請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/51566
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 余佳慧 | |
dc.contributor.author | Wei-Ting Kuo | en |
dc.contributor.author | 郭瑋庭 | zh_TW |
dc.date.accessioned | 2021-06-15T13:39:09Z | - |
dc.date.available | 2021-02-26 | |
dc.date.copyright | 2016-02-26 | |
dc.date.issued | 2016 | |
dc.date.submitted | 2016-01-21 | |
dc.identifier.citation | 1. Madara, J.L., Maintenance of the macromolecular barrier at cell extrusion sites in intestinal epithelium: physiological rearrangement of tight junctions. J Membr Biol, 1990. 116(2): p. 177-84.
2. Watson, A.J., et al., Epithelial barrier function in vivo is sustained despite gaps in epithelial layers. Gastroenterology, 2005. 129(3): p. 902-12. 3. Rosenblatt, J., M.C. Raff, and L.P. Cramer, An epithelial cell destined for apoptosis signals its neighbors to extrude it by an actin- and myosin-dependent mechanism. Curr Biol, 2001. 11(23): p. 1847-57. 4. Yen, T.H. and N.A. Wright, The gastrointestinal tract stem cell niche. Stem Cell Rev, 2006. 2(3): p. 203-12. 5. Yu, L.C., et al., Host-microbial interactions and regulation of intestinal epithelial barrier function: From physiology to pathology. World J Gastrointest Pathophysiol, 2012. 3(1): p. 27-43. 6. Yang, S.Y., et al., Apoptosis and colorectal cancer: implications for therapy. Trends Mol Med, 2009. 15(5): p. 225-33. 7. Loktionov, A., Cell exfoliation in the human colon: myth, reality and implications for colorectal cancer screening. Int J Cancer, 2007. 120(11): p. 2281-9. 8. Gunther, C., et al., Apoptosis, necrosis and necroptosis: cell death regulation in the intestinal epithelium. Gut, 2013. 62(7): p. 1062-71. 9. Humphries, F., et al., RIP kinases: key decision makers in cell death and innate immunity. Cell Death Differ, 2015. 22(2): p. 225-36. 10. Dejean, L.M., S. Martinez-Caballero, and K.W. Kinnally, Is MAC the knife that cuts cytochrome c from mitochondria during apoptosis? Cell Death Differ, 2006. 13(8): p. 1387-95. 11. Shanmugathasan, M. and S. Jothy, Apoptosis, anoikis and their relevance to the pathobiology of colon cancer. Pathol Int, 2000. 50(4): p. 273-9. 12. Hanahan, D. and R.A. Weinberg, Hallmarks of cancer: the next generation. Cell, 2011. 144(5): p. 646-74. 13. Bedi, A., et al., Inhibition of apoptosis during development of colorectal cancer. Cancer Res, 1995. 55(9): p. 1811-6. 14. Miura, K., et al., Inhibitor of apoptosis protein family as diagnostic markers and therapeutic targets of colorectal cancer. Surg Today, 2011. 41(2): p. 175-82. 15. Feagins, L.A., R.F. Souza, and S.J. Spechler, Carcinogenesis in IBD: potential targets for the prevention of colorectal cancer. Nat Rev Gastroenterol Hepatol, 2009. 6(5): p. 297-305. 16. Ashley, N., Regulation of intestinal cancer stem cells. Cancer Lett, 2013. 338(1): p. 120-6. 17. Duckworth, C.A. and D.M. Pritchard, Suppression of apoptosis, crypt hyperplasia, and altered differentiation in the colonic epithelia of bak-null mice. Gastroenterology, 2009. 136(3): p. 943-52. 18. Hu, B., et al., Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4. Proc Natl Acad Sci U S A, 2010. 107(50): p. 21635-40. 19. Palmer, C., et al., Development of the human infant intestinal microbiota. PLoS Biol, 2007. 5(7): p. e177. 20. Ley, R.E., D.A. Peterson, and J.I. Gordon, Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell, 2006. 124(4): p. 837-48. 21. O'Hara, A.M. and F. Shanahan, The gut flora as a forgotten organ. EMBO Rep, 2006. 7(7): p. 688-93. 22. Manson, J.M., M. Rauch, and M.S. Gilmore, The commensal microbiology of the gastrointestinal tract. Adv Exp Med Biol, 2008. 635: p. 15-28. 23. Andoh, A., et al., Recent advances in molecular approaches to gut microbiota in inflammatory bowel disease. Curr Pharm Des, 2009. 15(18): p. 2066-73. 24. Ley, R.E., et al., Microbial ecology: human gut microbes associated with obesity. Nature, 2006. 444(7122): p. 1022-3. 25. Frank, D.N., et al., Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A, 2007. 104(34): p. 13780-5. 26. Edelblum, K.L., et al., Regulation of apoptosis during homeostasis and disease in the intestinal epithelium. Inflamm Bowel Dis, 2006. 