請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/70342完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 楊雅倩(Ya-Chien Yang) | |
| dc.contributor.author | Yi-Hsuan Hsu | en |
| dc.contributor.author | 許翊萱 | zh_TW |
| dc.date.accessioned | 2021-06-17T04:26:11Z | - |
| dc.date.available | 2028-08-14 | |
| dc.date.copyright | 2018-10-03 | |
| dc.date.issued | 2018 | |
| dc.date.submitted | 2018-08-14 | |
| dc.identifier.citation | 1. Mundade, R., et al., Genetic pathways, prevention, and treatment of sporadic colorectal cancer. Oncoscience, 2014. 1(6): p. 400-406.
2. Jasperson, K. and R.W. Burt, The Genetics of Colorectal Cancer. Surg Oncol Clin N Am, 2015. 24(4): p. 683-703. 3. Half, E., D. Bercovich, and P. Rozen, Familial adenomatous polyposis. Orphanet J Rare Dis, 2009. 4: p. 22. 4. Vasen, H., P. Watson, J. Mecklin, and H. Lynch. New Clinical Criteria for Hereditary Nonpolyposis Colorectal Cancer (HNPCC, Lynch Syndrome) Proposed by the International Collaborative Group on HNPCC. Gastroenterology, 1999. 116(6): p. 1453-1456. 5. Haggar, F.A. and R.P. Boushey, Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg, 2009. 22(4): p. 191-7. 6. Fearon, E.R. and B. Vogelstein, A genetic model for colorectal tumorigenesis. Cell, 1990. 61(5): p. 759-67. 7. Tanaka, T., Colorectal carcinogenesis: Review of human and experimental animal studies. J Carcinog, 2009. 8: p. 5. 8. Kuipers, E.J., et al., Colorectal cancer. Nat Rev Dis Primers, 2015. 1: p. 15065. 9. Pino, M.S. and D.C. Chung, The chromosomal instability pathway in colon cancer. Gastroenterology, 2010. 138(6): p. 2059-72. 10. Tariq, K. and K. Ghias, Colorectal cancer carcinogenesis: a review of mechanisms. Cancer Biol Med, 2016. 13(1): p. 120-35. 11. Boland, C.R. and A. Goel, Microsatellite instability in colorectal cancer. Gastroenterology, 2010. 138(6): p. 2073-2087 e3. 12. Iacopetta, B., F. Grieu, and B. Amanuel, Microsatellite instability in colorectal cancer. Asia Pac J Clin Oncol, 2010. 6(4): p. 260-9. 13. Geiersbach, K.B. and W.S. Samowitz, Microsatellite instability and colorectal cancer. Arch Pathol Lab Med, 2011. 135(10): p. 1269-77. 14. Kawakami, H., A. Zaanan, and F.A. Sinicrope, Microsatellite instability testing and its role in the management of colorectal cancer. Curr Treat Options Oncol, 2015. 16(7): p. 30. 15. Curtin, K., M.L. Slattery, and W.S. Samowitz, CpG island methylation in colorectal cancer: past, present and future. Patholog Res Int, 2011. 2011: p. 902674. 16. Nazemalhosseini Mojarad, E., et al., The CpG island methylator phenotype (CIMP) in colorectal cancer. Gastroenterol Hepatol Bed Bench, 2013. 6(3): p. 120-8. 17. Ranscht, B., Sequence of contactin, a 130-kD glycoprotein concentrated in areas of interneuronal contact, defines a new member of the immunoglobulin supergene family in the nervous system. J Cell Biol, 1988. 107(4): p. 1561-73. 18. Shimoda, Y. and K. Watanabe, Contactins: emerging key roles in the development and function of the nervous system. Cell Adh Migr, 2009. 3(1): p. 64-70. 19. Low, M.G., Glycosyl-phosphatidylinositol: a versatile anchor for cell surface proteins. FASEB J, 1989. 3(5): p. 1600-8. 20. Yoshihara, Y., et al., Overlapping and differential expression of BIG-2, BIG-1, TAG-1, and F3: four members of an axon-associated cell adhesion molecule subgroup of the immunoglobulin superfamily. J Neurobiol, 1995. 28(1): p. 51-69. 