請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/16567
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 郭明良 | |
dc.contributor.author | Pei Yu | en |
dc.contributor.author | 余姵 | zh_TW |
dc.date.accessioned | 2021-06-07T18:21:11Z | - |
dc.date.copyright | 2012-03-02 | |
dc.date.issued | 2011 | |
dc.date.submitted | 2011-12-26 | |
dc.identifier.citation | 1. Srivatanakul, P., H. Sriplung, and S. Deerasamee, Epidemiology of liver cancer: an overview. Asian Pac J Cancer Prev, 2004. 5(2): p. 118-25.
2. Feitelson, M.A., et al., Genetic mechanisms of hepatocarcinogenesis. Oncogene, 2002. 21(16): p. 2593-604. 3. Farazi, P.A. and R.A. DePinho, Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer, 2006. 6(9): p. 674-87. 4. Teufel, A., et al., Genetics of hepatocellular carcinoma. World J Gastroenterol, 2007. 13(16): p. 2271-82. 5. Aravalli, R.N., C.J. Steer, and E.N. Cressman, Molecular mechanisms of hepatocellular carcinoma. Hepatology, 2008. 48(6): p. 2047-63. 6. Huang, S. and X. He, The role of microRNAs in liver cancer progression. Br J Cancer, 2011. 104(2): p. 235-40. 7. Arii, S., et al., Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. The Liver Cancer Study Group of Japan. Hepatology, 2000. 32(6): p. 1224-9. 8. Barger, J.F. and D.R. Plas, Balancing biosynthesis and bioenergetics: metabolic programs in oncogenesis. Endocr Relat Cancer, 2010. 17(4): p. R287-304. 9. Vander Heiden, M.G., L.C. Cantley, and C.B. Thompson, Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science, 2009. 324(5930): p. 1029-33. 10. Ristow, M., Oxidative metabolism in cancer growth. Curr Opin Clin Nutr Metab Care, 2006. 9(4): p. 339-45. 11. Dang, L., et al., Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature, 2009. 462(7274): p. 739-44. 12. Kuhajda, F.P., Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition, 2000. 16(3): p. 202-8. 13. Chen, Z., et al., Restriction of DNA replication to the reductive phase of the metabolic cycle protects genome integrity. Science, 2007. 316(5833): p. 1916-9. 14. Warburg, O., On the origin of cancer cells. Science, 1956. 123(3191): p. 309-14. 15. DeBerardinis, R.J., et al., Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A, 2007. 104(49): p. 19345-50. 16. Suzuki, S., et al., Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc Natl Acad Sci U S A, 2010. 107(16): p. 7461-6. 17. Kovacevic, Z. and J.D. McGivan, Mitochondrial metabolism of glutamine and glutamate and its physiological significance. Physiol Rev, 1983. 63(2): p. 547-605. 18. Smith, E.M. and M. Watford, Molecular cloning of a cDNA for rat hepatic glutaminase. Sequence similarity to kidney-type glutaminase. J Biol Chem, 1990. 265(18): p. 10631-6. 19. Watford, M., Hepatic glutaminase expression: relationship to kidney-type glutaminase and to the urea cycle. FASEB J, 1993. 7(15): p. 1468-74. 20. Hu, W., et al., Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc Natl Acad Sci U S A, 2010. 107(16): p. 7455-60. 21. Wise, D.R., et al., Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci U S A, 2008. 105(48): p. 18782-7. 22. Gao, P., et al., c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature, 2009. 458(7239): p. 762-5. 23. Yuneva, M., et al., Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J Cell Biol, 2007. 178(1): p. 93-105. 24. Cadoret, A., et al., New targets of beta-catenin signaling in the liver are involved in the glutamine metabolism. Oncogene, 2002. 21(54): p. 8293-301. 25. Gomez-Fabre, P.M., et al., Molecular cloning, sequencing and expression studies of the human breast cancer cell glutaminase. Biochem J, 2000. 345 Pt 2: p. 365-75. 26. Olalla, L., et al., Nuclear localization of L-type glutaminase in mammalian brain. J Biol Chem, 2002. 277(41): p. 38939-44. 