12(5): p. 413-24. 27. Danielsen, M., et al., Effects of bacterial colonization on the porcine intestinal proteome. J Proteome Res, 2007. 6(7): p. 2596-604. 28. Willing, B.P. and A.G. Van Kessel, Enterocyte proliferation and apoptosis in the caudal small intestine is influenced by the composition of colonizing commensal bacteria in the neonatal gnotobiotic pig. J Anim Sci, 2007. 85(12): p. 3256-66. 29. Kozakova, H., et al., Effect of bacterial monoassociation on brush-border enzyme activities in ex-germ-free piglets: comparison of commensal and pathogenic Escherichia coli strains. Microbes Infect, 2006. 8(11): p. 2629-39. 30. Shirkey, T.W., et al., Effects of commensal bacteria on intestinal morphology and expression of proinflammatory cytokines in the gnotobiotic pig. Exp Biol Med (Maywood), 2006. 231(8): p. 1333-45. 31. Yu, L.C., et al., SGLT-1-mediated glucose uptake protects intestinal epithelial cells against LPS-induced apoptosis and barrier defects: a novel cellular rescue mechanism? FASEB J, 2005. 19(13): p. 1822-35. 32. Yu, L.C., J.R. Turner, and A.G. Buret, LPS/CD14 activation triggers SGLT-1-mediated glucose uptake and cell rescue in intestinal epithelial cells via early apoptotic signals upstream of caspase-3. Exp Cell Res, 2006. 312(17): p. 3276-86. 33. Jarry, A., et al., Mucosal IL-10 and TGF-beta play crucial roles in preventing LPS-driven, IFN-gamma-mediated epithelial damage in human colon explants. J Clin Invest, 2008. 118(3): p. 1132-42. 34. Janeway, C.A., Jr., Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol, 1989. 54 Pt 1: p. 1-13. 35. Medzhitov, R. and C.A. Janeway, Jr., Innate immunity: the virtues of a nonclonal system of recognition. Cell, 1997. 91(3): p. 295-8. 36. da Silva Correia, J., et al., Lipopolysaccharide is in close proximity to each of the proteins in its membrane receptor complex. transfer from CD14 to TLR4 and MD-2. J Biol Chem, 2001. 276(24): p. 21129-35. 37. Cuschieri, J., J. Billgren, and R.V. Maier, Phosphatidylcholine-specific phospholipase C (PC-PLC) is required for LPS-mediated macrophage activation through CD14. J Leukoc Biol, 2006. 80(2): p. 407-14. 38. Martin-Villa, J.M., et al., Cell surface phenotype and ultramicroscopic analysis of purified human enterocytes: a possible antigen-presenting cell in the intestine. Tissue Antigens, 1997. 50(6): p. 586-92. 39. Cario, E. and D.K. Podolsky, Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun, 2000. 68(12): p. 7010-7. 40. Frolova, L., et al., Expression of Toll-like receptor 2 (TLR2), TLR4, and CD14 in biopsy samples of patients with inflammatory bowel diseases: upregulated expression of TLR2 in terminal ileum of patients with ulcerative colitis. J Histochem Cytochem, 2008. 56(3): p. 267-74. 41. Doan, H.Q., et al., Toll-like receptor 4 activation increases Akt phosphorylation in colon cancer cells. Anticancer Res, 2009. 29(7): p. 2473-8. 42. Wang, E.L., et al., High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer. Br J Cancer, 2010. 102(5): p. 908-15. 43. Franchimont, D., et al., Deficient host-bacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn's disease and ulcerative colitis. Gut, 2004. 53(7): p. 987-92. 44. Brand, S., et al., The role of Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms and CARD15/NOD2 mutations in the susceptibility and phenotype of Crohn's disease. Inflamm Bowel Dis, 2005. 11(7): p. 645-52. 45. Guo, Q.S., et al., Polymorphisms of CD14 gene and TLR4 gene are not associated with ulcerative colitis in Chinese patients. Postgrad Med J, 2005. 81(958): p. 526-9. 46. Baumgart, D.C., et al., The c.1-260C>T promoter variant of CD14 but not the c.896A>G (p.D299G) variant of toll-like receptor 4 (TLR4) genes is associated with inflammatory bowel disease. Digestion, 2007. 76(3-4): p. 196-202. 47. Browning, B.L., et al., Has toll-like receptor 4 been prematurely dismissed as an inflammatory bowel disease gene? Association study combined with meta-analysis shows strong evidence for association. Am J Gastroenterol, 2007. 102(11): p. 2504-12. 48. De Jager, P.L., et al., The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases. Genes Immun, 2007. 