21. Ogawa, J., et al., Novel neural adhesion molecules in the Contactin/F3 subgroup of the immunoglobulin superfamily: isolation and characterization of cDNAs from rat brain. Neurosci Lett, 1996. 218(3): p. 173-6. 22. Falk, J., et al., F3/contactin, a neuronal cell adhesion molecule implicated in axogenesis and myelination. Biol Cell, 2002. 94(6): p. 327-34. 23. Bizzoca, A., P. Corsi, and G. Gennarini, The mouse F3/contactin glycoprotein: structural features, functional properties and developmental significance of its regulated expression. Cell Adh Migr, 2009. 3(1): p. 53-63. 24. Furley, A.J., et al., The axonal glycoprotein TAG-1 is an immunoglobulin superfamily member with neurite outgrowth-promoting activity. Cell, 1990. 61(1): p. 157-70. 25. Gennarini, G., et al., Transfected F3/F11 neuronal cell surface protein mediates intercellular adhesion and promotes neurite outgrowth. Neuron, 1991. 6(4): p. 595-606. 26. Durbec, P., et al., A soluble form of the F3 neuronal cell adhesion molecule promotes neurite outgrowth. J Cell Biol, 1992. 117(4): p. 877-87. 27. Dodd, J., et al., Spatial regulation of axonal glycoprotein expression on subsets of embryonic spinal neurons. Neuron, 1988. 1(2): p. 105-16. 28. Namba, T., et al., Pioneering axons regulate neuronal polarization in the developing cerebral cortex. Neuron, 2014. 81(4): p. 814-29. 29. Gennarini, G., et al., The mouse neuronal cell surface protein F3: a phosphatidylinositol-anchored member of the immunoglobulin superfamily related to chicken contactin. J Cell Biol, 1989. 109(2): p. 775-88. 30. Stoeckli, E.T., Neural circuit formation in the cerebellum is controlled by cell adhesion molecules of the Contactin family. Cell Adh Migr, 2010. 4(4): p. 523-6. 31. Pierre, K., et al., Mobilization of the cell adhesion glycoprotein F3/contactin to axonal surfaces is activity dependent. Eur J Neurosci, 2001. 14(4): p. 645-56. 32. Perrin, F.E., F.G. Rathjen, and E.T. Stoeckli, Distinct subpopulations of sensory afferents require F11 or axonin-1 for growth to their target layers within the spinal cord of the chick. Neuron, 2001. 30(3): p. 707-23. 33. Ascano, M., D. Bodmer, and R. Kuruvilla, Endocytic trafficking of neurotrophins in neural development. Trends Cell Biol, 2012. 22(5): p. 266-73. 34. Peles, E. and J.L. Salzer, Molecular domains of myelinated axons. Curr Opin Neurobiol, 2000. 10(5): p. 558-65. 35. Mohebiany, A.N., S. Harroch, and S. Bouyain, New insights into the roles of the contactin cell adhesion molecules in neural development. Adv Neurobiol, 2014. 8: p. 165-94. 36. Guo, H., et al., Disruption of Contactin 4 in two subjects with autism in Chinese population. Gene, 2012. 505(2): p. 201-5. 37. Nava, C., et al., Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders. Eur J Hum Genet, 2014. 22(1): p. 71-8. 38. Cottrell, C.E., et al., Contactin 4 as an autism susceptibility locus. Autism Res, 2011. 4(3): p. 189-99. 39. Zuko, A., et al., Contactins: structural aspects in relation to developmental functions in brain disease. Adv Protein Chem Struct Biol, 2011. 84: p. 143-80. 40. Ye, H., et al., Receptor-like protein-tyrosine phosphatase alpha enhances cell surface expression of neural adhesion molecule NB-3. J Biol Chem, 2011. 286(29): p. 26071-80. 41. Mercati, O., et al., Contactin 4, -5 and -6 differentially regulate neuritogenesis while they display identical PTPRG binding sites. Biol Open, 2013. 2(3): p. 324-34. 42. Kamei, Y., et al., Human NB-2 of the contactin subgroup molecules: chromosomal localization of the gene (CNTN5) and distinct expression pattern from other subgroup members. Genomics, 2000. 