 3667692 bytes, checksum: d52433331875220b3fbf6220e4d739f0 (MD5) Previous issue date: 2017 | en |
dc.description.tableofcontents | 致謝 i
中文摘要 ii Abstract v Abbreviations viii Contents x List of Figures xii List of Tables xiv Chapter I – Overview and Rationale. 1 1. Hepatocellular Carcinoma (HCC) 1 1.1 Significance of HCC worldwide and in Taiwan 1 1.2 Risk factors for the development of HCC 2 1.3 Staging and treatment of HCC 3 1.4 Systemic therapy for advanced HCC 4 2. Sorafenib: the only approved systemic agent for HCC 7 2.1 Clinical activity of sorafenib in HCC 7 2.2 Anti-cancer mechanisms of sorafenib 7 2.3 Inherent and acquired drug resistance of sorafenib 9 3. Wnt/β-catenin signaling pathway 11 3.1 The Canonical pathway of Wnt/β-catenin 11 3.2 Aberrant Wnt/β-catenin signaling in cancer 12 3.3 Aberrant Wnt/β-catenin signaling in HCC 13 3.4 Drug resistance through Wnt/β-catenin activation in cancer 14 4. Hypothesis of the current thesis work 15 Chapter II – Inhibition of the Wnt/β-catenin signaling pathway improves the anti-tumor effects of sorafenib against hepatocellular carcinoma. 17 1. Introduction 17 2. Materials and Methods 18 3. Results 24 4. Conclusion and Discussions 30 Chapter III – Activating Mutation of β-catenin confers sensitivity to certain types of Wnt/β-catenin inhibitors in HCC cells 34 1. Introduction 34 2. Materials and Methods 36 3. Results 42 4. Discussion 46 Chapter IV – Summary and Discussions 51 Figures 57 Tables 81 Reference 84 Appendices 95 | |
dc.language.iso | en | |
dc.title | 阻斷Wnt/β-catenin訊息傳遞路徑以治療肝細胞癌 | zh_TW |
dc.title | Targeting the Wnt/β-catenin Signaling Pathway in the Treatment of Hepatocellular Carcinoma | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-1 | |
dc.description.degree | 博士 | |
dc.contributor.coadvisor | 徐志宏(Chih-Hung Hsu) | |
dc.contributor.oralexamcommittee | 楊志新(Chih-Hsin Yang),許鵔(Chiun Hsu),葉秀慧(Shiou-Hwei Yeh),趙毅(Yee Chao),謝森永(Sen-Yung Hsieh) | |
dc.subject.keyword | Wnt/β-catenin訊息傳遞路徑,肝細胞癌,蕾莎瓦,ICG-001小分子抑制劑,活化突變,CTNNB1基因, | zh_TW |
dc.subject.keyword | Wnt/β-catenin,hepatocellular carcinoma,sorafenib,ICG-001,activating mutation,CTNNB1, | en |
dc.relation.page | 95 | |
dc.identifier.doi | 10.6342/NTU201700615 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2017-02-15 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 腫瘤醫學研究所 | zh_TW |
顯示於系所單位: | 腫瘤醫學研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-106-1.pdf 目前未授權公開取用 | 3.58 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。