27. Heery, D.M., et al., A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature, 1997. 387(6634): p. 733-6. 28. Sachdev, S., A. Hoffmann, and M. Hannink, Nuclear localization of IkappaB alpha is mediated by the second ankyrin repeat: the IkappaB alpha ankyrin repeats define a novel class of cis-acting nuclear import sequences. Mol Cell Biol, 1998. 18(5): p. 2524-34. 29. Olalla, L., et al., The C-terminus of human glutaminase L mediates association with PDZ domain-containing proteins. FEBS Lett, 2001. 488(3): p. 116-22. 30. Castell, L., et al., Granule localization of glutaminase in human neutrophils and the consequence of glutamine utilization for neutrophil activity. J Biol Chem, 2004. 279(14): p. 13305-10. 31. Kalluri, R. and E.G. Neilson, Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest, 2003. 112(12): p. 1776-84. 32. Kalluri, R. and R.A. Weinberg, The basics of epithelial-mesenchymal transition. J Clin Invest, 2009. 119(6): p. 1420-8. 33. Thiery, J.P., Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer, 2002. 2(6): p. 442-54. 34. Shih, J.Y. and P.C. Yang, The EMT regulator slug and lung carcinogenesis. Carcinogenesis, 2011. 32(9): p. 1299-304. 35. Hsu, P.P. and D.M. Sabatini, Cancer cell metabolism: Warburg and beyond. Cell, 2008. 134(5): p. 703-7. 36. Warburg, O., On respiratory impairment in cancer cells. Science, 1956. 124(3215): p. 269-70. 37. DeBerardinis, R.J. and T. Cheng, Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene, 2010. 29(3): p. 313-24. 38. Wise, D.R. and C.B. Thompson, Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci, 2010. 35(8): p. 427-33. 39. Newsholme, P., et al., Glutamine and glutamate--their central role in cell metabolism and function. Cell Biochem Funct, 2003. 21(1): p. 1-9. 40. Curthoys, N.P. and M. Watford, Regulation of glutaminase activity and glutamine metabolism. Annu Rev Nutr, 1995. 15: p. 133-59. 41. Christa, L., et al., Overexpression of glutamine synthetase in human primary liver cancer. Gastroenterology, 1994. 106(5): p. 1312-20. 42. Di Tommaso, L., et al., The application of markers (HSP70 GPC3 and GS) in liver biopsies is useful for detection of hepatocellular carcinoma. J Hepatol, 2009. 50(4): p. 746-54. 43. Knox, W.E., M.L. Horowitz, and G.H. Friedell, The proportionality of glutaminase content to growth rate and morphology of rat neoplasms. Cancer Res, 1969. 29(3): p. 669-80. 44. Linder-Horowitz, M., W.E. Knox, and H.P. Morris, Glutaminase activities and growth rates of rat hepatomas. Cancer Res, 1969. 29(6): p. 1195-9. 45. Wu, Y. and B.P. Zhou, Snail: More than EMT. Cell Adh Migr, 2010. 4(2): p. 199-203. 46. De Craene, B., F. van Roy, and G. Berx, Unraveling signalling cascades for the Snail family of transcription factors. Cell Signal, 2005. 17(5): p. 535-47. 47. Peinado, H., et al., A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression. EMBO J, 2005. 24(19): p. 3446-58. 48. Yook, J.I., et al., Wnt-dependent regulation of the E-cadherin repressor snail. J Biol Chem, 2005. 280(12): p. 11740-8. 49. Siemens, H., et al., miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions. Cell Cycle, 2011. 10(24). 50. Palena, C., et al., Strategies to target molecules that control the acquisition of a mesenchymal-like phenotype by carcinoma cells. Exp Biol Med (Maywood), 2011. 236(5): p. 537-45. 51. Rajagopalan, K.N. and R.J. DeBerardinis, Role of glutamine in cancer: therapeutic and imaging implications. J Nucl Med, 2011. 52(7): p. 1005-8. 52. Marquez, J., et al., Glutaminase: a multifaceted protein not only involved in generating glutamate. Neurochem Int, 2006. 48(6-7): p. 465-71. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/16567 | - |