69(1): p. 113-9. 43. Zuko, A., et al., Developmental role of the cell adhesion molecule Contactin-6 in the cerebral cortex and hippocampus. Cell Adh Migr, 2016. 10(4): p. 378-92. 44. Maness, P.F. and M. Schachner, Neural recognition molecules of the immunoglobulin superfamily: signaling transducers of axon guidance and neuronal migration. Nat Neurosci, 2007. 10(1): p. 19-26. 45. Gollan, L., et al., Caspr regulates the processing of contactin and inhibits its binding to neurofascin. J Cell Biol, 2003. 163(6): p. 1213-8. 46. Traut, W., et al., New members of the neurexin superfamily: multiple rodent homologues of the human CASPR5 gene. Mamm Genome, 2006. 17(7): p. 723-31. 47. Horresh, I., et al., Multiple molecular interactions determine the clustering of Caspr2 and Kv1 channels in myelinated axons. J Neurosci, 2008. 28(52): p. 14213-22. 48. Horresh, I., et al., Organization of myelinated axons by Caspr and Caspr2 requires the cytoskeletal adapter protein 4.1B. J Neurosci, 2010. 30(7): p. 2480-9. 49. Hu, Q.D., et al., F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation. Cell, 2003. 115(2): p. 163-75. 50. Ma, Q.H., et al., A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis. Nat Cell Biol, 2008. 10(3): p. 283-94. 51. Peles, E., et al., The carbonic anhydrase domain of receptor tyrosine phosphatase beta is a functional ligand for the axonal cell recognition molecule contactin. Cell, 1995. 82(2): p. 251-60. 52. Lamprianou, S., et al., Receptor protein tyrosine phosphatase gamma is a marker for pyramidal cells and sensory neurons in the nervous system and is not necessary for normal development. Mol Cell Biol, 2006. 26(13): p. 5106-19. 53. Bouyain, S. and D.J. Watkins, The protein tyrosine phosphatases PTPRZ and PTPRG bind to distinct members of the contactin family of neural recognition molecules. Proc Natl Acad Sci U S A, 2010. 107(6): p. 2443-8. 54. Osterfield, M., et al., Interaction of amyloid precursor protein with contactins and NgCAM in the retinotectal system. Development, 2008. 135(6): p. 1189-99. 55. Ye, H., et al., Neural recognition molecules CHL1 and NB-3 regulate apical dendrite orientation in the neocortex via PTP alpha. EMBO J, 2008. 27(1): p. 188-200. 56. Lee, S., et al., Expression and regulation of a gene encoding neural recognition molecule NB-3 of the contactin/F3 subgroup in mouse brain. Gene, 2000. 245(2): p. 253-66. 57. Mercati, O., et al., CNTN6 mutations are risk factors for abnormal auditory sensory perception in autism spectrum disorders. Mol Psychiatry, 2017. 22(4): p. 625-633. 58. Gautam, V., et al., BACE1 activity regulates cell surface contactin-2 levels. Mol Neurodegener, 2014. 9: p. 4. 59. Zoupi, L., et al., Alterations of juxtaparanodal domains in two rodent models of CNS demyelination. Glia, 2013. 61(8): p. 1236-49. 60. Su, J.L., et al., Knockdown of contactin-1 expression suppresses invasion and metastasis of lung adenocarcinoma. Cancer Res, 2006. 66(5): p. 2553-61. 61. Liu, P., et al., Contactin-1 (CNTN-1) overexpression is correlated with advanced clinical stage and lymph node metastasis in oesophageal squamous cell carcinomas. Jpn J Clin Oncol, 2012. 42(7): p. 612-8. 62. Li, G.Y., et al., Expression and prognostic significance of contactin 1 in human hepatocellular carcinoma. Onco Targets Ther, 2016. 9: p. 387-94. 