8(5): p. 387-97. 49. Hsiao, C.H., et al., Pediatric Crohn disease: clinical and genetic characteristics in Taiwan. J Pediatr Gastroenterol Nutr, 2007. 44(3): p. 342-6. 50. Ortega-Cava, C.F., et al., Strategic compartmentalization of Toll-like receptor 4 in the mouse gut. J Immunol, 2003. 170(8): p. 3977-85. 51. Ortega-Cava, C.F., et al., Epithelial toll-like receptor 5 is constitutively localized in the mouse cecum and exhibits distinctive down-regulation during experimental colitis. Clin Vaccine Immunol, 2006. 13(1): p. 132-8. 52. Meijssen, M.A., et al., Alteration of gene expression by intestinal epithelial cells precedes colitis in interleukin-2-deficient mice. Am J Physiol, 1998. 274(3 Pt 1): p. G472-9. 53. Fukata, M., et al., Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology, 2007. 133(6): p. 1869-81. 54. Abreu, M.T., et al., Decreased expression of Toll-like receptor-4 and MD-2 correlates with intestinal epithelial cell protection against dysregulated proinflammatory gene expression in response to bacterial lipopolysaccharide. J Immunol, 2001. 167(3): p. 1609-16. 55. Suzuki, M., T. Hisamatsu, and D.K. Podolsky, Gamma interferon augments the intracellular pathway for lipopolysaccharide (LPS) recognition in human intestinal epithelial cells through coordinated up-regulation of LPS uptake and expression of the intracellular Toll-like receptor 4-MD-2 complex. Infect Immun, 2003. 71(6): p. 3503-11. 56. Eckmann, L., et al., Differential cytokine expression by human intestinal epithelial cell lines: regulated expression of interleukin 8. Gastroenterology, 1993. 105(6): p. 1689-97. 57. Chin, A.C., et al., The role of caspase-3 in lipopolysaccharide-mediated disruption of intestinal epithelial tight junctions. Can J Physiol Pharmacol, 2006. 84(10): p. 1043-50. 58. Ruemmele, F.M., et al., Lipopolysaccharide modulation of normal enterocyte turnover by toll-like receptors is mediated by endogenously produced tumour necrosis factor alpha. Gut, 2002. 51(6): p. 842-8. 59. Grondin, V., et al., Regulation of colon cancer cell proliferation and migration by MD-2 activity. Innate Immun, 2011. 17(4): p. 414-22. 60. Triantafilou, M., et al., Mediators of innate immune recognition of bacteria concentrate in lipid rafts and facilitate lipopolysaccharide-induced cell activation. J Cell Sci, 2002. 115(Pt 12): p. 2603-11. 61. Dunzendorfer, S., et al., TLR4 is the signaling but not the lipopolysaccharide uptake receptor. J Immunol, 2004. 173(2): p. 1166-70. 62. Wesche, H., et al., MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity, 1997. 7(6): p. 837-47. 63. Li, S., et al., IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. Proc Natl Acad Sci U S A, 2002. 99(8): p. 5567-72. 64. Zhang, H., et al., Integrin-nucleated Toll-like receptor (TLR) dimerization reveals subcellular targeting of TLRs and distinct mechanisms of TLR4 activation and signaling. FEBS Lett, 2002. 532(1-2): p. 171-6. 65. Akira, S. and K. Takeda, Toll-like receptor signalling. Nat Rev Immunol, 2004. 4(7): p. 499-511. 66. Lee, H.K., S. Dunzendorfer, and P.S. Tobias, Cytoplasmic domain-mediated dimerizations of toll-like receptor 4 observed by beta-lactamase enzyme fragment complementation. J Biol Chem, 2004. 279(11): p. 10564-74. 67. Cao, Z., et al., TRAF6 is a signal transducer for interleukin-1. Nature, 1996. 383(6599): p. 443-6. 68. Wang, C., et al., TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature, 2001. 412(6844): p. 346-51. 69. Chen, Z., et al., Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway. Genes Dev, 1995. 9(13): p. 1586-97. 70. Li, X., et al., Phosphoinositide 3 kinase mediates Toll-like receptor 4-induced activation of NF-kappa B in endothelial cells. Infect Immun, 2003. 71(8): p. 4414-20. 71. Wong, F., et al., Lipopolysaccharide initiates a TRAF6-mediated endothelial survival signal. Blood, 2004. 103(12): p. 4520-6. 72. Ojaniemi, M., et al., Phosphatidylinositol 3-kinase is involved in Toll-like receptor 4-mediated cytokine expression in mouse macrophages. Eur J Immunol, 2003. 33(3): p. 597-605. 