dc.description.abstract | Glutaminase 2 (GLS2) ,在肝臟大量表現,唯一負責麩醯胺代謝的酵素,將麩醯胺轉換為麩胺酸。此外, GLS2 在維持體內氨的恆定扮演重要的角色。研究發現, GLS2 在肝癌細胞中的表現量較非肝癌細胞中的表現量少,大量表現 GLS2 亦會減少肝癌細胞群落的形成,但目前其在肝癌扮演的角色仍不清楚。因此,我們試圖探討 GLS2 在肝癌進程的重要性及其調控機轉。首先,臨床的結果顯示 GLS2 的表現在肝癌癌化的部位遠低於非癌化部位,另外, GLS2 的表現量也與腫瘤大小、早期復發率及期別呈現負相關、與病人存活率呈現正相關。在細胞實驗發現 GLS2 的表現會降低細胞的移動能力,並且會藉由調控轉錄因子 Snail 的表現,抑制具有類上皮-間葉轉換 (EMT) 的現象。我們進一步發現 GLS2 抑制 Snail 的表現並非透過減少 Snail 的轉錄或改變 Snail 蛋白質的穩定度。另外,在動物實驗也證實 GLS2 的表現不僅減緩腫瘤的生長,更抑制腫瘤的轉移。最後,透過處理麩醯胺代謝的中間產物及測量細胞內活性氧物質 (ROS) 及細胞內麩醯胺的量,發現 GLS2 抑制肝癌進程並非透過 GLS2 在麩醯胺代謝中所扮演的角色。綜合以上, GLS2 透過抑制細胞形態的轉變及抑制細胞的移動力進而抑制癌細胞的轉移。 | zh_TW |
dc.description.provenance | Made available in DSpace on 2021-06-07T18:21:11Z (GMT). No. of bitstreams: 1 ntu-100-R98447002-1.pdf: 5749153 bytes, checksum: 826dc400185cc8bbd36ef7408eef03e0 (MD5) Previous issue date: 2011 | en |
dc.description.tableofcontents | Contents
摘要 ...................................................................................................................... i Abstract ..................................................................................................................... ii Chapter 1. Introduction 1.1 Hepatocellular carcinoma (HCC) .............................................................. 2 1.2 Metabolism in cancer cells ...................................................................... 3 1.3 Glutamine metabolism and cancer .......................................................... 5 1.4 Liver-type glutaminase (LGA, glutaminase 2, GLS2) ................................ 8 1.5 Epithelial-mesenchymal transition (EMT) ................................................ 9 1.6 Motivation and purpose ........................................................................ 10 Chapter 2. Materials and methods .............................................................. 11 Chapter 3. Results 3.1 Expression of GLS2 inversely correlates with tumor size, early recurrence, stage and poor survival of HCC patients ............................. 18 3.2 GLS2 suppresses the mobility and metastasis of HCC ........................... 19 3.3 GLS2 is a negative regulator in the epithelial to mesenchymal transition. ............................................................................................................. 21 3.4 Snail acts as a critical downstream effector in GLS2-repressed migration and invasion ......................................................................................... 22 3.5 GLS2 de-regulates Snail expression is not through mRNA level, either in a proteasome-dependent manner ..................................................... 23 3.6 The suppression of GLS2 on HCC progression is glutamine metabolism- independent ......................................................................................... 24 Chapter 4. Discussion ................................................................................. 25 Chapter 5. Figures and figure legends ........................................................ 30 Chapter 6. References ................................................................................ 60 | |
dc.language.iso | en | |
dc.title | 探討代謝酵素Glutaminase 2在肝癌進程中的角色 | zh_TW |
dc.title | Evaluation the Role of Metabolic Enzyme Glutaminase 2 in Hepatocellular Carcinoma Progression | en |
dc.type | Thesis | |
dc.date.schoolyear | 100-1 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 林明燦,吳明賢,葉松鈴 | |
dc.subject.keyword | glutaminase 2 (GLS2),肝癌,上皮-間葉轉換,Snail, | zh_TW |
dc.subject.keyword | glutaminase 2 (GLS2),hepatocellular carcinoma (HCC),epithelial-mesenchymal transition (EMT),Snail, | en |
dc.relation.page | 64 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2011-12-27 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 毒理學研究所 | zh_TW |
顯示於系所單位: | 毒理學研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-100-1.pdf 目前未授權公開取用 | 5.61 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。