63. Qin, X.J., et al., Effect of lentivirus-mediated shRNA targeting VEGFR-3 on proliferation, apoptosis and invasion of gastric cancer cells. Int J Mol Med, 2011. 28(5): p. 761-8. 64. Chen, D.H., et al., Significances of contactin-1 expression in human gastric cancer and knockdown of contactin-1 expression inhibits invasion and metastasis of MKN45 gastric cancer cells. J Cancer Res Clin Oncol, 2015. 141(12): p. 2109-20. 65. Eckerich, C., et al., Contactin is expressed in human astrocytic gliomas and mediates repulsive effects. Glia, 2006. 53(1): p. 1-12. 66. Rickman, D.S., et al., The gene for the axonal cell adhesion molecule TAX-1 is amplified and aberrantly expressed in malignant gliomas. Cancer Res, 2001. 61(5): p. 2162-8. 67. Zhen, Y.B., et al., Expression of TAG1/APP signaling pathway in the proliferation and differentiation of glioma stem cells. Oncol Lett, 2017. 14(2): p. 2137-2140. 68. Evenepoel, L., et al., Expression of Contactin 4 is associated with malignant behavior in pheochromocytomas and paragangliomas. J Clin Endocrinol Metab, 2017. 69. Mimmack, M.L., et al., A novel splice variant of the cell adhesion molecule BIG-2 is expressed in the olfactory and vomeronasal neuroepithelia. Brain Res Mol Brain Res, 1997. 47(1-2): p. 345-50. 70. Zeng, L., et al., A novel splice variant of the cell adhesion molecule contactin 4 ( CNTN4) is mainly expressed in human brain. J Hum Genet, 2002. 47(9): p. 497-9. 71. Mayor, S. and H. Riezman, Sorting GPI-anchored proteins. Nat Rev Mol Cell Biol, 2004. 5(2): p. 110-20. 72. Kaneko-Goto, T., et al., BIG-2 mediates olfactory axon convergence to target glomeruli. Neuron, 2008. 57(6): p. 834-46. 73. Osterhout, J.A., et al., Contactin-4 mediates axon-target specificity and functional development of the accessory optic system. Neuron, 2015. 86(4): p. 985-99. 74. Fernandez, T., et al., Disruption of contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome. Am J Hum Genet, 2004. 74(6): p. 1286-93. 75. Miura, S., et al., The contactin 4 gene locus at 3p26 is a candidate gene of SCA16. Neurology, 2006. 67(7): p. 1236-41. 76. Nikolaienko, R.M., B. Agyekum, and S. Bouyain, Receptor protein tyrosine phosphatases and cancer: new insights from structural biology. Cell Adh Migr, 2012. 6(4): p. 356-64. 77. Vezzalini, M., et al., Expression of transmembrane protein tyrosine phosphatase gamma (PTPgamma) in normal and neoplastic human tissues. Histopathology, 2007. 50(5): p. 615-28. 78. Lubinski, J., et al., Common regions of deletion in chromosome regions 3p12 and 3p14.2 in primary clear cell renal carcinomas. Cancer Res, 1994. 54(14): p. 3710-3. 79. Du, Y. and J.R. Grandis, Receptor-type protein tyrosine phosphatases in cancer. Chin J Cancer, 2015. 34(2): p. 61-9. 80. Nalivaeva, N.N. and A.J. Turner, The amyloid precursor protein: a biochemical enigma in brain development, function and disease. FEBS Lett, 2013. 587(13): p. 2046-54. 81. Wilkins, H.M. and R.H. Swerdlow, Amyloid precursor protein processing and bioenergetics. Brain Res Bull, 2017. 133: p. 71-79. 82. Pandey, P., et al., Amyloid precursor protein and amyloid precursor-like protein 2 in cancer. Oncotarget, 2016. 7(15): p. 19430-44. 83. Hansford, L.M., et al., Cloning and characterization of the human neural cell adhesion molecule, CNTN4 (alias BIG-2). Cytogenet Genome Res, 2003. 101(1): p. 17-23. 84. Yete, S., S. Pradhan, and D. Saranath, Single nucleotide polymorphisms in an Indian cohort and association of CNTN4, MMP2 and SNTB1 variants with oral cancer. Cancer Genet, 2017. 