73. Oshiumi, H., et al., TIR-containing adapter molecule (TICAM)-2, a bridging adapter recruiting to toll-like receptor 4 TICAM-1 that induces interferon-beta. J Biol Chem, 2003. 278(50): p. 49751-62. 74. Yamamoto, M., et al., TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol, 2003. 4(11): p. 1144-50. 75. Yamamoto, M., et al., Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science, 2003. 301(5633): p. 640-3. 76. Kaiser, W.J. and M.K. Offermann, Apoptosis induced by the toll-like receptor adaptor TRIF is dependent on its receptor interacting protein homotypic interaction motif. J Immunol, 2005. 174(8): p. 4942-52. 77. Fitzgerald, K.A., et al., IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol, 2003. 4(5): p. 491-6. 78. Taniguchi, T., et al., IRF family of transcription factors as regulators of host defense. Annu Rev Immunol, 2001. 19: p. 623-55. 79. Sasai, M., et al., Cutting Edge: NF-kappaB-activating kinase-associated protein 1 participates in TLR3/Toll-IL-1 homology domain-containing adapter molecule-1-mediated IFN regulatory factor 3 activation. J Immunol, 2005. 174(1): p. 27-30. 80. Colell, A., et al., Ceramide generated by acidic sphingomyelinase contributes to tumor necrosis factor-alpha-mediated apoptosis in human colon HT-29 cells through glycosphingolipids formation. Possible role of ganglioside GD3. FEBS Lett, 2002. 526(1-3): p. 135-41. 81. Kim, M., et al., Polarity proteins PAR6 and aPKC regulate cell death through GSK-3beta in 3D epithelial morphogenesis. J Cell Sci, 2007. 120(Pt 14): p. 2309-17. 82. Garcia-Barros, M., et al., Sphingolipids in colon cancer. Biochim Biophys Acta, 2014. 1841(5): p. 773-82. 83. Hertervig, E., et al., Reduction in alkaline sphingomyelinase in colorectal tumorigenesis is not related to the APC gene mutation. Int J Colorectal Dis, 2003. 18(4): p. 309-13. 84. Ma, L., et al., Control of nutrient stress-induced metabolic reprogramming by PKCzeta in tumorigenesis. Cell, 2013. 152(3): p. 599-611. 85. Greten, F.R., et al., IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell, 2004. 118(3): p. 285-96. 86. Fukata, M., et al., Cox-2 is regulated by Toll-like receptor-4 (TLR4) signaling: Role in proliferation and apoptosis in the intestine. Gastroenterology, 2006. 131(3): p. 862-77. 87. Nenci, A., et al., Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature, 2007. 446(7135): p. 557-61. 88. Edelblum, K.L., et al., Raf protects against colitis by promoting mouse colon epithelial cell survival through NF-kappaB. Gastroenterology, 2008. 135(2): p. 539-51. 89. Rakoff-Nahoum, S. and R. Medzhitov, Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science, 2007. 317(5834): p. 124-7. 90. Mullarkey, M., et al., Inhibition of endotoxin response by e5564, a novel Toll-like receptor 4-directed endotoxin antagonist. J Pharmacol Exp Ther, 2003. 304(3): p. 1093-102. 91. Opal, S.M., et al., Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA, 2013. 309(11): p. 1154-62. 92. Carpenter, S. and L.A. O'Neill, Recent insights into the structure of Toll-like receptors and post-translational modifications of their associated signalling proteins. Biochem J, 2009. 422(1): p. 1-10. 93. Jiang, Q., et al., Lipopolysaccharide induces physical proximity between CD14 and toll-like receptor 4 (TLR4) prior to nuclear translocation of NF-kappa B. J Immunol, 2000. 165(7): p. 3541-4. 94. Park, B.S., et al., The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature, 2009. 458(7242): p. 1191-5. 95. Kim, H.M., et al., Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell, 2007. 130(5): p. 906-17. 96. Yeh, Y.C., et al., Effects of eritoran tetrasodium, a toll-like receptor 4 antagonist, on intestinal microcirculation in endotoxemic rats. Shock, 2012. 37(5): p. 556-61. 97. Rallabhandi, P., et al., Respiratory syncytial virus fusion protein-induced toll-like receptor 4 (TLR4) signaling is inhibited by the TLR4 antagonists Rhodobacter sphaeroides lipopolysaccharide and eritoran (E5564) and requires direct interaction with MD-2. MBio, 2012. 3(4). 98. Shirey, K.A., et al., The TLR4 antagonist Eritoran protects mice from lethal influenza infection. Nature, 2013. 497(7450): p. 498-502. 