214-215: p. 16-25. 85. Sjoblom, T., et al., The consensus coding sequences of human breast and colorectal cancers. Science, 2006. 314(5797): p. 268-74. 86. Ashktorab, H., et al., Distinct genetic alterations in colorectal cancer. PLoS One, 2010. 5(1): p. e8879. 87. Masson, A.L., et al., Copy number variation in hereditary non-polyposis colorectal cancer. Genes (Basel), 2013. 4(4): p. 536-55. 88. Fang, L.T., et al., Comprehensive genomic analyses of a metastatic colon cancer to the lung by whole exome sequencing and gene expression analysis. Int J Oncol, 2014. 44(1): p. 211-21. 89. TH., A. and M. JP., Angiogenesis. San Rafael (CA): Morgan & Claypool Life Sciences, 2010: p. Chapter 1, Overview of Angiogenesis. 90. Tahergorabi, Z. and M. Khazaei, A review on angiogenesis and its assays. Iran J Basic Med Sci, 2012. 15(6): p. 1110-26. 91. Bergers, G. and L.E. Benjamin, Tumorigenesis and the angiogenic switch. Nat Rev Cancer, 2003. 3(6): p. 401-410. 92. Folkman, J., Tumor angiogenesis: therapeutic implications. N Engl J Med, 1971. 285(21): p. 1182-6. 93. Yadav, L., et al., Tumour Angiogenesis and Angiogenic Inhibitors: A Review. J Clin Diagn Res, 2015. 9(6): p. XE01-XE05. 94. Tonini, T., F. Rossi, and P.P. Claudio, Molecular basis of angiogenesis and cancer. Oncogene, 2003. 22(42): p. 6549-56. 95. Goodwin, A.M., In vitro assays of angiogenesis for assessment of angiogenic and anti-angiogenic agents. Microvasc Res, 2007. 74(2-3): p. 172-83. 96. DeCicco-Skinner, K.L., et al., Endothelial cell tube formation assay for the in vitro study of angiogenesis. J Vis Exp, 2014(91): p. e51312. 97. Aranda, E. and G.I. Owen, A semi-quantitative assay to screen for angiogenic compounds and compounds with angiogenic potential using the EA.hy926 endothelial cell line. Biol Res, 2009. 42(3): p. 377-89. 98. Edgell, C.J., C.C. McDonald, and J.B. Graham, Permanent cell line expressing human factor VIII-related antigen established by hybridization. Proc Natl Acad Sci U S A, 1983. 80(12): p. 3734-7. 99. Edgell, C.J., et al., Endothelium specific Weibel-Palade bodies in a continuous human cell line, EA.hy926. In Vitro Cell Dev Biol, 1990. 26(12): p. 1167-72. 100. Emeis, J.J. and C.J. Edgell, Fibrinolytic properties of a human endothelial hybrid cell line (Ea.hy 926). Blood, 1988. 71(6): p. 1669-75. 101. Thornhill, M.H., J. Li, and D.O. Haskard, Leucocyte endothelial cell adhesion: a study comparing human umbilical vein endothelial cells and the endothelial cell line EA-hy-926. Scand J Immunol, 1993. 38(3): p. 279-86. 102. Saijonmaa, O., et al., Endothelin-1 is expressed and released by a human endothelial hybrid cell line (EA.hy 926). Biochem Biophys Res Commun, 1991. 181(2): p. 529-36. 103. van Oost, B.A., et al., Isolation of a human von Willebrand factor cDNA from the hybrid endothelial cell line EA.hy926. Biochem Cell Biol, 1986. 64(7): p. 699-705. 104. Suggs, J.E., et al., Prostacyclin expression by a continuous human cell line derived from vascular endothelium. Blood, 1986. 68(4): p. 825-9. 105. Tsai, M.H., et al., Mapping of genetic deletions on chromosome 3 in colorectal cancer: loss of 3p25-pter is associated with distant metastasis and poor survival. Ann Surg Oncol, 2011. 18(9): p. 2662-70. 106. 江紹瑜, Contactin 4 於大腸直腸癌抑癌功能之研究, in 醫學檢驗暨生物技術學研究所. 2015, 國立臺灣大學: 台北市. p. 71. 107. 蕭聿昕, 探討 Contactin 4對大腸直腸癌之促血管新生因子 uPA 的調控及表現分泌型 Contactin 4 蛋白, in 醫學檢驗暨生物技術學研究所. 2017, 國立臺灣大學: 台北市. p. 64. 108. Ko, J.M. and M.L. Lung, In vitro Human Umbilical Vein Endothelial Cells (HUVEC) Tube-formation Assay. Bio-protocol 2012. 2(18): p. e260. 109. Woolston, C. and S. Martin, Analysis of tumor and endothelial cell viability and survival using sulforhodamine B and clonogenic assays. Methods Mol Biol, 2011. 740: p. 45-56. 110. Menyhart, O., et al., Guidelines for the selection of functional assays to evaluate the hallmarks of cancer. Biochim Biophys Acta, 2016. 1866(2): p. 300-319. 111. Mahal, K., et al., Combretastatin A-4 derived imidazoles show cytotoxic, antivascular, and antimetastatic effects based on cytoskeletal reorganisation. Invest New Drugs, 2015. 33(3): p. 541-54. 112. Waugh, D.S., An overview of enzymatic reagents for the removal of affinity tags. Protein Expr Purif, 2011. 80(2): p. 283-93. 113. Goh, H.C., et al., Going native: Complete removal of protein purification affinity tags by simple modification of existing tags and proteases. Protein Expr Purif, 2017. 129: p. 18-24. 114. Suh-Lailam, B.B. and J.M. Hevel, Efficient cleavage of problematic tobacco etch virus (TEV)-protein arginine methyltransferase constructs. Anal Biochem, 2009. 387(1): p. 130-2. 115. Yu, Z.H. and Z.Y. Zhang, Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases. Chem Rev, 2018. 118(3): p. 1069-1091. 116. Bourgonje, A.M., et al., Intracellular and extracellular domains of protein tyrosine phosphatase PTPRZ-B differentially regulate glioma cell growth and motility. Oncotarget, 2014. 5(18): p. 8690-702. 117. Cheung, A.K., et al., Functional analysis of a cell cycle-associated, tumor-suppressive gene, protein tyrosine phosphatase receptor type G, in nasopharyngeal carcinoma. Cancer Res, 2008. 68(19): p. 8137-45. 118. van Roon, E.H., et al., Tumour-specific methylation of PTPRG intron 1 locus in sporadic and Lynch syndrome colorectal cancer. Eur J Hum Genet, 2011. 19(3): p. 307-12. 119. Shu, S.T., et al., Function and regulatory mechanisms of the candidate tumor suppressor receptor protein tyrosine phosphatase gamma (PTPRG) in breast cancer cells. Anticancer Res, 2010. 30(6): p. 1937-46. 120. Xiao, J., et al., PTPRG inhibition by DNA methylation and cooperation with RAS gene activation in childhood acute lymphoblastic leukemia. Int J Cancer, 2014. 135(5): p. 1101-9. 121. Cheung, A.K., et al., PTPRG suppresses tumor growth and invasion via inhibition of Akt signaling in nasopharyngeal carcinoma. Oncotarget, 2015. 6(15): p. 13434-47. 122. Hashemi, H., et al., Receptor tyrosine phosphatase PTPgamma is a regulator of spinal cord neurogenesis. Mol Cell Neurosci, 2011. 46(2): p. 469-82. 123. Willnow, T.E., C.M. Petersen, and A. Nykjaer, VPS10P-domain receptors - regulators of neuronal viability and function. Nat Rev Neurosci, 2008. 9(12): p. 899-909. 124. Zhou, F., et al., The APP intracellular domain (AICD) inhibits Wnt signalling and promotes neurite outgrowth. Biochim Biophys Acta, 2012. 1823(8): p. 1233-41. 125. Bouis, D., et al., Endothelium in vitro: a review of human vascular endothelial cell lines for blood vessel-related research. Angiogenesis, 2001. 4(2): p. 91-102. 126. Hauser, S., F. Jung, and J. Pietzsch, Human Endothelial Cell Models in Biomaterial Research. Trends Biotechnol, 2017. 35(3): p. 265-277. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/70342 | - |