99. Kuo, W.T., et al., LPS receptor subunits have antagonistic roles in epithelial apoptosis and colonic carcinogenesis. Cell Death Differ, 2015. 22(10): p. 1590-604. 100. Wu, L.L., et al., Epithelial inducible nitric oxide synthase causes bacterial translocation by impairment of enterocytic tight junctions via intracellular signals of Rho-associated kinase and protein kinase C zeta. Crit Care Med, 2011. 39(9): p. 2087-98. 101. Huang, C.Y., et al., Anti-apoptotic PI3K/Akt signaling by sodium/glucose transporter 1 reduces epithelial barrier damage and bacterial translocation in intestinal ischemia. Lab Invest, 2011. 91(2): p. 294-309. 102. Chen, T.L., et al., Persistent gut barrier damage and commensal bacterial influx following eradication of Giardia infection in mice. Gut Pathog, 2013. 5(1): p. 26. 103. Uronis, J.M., et al., Modulation of the intestinal microbiota alters colitis-associated colorectal cancer susceptibility. PLoS One, 2009. 4(6): p. e6026. 104. Sato, T., et al., Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology, 2011. 141(5): p. 1762-72. 105. Chen, J., J.H. Winston, and S.K. Sarna, Neurological and cellular regulation of visceral hypersensitivity induced by chronic stress and colonic inflammation in rats. Neuroscience, 2013. 248: p. 469-78. 106. Chen, Y., et al., Ischemic preconditioning increased the intestinal stem cell activities in the intestinal crypts in mice. J Surg Res, 2014. 187(1): p. 85-93. 107. Huang, C.Y., et al., Resistance to hypoxia-induced necroptosis is conferred by glycolytic pyruvate scavenging of mitochondrial superoxide in colorectal cancer cells. Cell Death Dis, 2013. 4: p. e622. 108. Yoo, H.H., J. Son, and D.H. Kim, Liquid chromatography-tandem mass spectrometric determination of ceramides and related lipid species in cellular extracts. J Chromatogr B Analyt Technol Biomed Life Sci, 2006. 843(2): p. 327-33. 109. Yu, L.C., et al., Enteric dysbiosis promotes antibiotic-resistant bacterial infection: systemic dissemination of resistant and commensal bacteria through epithelial transcytosis. Am J Physiol Gastrointest Liver Physiol, 2014. 307(8): p. G824-35. 110. Nambiar, P.R., et al., Preliminary analysis of azoxymethane induced colon tumors in inbred mice commonly used as transgenic/knockout progenitors. Int J Oncol, 2003. 22(1): p. 145-50. 111. Nagamine, C.M., et al., Helicobacter hepaticus promotes azoxymethane-initiated colon tumorigenesis in BALB/c-IL10-deficient mice. Int J Cancer, 2008. 122(4): p. 832-8. 112. Araki, Y., H. Sugihara, and T. Hattori, In vitro effects of dextran sulfate sodium on a Caco-2 cell line and plausible mechanisms for dextran sulfate sodium-induced colitis. Oncol Rep, 2006. 16(6): p. 1357-62. 113. Cuschieri, J., et al., Acid sphingomyelinase is required for lipid Raft TLR4 complex formation. Surg Infect (Larchmt), 2007. 8(1): p. 91-106. 114. Nishikawa, K., et al., Determination of the specific substrate sequence motifs of protein kinase C isozymes. J Biol Chem, 1997. 272(2): p. 952-60. 115. Hirai, T. and K. Chida, Protein kinase Czeta (PKCzeta): activation mechanisms and cellular functions. J Biochem, 2003. 133(1): p. 1-7. 116. Wooten, M.W., et al., Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase C's via a src kinase pathway. Mol Cell Biol, 2001. 21(24): p. 8414-27. 117. Ranganathan, S., et al., Activation loop phosphorylation-independent kinase activity of human protein kinase C zeta. Proteins, 2007. 67(3): p. 709-19. 118. Belmonte, L., et al., Role of toll like receptors in irritable bowel syndrome: differential mucosal immune activation according to the disease subtype. PLoS One, 2012. 7(8): p. e42777. 119. Chen, R., et al., LBP and CD14 polymorphisms correlate with increased colorectal carcinoma risk in Han Chinese. World J Gastroenterol, 2011. 17(18): p. 2326-31. 120. Eyking, A., et al., Toll-like receptor 4 variant D299G induces features of neoplastic progression in Caco-2 intestinal cells and is associated with advanced human colon cancer. Gastroenterology, 2011. 141(6): p. 2154-65. 121. Pimentel-Nunes, P., et al., Functional polymorphisms of Toll-like receptors 2 and 4 alter the risk for colorectal carcinoma in Europeans. Dig Liver Dis, 2013. 