| dc.description.abstract | 大腸直腸癌於全世界及臺灣均是癌症死亡原因的前三名，且在臺灣大腸直腸癌已攀升為每年發生率最高之癌症。於人類癌症常見抑癌基因座因基因組缺失造成抑癌基因靜默，本實驗室先前的研究，於人類第三號染色體 3p25.3-p26.3鑑定 Contactin 4 (CNTN4) 於大腸直腸癌可能扮演抑癌基因的角色。於大腸直腸癌細胞株 HCT116大量表現 CNTN4可抑制細胞增生、固著依賴性及非固著依賴性胞落形成的能力，同時，在活體動物實驗則發現表現 CNTN4 可以抑制 HCT116細胞於裸鼠皮下腫瘤的生成及減少腫瘤的血管密度，初步亦觀察到可溶性 CNTN4可抑制細胞增生之能力。目前可溶性 CNTN4 的功能尚未清楚，本論文分為三個部分探討： (一) 為探討可溶性 CNTN4 發展成為抗癌藥物的潛力，首先將分泌型 CNTN4 表現質體以轉染方式送入 HCT116 和 HEK293 細胞，使其表現可溶性 CNTN4，並以細胞模型進行功能性試驗，結果顯示含有可溶性 CNTN4 之條件培養液可抑制細胞增生、固著依賴性及非固著依賴性胞落形成之能力。(二) 為進一步瞭解 CNTN4 之抑癌作用區域，故建構兩種分泌型截斷 CNTN4 (truncated CNTN4) 表現質體：pSecTag2/sCNTN4_IGc2 和 pSecTag2/sCNTN4_FN3，以轉染方式送入HCT116 和 HEK293 細胞，確認其可正確表現，之後即可用於體外細胞功能性試驗，以探討其對大腸直腸癌細胞之抑制作用。(三) 為探討可溶性 CNTN4抑制體外血管生成試驗之形成管狀結構能力，首先建立體外血管生成試驗之實驗條件，後續即可用於可溶性全長 CNTN4 和兩種截斷 CNTN4 之研究。綜合目前結果，可溶性 CNTN4 可抑制大腸直腸癌細胞株增生、固著依賴性及非固著依賴性胞落形成之能力，相似於細胞膜之CNTN4 皆對大腸直腸癌細胞株具有生長抑制的功能。 | zh_TW |
| dc.description.abstract | Colorectal cancer (CRC) is one of the top three leading causes of cancer death in the world and Taiwan. Nowadays, CRC is the cancer with the highest annual incidence in Taiwan. Genomic deletion at tumor suppressor loci is common in human cancers and contributes to tumor suppressor genes (TSGs) silencing. In our previous study, we have identified Contactin 4 (CNTN4) as a novel tumor suppressor gene located at chromosome 3p25.3-p26.3 that is silenced or markedly down-regulated in CRC cell lines and colorectal carcinomas compared with their matched normal mucosae. Ectopic expression of CNTN4 indeed reduced cell proliferation, anchorage-dependent and -independent colony formation of CRC HCT116 cells in vitro. Subcutaneous injection of CNTN4-expressing CRC cells in BALB/c nude mice showed the reduction of tumor growth and less microvessel density compared with that observed in Mock-inoculated mice. In addition, the conditioned medium containing soluble CNTN4 (sCNTN4) could suppress cell growth of HCT116. The function of sCNTN4 is still not clear currently. In the study, there are three specific aims. First, to explore the potential of sCNTN4 for an innovative anti-cancer protein drug, the secretory CNTN4-expressing plasmid, pSecTag2/sCNTN4 was transiently transfected into HCT116 and HEK293 cells. By in vitro cell functional assays, we demonstrated that the conditioned media containing sCNTN4 could inhibit the cell proliferation, anchorage-dependent and -independent colony formation of HCT116 cells. As for the second aim, in terms of small molecule protein drugs, we attempted to part the soluble full-length CNTN4 into two truncated proteins containing immunoglobulin-like C2 (IGc2) domains and fibronectin type-III (FN3) domains separately. To identify whether both of truncated proteins could suppress tumor behaviors, we have constructed the soluble truncated CNTN4-expressing plasmids, pSecTag2/sCNTN4_IGc2 and pSecTag2/sCNTN4_FN3, which exhibit correct expression in HCT116 and HEK293 cells by transient transfection. In the third part, to investigate whether sCNTN4 could inhibit angiogenesis by in vitro angiogenesis assay, the experimental conditions for in vitro angiogenesis assay to test the ability of forming tubular structures have been established, followed by studies of soluble full-length CNTN4 and truncated CNTN4. Taken together, the conditioned media containing soluble CNTN4 could inhibit cell proliferation, anchorage-dependent and anchorage-independent colony formation of CRC cells in vitro. Either membrane-anchored CNTN4 or soluble CNTN4 could inhibit cell growth of CRC. Our findings illustrate CNTN4 as a novel human TSG and suggest an antitumor potential of soluble CNTN4 for a therapeutic drug. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T04:26:11Z (GMT). No. of bitstreams: 1 ntu-107-R05424020-1.pdf: 8602096 bytes, checksum: a45206f16ea2880d35e161f8fceaa94f (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 誌謝 i