45(1): p. 63-9. 122. Fukata, M., et al., Constitutive activation of epithelial TLR4 augments inflammatory responses to mucosal injury and drives colitis-associated tumorigenesis. Inflamm Bowel Dis, 2011. 17(7): p. 1464-73. 123. Santaolalla, R., et al., TLR4 activates the beta-catenin pathway to cause intestinal neoplasia. PLoS One, 2013. 8(5): p. e63298. 124. Fukata, M., et al., Innate immune signaling by Toll-like receptor-4 (TLR4) shapes the inflammatory microenvironment in colitis-associated tumors. Inflamm Bowel Dis, 2009. 15(7): p. 997-1006. 125. Czerkies, M., et al., An interplay between scavenger receptor A and CD14 during activation of J774 cells by high concentrations of LPS. Immunobiology, 2013. 218(10): p. 1217-26. 126. Cario, E., et al., Lipopolysaccharide activates distinct signaling pathways in intestinal epithelial cell lines expressing Toll-like receptors. J Immunol, 2000. 164(2): p. 966-72. 127. Yagi, S., et al., Enteric lipopolysaccharide raises plasma IL-6 levels in the hepatoportal vein during non-inflammatory stress in the rat. Fukuoka Igaku Zasshi, 2002. 93(3): p. 38-51. 128. Zanoni, I., et al., CD14 regulates the dendritic cell life cycle after LPS exposure through NFAT activation. Nature, 2009. 460(7252): p. 264-8. 129. Dobrovolskaia, M.A. and S.N. Vogel, Toll receptors, CD14, and macrophage activation and deactivation by LPS. Microbes Infect, 2002. 4(9): p. 903-14. 130. Hsu, L.C., et al., The protein kinase PKR is required for macrophage apoptosis after activation of Toll-like receptor 4. Nature, 2004. 428(6980): p. 341-5. 131. Rallabhandi, P., et al., Analysis of TLR4 polymorphic variants: new insights into TLR4/MD-2/CD14 stoichiometry, structure, and signaling. J Immunol, 2006. 177(1): p. 322-32. 132. Tang, X.Y., et al., Expression and functional research of TLR4 in human colon carcinoma. Am J Med Sci, 2010. 339(4): p. 319-26. 133. Tang, X. and Y. Zhu, TLR4 signaling promotes immune escape of human colon cancer cells by inducing immunosuppressive cytokines and apoptosis resistance. Oncol Res, 2012. 20(1): p. 15-24. 134. Yang, K.J., et al., Regulation of 3-phosphoinositide-dependent protein kinase-1 (PDK1) by Src involves tyrosine phosphorylation of PDK1 and Src homology 2 domain binding. J Biol Chem, 2008. 283(3): p. 1480-91. 135. Hsu, R.Y., et al., LPS-induced TLR4 signaling in human colorectal cancer cells increases beta1 integrin-mediated cell adhesion and liver metastasis. Cancer Res, 2011. 71(5): p. 1989-98. 136. Rousseau, M.C., et al., Lipopolysaccharide-induced toll-like receptor 4 signaling enhances the migratory ability of human esophageal cancer cells in a selectin-dependent manner. Surgery, 2013. 154(1): p. 69-77. 137. Kawai, T. and S. Akira, TLR signaling. Cell Death Differ, 2006. 13(5): p. 816-25. 138. Kuo, W.T., T.C. Lee, and L.C. Yu, Janus-faced bacterial regulation of epithelial cell death and survival: association with colon carcinogenesis. Molecular & Cellular Oncology, 2015. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/51566 | - |
dc.description.abstract | 研究背景:結直腸癌之特徵在於腸道上皮細胞無限增殖及細胞抗凋亡。細菌脂多醣受體 (LPS receptors,包括CD14/TLR4/MD2) 的訊息傳遞途徑與有上皮細胞增生凋亡及腫瘤癌化過程有關,但其次單元參與之機制仍不清楚。此外,Eritoran為治療嚴重敗血症之研發新藥,因其結構類似脂多醣lipid A官能基,故可作為TLR4抑制劑;然而,eritoran抗癌之療效仍有待證實。目的:(1) 探討脂多醣受體次單元 (CD14和TLR4) 在上皮細胞凋亡與存活反應及腫瘤生成的個別角色,(2) 闡述eritoran抗癌效應之分子機制。結果:研究結果發現人類正常結腸上皮細胞之脂多醣受體次單元表現為 CD14+TLR4-,而腫瘤組織為CD14+TLR4+。利用氧化偶氮甲烷/硫酸葡聚醣鈉 (AOM/DSS) 誘發發炎性結直腸癌模式發現,TLR4 突變小鼠相較於野生型小鼠 (CD14+TLR4+) 在腫瘤形成早期階段有上皮細胞凋亡增加,且後期階段有腫瘤生成降低之現象。此兩種小鼠品系在結直腸癌模式中均可見黏膜層脂多醣含量升高。在結腸內給予中和性抗CD14抗體可抑制脂多醣誘導上皮細胞凋亡。此外,利用小鼠結腸腺窩培養之初代結腸類器官 (organoid) 模式發現,給予脂多醣刺激TLR4 突變小鼠者會引起細胞凋亡,但在野生型小鼠則不會。將野生型小鼠初代結腸類器官之TLR4基因沉默後,脂多醣引起之細胞凋亡量會增加;反之,若將TLR4突變小鼠初代結腸類器官之CD14基因沉默,脂多醣引起之細胞凋亡則會被抑制。體外實驗結果顯示脂多醣刺激會引起人類結直腸癌腺癌細胞株Caco-2 (CD14+TLR4-) 細胞凋亡,但在HT29細胞 (CD14+TLR4+) 則不會;此現象與CD14、磷脂醯膽鹼特異性磷脂酶、鞘磷脂酶或蛋白激酶Cζ (PKCζ)有關。相反地,轉染野生型而非突變型TLR4 (Asp299Gly、Thr399Ile或Pro714His) 可使Caco-2細胞免於凋亡; 反之,TLR4基因沉默後之HT29細胞則無法生存。後續研究發現,經肛門端、經口端及經靜脈給予eritoran可顯著降低發炎性結直腸癌模式小鼠之腫瘤數目、大小及進程。給予eritoran治療可減少腫瘤部位細胞增生及促進細胞凋亡。利用小鼠初代腫瘤細胞培養及人類腺癌細胞株發現,藉由脂多醣/TLR4引起之細胞增生現象可被eritoran及CD14、TLR4基因沉默所抑制。此外,將CD14及PKCζ基因沉默可阻斷由eritoran引起之細胞凋亡,但將TLR4基因沉默則無效。最後,脂多醣及eritoran刺激可使PKCζ在Thr410、Thr560及Tyr位置磷酸化,此現象藉由CD14介導而與TLR4無關。給予Src激酶及PKCζ偽受質可阻止PKCζ活化引起之細胞凋亡。總體而言,eritoran治療可藉由刺激CD14/Src/PKCζ誘導細胞凋亡及阻斷TLR4依賴性細胞增生,來達到抑制結腸癌的目的。結論:本研究指出CD14/TLR4拮抗失衡會導致正常上皮細胞癌化形成腫瘤,eritoran藉由調控CD14/TLR4拮抗的偏倚作用,因此可作為治療結直腸癌之嶄新策略。 | zh_TW |
dc.description.abstract | Background: Colorectal carcinoma (CRC) is characterized by unlimited proliferation and suppression of apoptosis. Signaling of lipopolysaccharide (LPS) receptors (CD14/TLR4/MD2) is involved in both epithelial homeostasis and tumorigenesis, but the mechanisms remain poorly understood. Furthermore, eritoran is an investigational drug for treatment of severe sepsis as a TLR4 inhibitor based on its structural similarity to lipid A moiety. Potential therapeutic use of eritoran in cancer reduction has yet to be determined. Aims: (1) To characterize individual roles of LPS receptor subunits (CD14 and TLR4) in epithelial death versus survival responses, and tumor development; (2) To clarify the underlying molecular mechanisms for the anticancer effect of eritoran. Results: Our study showed that normal human colonocytes were CD14+TLR4−, whereas cancerous tissues were CD14+TLR4+, by immunofluorescent staining. Using a chemical-induced CRC model, increased epithelial apoptosis and decreased tumor multiplicity and sizes were observed in TLR4-mutant mice compared with wild-type (WT) mice with CD14+TLR4+ colonocytes. Mucosa-associated LPS content was elevated in response to CRC induction. Epithelial apoptosis induced by LPS hypersensitivity in TLR4-mutant mice was prevented by intracolonic administration of neutralizing anti-CD14. Moreover, LPS-induced apoptosis was observed in primary colonic organoid cultures derived from TLR4 mutant but not WT murine crypts. Gene silencing of TLR4 increased cell apoptosis in WT organoids, whereas knockdown of CD14 ablated cell death in TLR4-mutant organoids. In vitro studies showed that LPS challenge caused apoptosis in Caco-2 cells (CD14+TLR4−) in a CD14-, phosphatidylcholine-specific phospholipase C-, sphingomyelinase-, and protein kinase C-ζ (PKCζ)-dependent manner. Conversely, expression of functional but not mutant TLR4 (Asp299Gly, Thr399Ile, and Pro714His) rescued cells from LPS/CD14-induced apoptosis. Further studies demonstrated that eritoran administration via intracolonic, intragastric, or intravenous routes significantly reduced tumor burden and stage in mouse CRC models. Decreased proliferation and increased apoptosis were observed in mouse tumor cells after eritoran treatment. In vitro cultures of mouse primary tumor spheroids and human cancer cell lines displayed augmented cell proliferation and cell cycle progression following LPS challenge, which was inhibited by eritoran and by knockdown of CD14 or TLR4. In contrast, cancer cell apoptosis induced by eritoran was ablated by gene silencing of CD14 or PKCζ, but not TLR4. Finally, LPS and eritoran caused hyperphosphorylation of PKCζ at Thr410, Thr560 and tyrosine sites in a CD14-dependent and TLR4-independent manner. Blockade of PKCζ activation by inhibitors to Src kinase prevented the eritoran-induced apoptosis. In summary, eritoran treatment suppressed colon cancer growth by dual mechanisms, including induction of CD14/Src/PKCζ-mediated cell apoptosis and blockade of TLR4-dependent cell proliferation. Conclusion: Our findings indicate that dysfunction in the CD14/TLR4 antagonism may contribute to normal epithelial transition to carcinogenesis. Eritoran treatment via diversion of functional antagonism of LPS receptors may serve as a novel strategy for intervention against colorectal cancer. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T13:39:09Z (GMT). No. of bitstreams: 1 ntu-105-D98441005-1.pdf: 10074884 bytes, checksum: c3f2a556d61dc6232923fe05017a740e (MD5) Previous issue date: 2016 | en |
dc.description.tableofcontents | 目 錄