中文摘要 ii Abstract iii 縮寫對照表 v 圖目錄 xi 表目錄 xiii 一、研究背景 1 1. 大腸直腸癌 1 1.1 大腸直腸癌簡介 1 1.2 大腸直腸癌生成機制 2 1.2.1 染色體不穩定性 (Chromosomal instability, CIN) 2 1.2.2 微衛星不穩定性 (microsatellite instability, MSI) 2 1.2.3 CpG島甲基化表現型 3 2. Contactin 家族 3 2.1 Contactin 家族簡介 3 2.1.1 Contactin-1和Contactin-2 3 2.1.2 Contactin-3, -4, -5和6 4 2.2 Contactin 仰賴之蛋白交互作用 5 2.3 可溶性 Contactin 蛋白 6 2.4 Contactin與癌症 7 3. Contactin 4 (CNTN4) 7 3.1 Contactin 4 簡介 7 3.2 CNTN4與結合蛋白 8 3.2.1 CNTN4 與 PTPRG (protein tyrosine phosphatases receptor type G) 的結合 9 3.2.2 CNTN4 與 APP (amyloid precursor protein) 的結合 9 3.3 CNTN4 與癌症相關研究 10 4. 血管新生 11 4.1 血管新生簡介 11 4.2 腫瘤血管新生 (Neoangiogenesis) 11 4.3 體外血管生成試驗 (in vitro angiogenesis assay) 12 4.3.1 體外血管生成試驗簡介 12 3.3.2 EA.hy926 內皮細胞株 12 5. 實驗室先前相關研究 13 5.1 第三號染色體之失異合性檢測 13 5.2 CNTN4 抑癌功能鑑定 13 5.3 可溶性 CNTN4 抑癌功能鑑定 14 二、研究目標 15 三、材料與方法 17 1. 試劑、材料及抗體 17 2. 細胞培養 17 3. 建構分泌型 truncated CNTN4 表現質體 17 3.1 sCNTN4_IGc2 17 3.2 Site-directed mutagenesis 18 3.2 sCNTN4_FN3 19 4. 細胞轉染 19 5. 可溶性CNTN4重組蛋白穩定表現細胞株篩選 20 6. 可溶性CNTN4重組蛋白穩定表現細胞株條件培養液製備 20 7. 可溶性CNTN4重組蛋白純化 20 8. 蛋白質的抽取及定量 21 9. 西方墨點法 21 10. 短暫轉染之 sCNTN4條件培養液製備 22 11. 細胞增生分析 22 12. 非固著依賴性胞落形成試驗 23 13. 固著依賴性胞落形成試驗 23 14. 內皮細胞血管生成試驗 (tube formation assay) 23 15. 統計方法 24 四、研究結果 25 1. CNTN4 於大腸直腸癌細胞株及條件培養液之蛋白質表現量 25 2. 確認 Lipofectamine® 3000 試劑對 HCT116 細胞的毒性 25 3. 含 sCNTN4 之條件培養液抑制 HCT116 細胞之增生能力 26 4. 含 sCNTN4 之條件培養液抑制 HCT116 細胞之貼附依賴性胞落形成能力 27 5. 含 sCNTN4 之條件培養液抑制不同 HCT116 細胞密度之貼附依賴性胞落形成能力 27 6. 含 sCNTN4 之條件培養液抑制HCT116 細胞之非貼附依賴性胞落形成能力 27 7. sCNTN4 穩定表現細胞株篩選及 HEK293之增生速率不受重組蛋白 sCNTN4 影響 28 8. HEK293 單一穩定表現 sCNTN4 細胞株之條件培養液抑制大腸直腸癌細胞株之增生能力 28 9. HEK293 單一穩定表現 sCNTN4 細胞株之條件培養液抑制大腸直腸癌細胞株之貼附依賴性胞落形成能力 29 10. HEK293 單一穩定表現 sCNTN4 細胞株之條件培養液抑制 HCT15 細胞之非貼附依賴性胞落形成能力 29 11. 純化可溶性 CNTN4 重組蛋白及純化之可溶性 CNTN4 蛋白對 HCT116 細胞增生速率之影響 30 12. 建構分泌型truncated CNTN4表現質體及挑選穩定表現可溶性truncated CNTN4細胞株 30 13. 含可溶性truncated CNTN4 之條件培養液不影響HCT116 細胞之增生能力 31 14. 建立血管生成試驗之實驗條件 31 五、討論 32 1. 可溶性 CNTN4 細胞功能性試驗 32 2. 可溶性 CNTN4 重組蛋白純化 33 3. 可溶性截斷 CNTN4 34 4. 血管生成試驗 36 圖 38 表 58 參考文獻 59 附錄 69 | |
| dc.language.iso | zh-TW | |
| dc.subject | 血管新生 | zh_TW |
| dc.subject | 可溶性 CNTN4 | zh_TW |
| dc.subject | 抑癌基因 | zh_TW |
| dc.subject | Contactin 4 | zh_TW |
| dc.subject | 大腸直腸癌 | zh_TW |
| dc.subject | Colorectal cancer | en |
| dc.subject | Contactin 4 | en |
| dc.subject | Tumor suppressor gene | en |
| dc.subject | Soluble CNTN4 | en |
| dc.subject | Angiogenesis | en |
| dc.title | 可溶性Contactin 4於大腸直腸癌細胞抑癌功能之研究 | zh_TW |
| dc.title | Study of tumor suppressor functions of soluble Contactin 4
in colorectal cancer | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 106-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 張育嘉(Yu-Jia Chang),潘思樺(Szu-Hua Pan),蘇剛毅(Kang-Yi Su),郭靜穎(Ching-Ying Kuo) | |
| dc.subject.keyword | 大腸直腸癌,Contactin 4,抑癌基因,可溶性 CNTN4,血管新生, | zh_TW |
| dc.subject.keyword | Colorectal cancer,Contactin 4,Tumor suppressor gene,Soluble CNTN4,Angiogenesis, | en |
| dc.relation.page | 71 | |
| dc.identifier.doi | 10.6342/NTU201803375 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2018-08-14 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-107-1.pdf 未授權公開取用 | 8.4 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。