口試委員會審定書……………………………………………………….……………..I 致謝……………………………………………………………………………………..II 中文摘要………………………………………………………………………………III Abstract…………………………………………………………………………………V List of abbreviations…………………………………………………………….……VII Chapter 1 Introduction…………………………………………………………………..1 1.1 Intestinal epithelial cell proliferation and apoptosis……………………………..1 1.1.1 Crypt-villus axis and enterocytic turnover rates……………………………1 1.1.2 Apoptotic pathways…………………………………………………………1 1.2 Hallmarks of colorectal carcinoma………………………………………………2 1.3 Interaction between gut microbiota and epithelial cells…………………………3 1.4 Lipopolysaccharide receptors in intestinal epithelial cells………………………4 1.4.1 Bacterial lipopolysaccharide………………………………………………..4 1.4.2 Expression pattern of LPS receptor subunits in human normal enterocytes..4 1.4.3 Expression pattern of LPS receptor subunits in epithelial cells of inflammatory bowel disease and colorectal carcinoma…………………….5 1.4.4 Expression pattern of LPS receptor subunits in colorectal cancer cell line…6 1.5 Intestinal epithelial response to LPS……………………………………………..6 1.5.1 Proinflammatory response……………………………………………..……6 1.5.2 Apoptotic, survival and proliferative responses…………………………….7 1.6 Signaling pathways of LPS receptors……………………………………………7 1.7 Eritoran…………………………………………………………………………..9 1.8 Aims of the study……………………………………………………………….10 Chapter 2 Materials and Methods………………………………………….…………..11 2.1 Human colonic surgical specimens………………………………….………….11 2.2 Animal studies……………………………………………………….………….11 2.2.1 Mice strains………………………………………………………………..11 2.2.2 Models of colitis-associated CRC…………………………………………12 2.2.3 Administration of eritoran…………………………………………………12 2.2.4 Commensal overgrowth (CO) by intestinal loop ligation…………………13 2.3 Histopathological examination…………………………………………………14 2.4 LPS challenge to mouse colonic tissues in ex vivo tissue baths………………..14 2.5 Primary intestinal organoid cultures……………………………………………15 2.6 Primary intestinal spheroid cultures……………………………………………16 2.7 Isolation of mouse intestinal epithelial cells and blood mononuclear leukocytes (ML)……………………………………………………………………………..18 2.8 Measurement of cell apoptosis………………………………………………….19 2.9 Quantification of mucosa-associated LPS levels……………………………….19 2.10 Cell lines………………………………………………………………………20 2.10.1 Apical LPS challenge in cell cultures……………………………………21 2.10.2 siRNA-mediated knockdown…………………………………………….21 2.10.3 Plasmid constructs and cell transfection…………………………………22 2.11 Lipid extraction and ultra-performance liquid chromatography (UPLC)-tandem mass spectrometry (UPLC-MS/MS)…………………………………………23 2.12 Reverse transcription-polymerase chain reaction (RT-PCR)………………….24 2.13 Immunofluorescent staining and confocal microscopy……………………….25 2.14 Western blotting……………………………………………………………….26 2.15 Enzyme-linked immunosorbent assay (ELISA)………………………………27 2.16 Evaluation of cell cycle progression…………………………………………..27 2.17 Statistical analysis……………………………………………………………..28 Chapter 3 Results………………………………………………………………………29 3.1 LPS receptor subunits play antagonistic roles in epithelial apoptosis and colonic carcinogenesis.…………………………………………………………………..28 3.2 Dual modes of action by eritoran in colon cancer suppression through alterations in the functional antagonism of LPS receptors………………………………….36 Chapter 4 Discussion…………………………………………………………………..42 Chapter 5 Concluding remarks…………………………………………………………48 Chapter 6 Figures………………………………………………………………………49 Bibliography……………………………………………………………………………82 | |
dc.language.iso | en | |
dc.title | 脂多醣受體次單元在結腸上皮細胞凋亡及腫瘤生成中的拮抗作用:分子機制及治療應用之探討 | zh_TW |
dc.title | LPS receptor subunits have antagonistic roles in epithelial apoptosis and colonic carcinogenesis: molecular mechanisms and therapeutic implication | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 倪衍玄,林琬琬,徐立中,繆希椿 | |
dc.subject.keyword | 結直腸癌,共生菌,脂多醣受體,上皮細胞凋亡,細胞增生,脂質信使,腫瘤抑制因子,免疫治療, | zh_TW |
dc.subject.keyword | colorectal cancer,commensal bacteria,LPS receptors,epithelial apoptosis,cell proliferation,lipid messengers,tumor suppressor,immunotherapy, | en |
dc.relation.page | 97 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2016-01-21 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 生理學研究所 | zh_TW |
顯示於系所單位: | 生理學科所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-105-1.pdf 目前未授權公開取用 | 9.84 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。