請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78970
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 胡孟君 | zh_TW |
dc.contributor.advisor | Meng-Chun Hu | en |
dc.contributor.author | 陳昕梅 | zh_TW |
dc.contributor.author | Hsin-Mei Chen | en |
dc.date.accessioned | 2021-07-11T15:33:10Z | - |
dc.date.available | 2024-02-28 | - |
dc.date.copyright | 2018-10-05 | - |
dc.date.issued | 2018 | - |
dc.date.submitted | 2002-01-01 | - |
dc.identifier.citation | Alvira CM. 2014. Nuclear factor-kappa-B signaling in lung development and disease: one pathway, numerous functions. Birth defects research Part A, Clinical and molecular teratology 100: 202-216.
Bankaitis KV, Fingleton B. 2015. Targeting IL4/IL4R for the treatment of epithelial cancer metastasis. Clinical & Experimental Metastasis 32: 847-856. Bhogal RK, Bona CA. 2008. Regulatory effect of extracellular signal-regulated kinases (ERK) on type I collagen synthesis in human dermal fibroblasts stimulated by IL-4 and IL-13. International reviews of immunology 27: 472-496. Blazkova H, von Schubert C, Mikule K, Schwab R, Angliker N, Schmuckli-Maurer J, Fernandez PC, Doxsey S, Dobbelaere DA. 2007. The IKK inhibitor BMS-345541 affects multiple mitotic cell cycle transitions. Cell cycle (Georgetown, Tex) 6: 2531-2540. Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist U. 1995. Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science (New York, NY) 267: 1485-1488. Cataldi M, Shah NR, Felt SA, Grdzelishvili VZ. 2015. Breaking resistance of pancreatic cancer cells to an attenuated vesicular stomatitis virus through a novel activity of IKK inhibitor TPCA-1. Virology 485: 340-354. Chariot A. 2009. The NF-kappaB-independent functions of IKK subunits in immunity and cancer. Trends in cell biology 19: 404-413. Chen CG, Malliaros J, Katerelos M, d'Apice AJ, Pearse MJ. 1996. Inhibition of NF-kappaB activation by a dominant-negative mutant of IkappaBalpha. Molecular immunology 33: 57-61. Chiba Y, Todoroki M, Misawa M. 2010. Interleukin-4 upregulates RhoA protein via an activation of STAT6 in cultured human bronchial smooth muscle cells. Pharmacological research 61: 188-192. Chomarat P, Banchereau J. 1998. Interleukin-4 and interleukin-13: their similarities and discrepancies. Int Rev Immunol 17: 1-52. Cidlowski LIMaJA. 2003. Hormones of the adrenal cortex. in Holland-Frei Cancer Medicine (ed. PR Kufe DW, Weichselbaum RR, et al). BC Decker, Hamilton (ON). Cima I, Corazza N, Dick B, Fuhrer A, Herren S, Jakob S, Ayuni E, Mueller C, Brunner T. 2004. Intestinal epithelial cells synthesize glucocorticoids and regulate T cell activation. The Journal of experimental medicine 200: 1635-1646. Cuadrado A, Nebreda AR. 2010. Mechanisms and functions of p38 MAPK signalling. The Biochemical journal 429: 403-417. Davies E, MacKenzie SM. 2003. Extra-adrenal production of corticosteroids. Clinical and experimental pharmacology & physiology 30: 437-445. Ear T, Fortin CF, Simard FA, McDonald PP. 2010. Constitutive association of TGF-beta-activated kinase 1 with the IkappaB kinase complex in the nucleus and cytoplasm of human neutrophils and its impact on downstream processes. Journal of immunology (Baltimore, Md : 1950) 184: 3897-3906. Espinosa L, Margalef P, Bigas A. 2015. Non-conventional functions for NF-kappaB members: the dark side of NF-kappaB. Oncogene 34: 2279-2287. Fayard E, Auwerx J, Schoonjans K. 2004. LRH-1: an orphan nuclear receptor involved in development, metabolism and steroidogenesis. Trends in cell biology 14: 250-260. Ghosh S, Karin M. 2002. Missing pieces in the NF-kappaB puzzle. Cell 109 Suppl: S81-96. Ghosh S, May MJ, Kopp EB. 1998. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annual review of immunology 16: 225-260. Gilmore TD. 2006. Introduction to NF-kappaB: players, pathways, perspectives. Oncogene 25: 6680-6684. Gingras S, Cote S, Simard J. 2000. Multiple signaling pathways mediate interleukin-4-induced 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase type 1 gene expression in human breast cancer cells. Molecular endocrinology (Baltimore, Md) 14: 229-240. Gingras S, Moriggl R, Groner B, Simard J. 1999. Induction of 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase type 1 gene transcription in human breast cancer cell lines and in normal mammary epithelial cells by interleukin-4 and interleukin-13. Molecular endocrinology (Baltimore, Md) 13: 66-81. Gingras S, Simard J. 1999. Induction of 3beta-hydroxysteroid dehydrogenase/isomerase type 1 expression by interleukin-4 in human normal prostate epithelial cells, immortalized keratinocytes, colon, and cervix cancer cell lines. Endocrinology 140: 4573-4584. Goosen P. 2012. The influence of 3βHSD on adrenal steroidogenesis and the factors which influence its activity Stellenbosch University. Hallett MA, Venmar KT, Fingleton B. 2012. Cytokine Stimulation of Epithelial Cancer Cells: The Similar and Divergent Functions of IL-4 and IL-13. Cancer Research 72: 6338-6343. Hauge C, Frodin M. 2006. RSK and MSK in MAP kinase signalling. Journal of cell science 119: 3021-3023. Huang SC, Lee CT, Chung BC. 2014. Tumor necrosis factor suppresses NR5A2 activity and intestinal glucocorticoid synthesis to sustain chronic colitis. Science signaling 7: ra20. Johnson GL, Lapadat R. 2002. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science (New York, NY) 298: 1911-1912. Jäntti S. 2013. Liquid chromatography-tandem mass spectrometry in studies of steroid hormones and steroid glucuronide conjugates in brain and urine. University of Helsinki. Kannan Y, Wilson MS. 2012. TEC and MAPK Kinase Signalling Pathways in T helper (TH) cell Development, TH2 Differentiation and Allergic Asthma. Journal of clinical & cellular immunology Suppl 12: 11. Kawakami M, Kawakami K, Stepensky VA, Maki RA, Robin H, Muller W, Husain SR, Puri RK. 2002. Interleukin 4 receptor on human lung cancer: a molecular target for cytotoxin therapy. Clinical cancer research : an official journal of the American Association for Cancer Research 8: 3503-3511. Koller FL, Hwang DG, Dozier EA, Fingleton B. 2010. Epithelial interleukin-4 receptor expression promotes colon tumor growth. Carcinogenesis 31: 1010-1017. Kress TR, Raabe T, Feller SM. 2010. High Erk activity suppresses expression of the cell cycle inhibitor p27Kip1 in colorectal cancer cells. Cell communication and signaling : CCS 8: 1. Lai TC, Li HF, Li YS, Hung PY, Shyu MK, Hu MC. 2017. Proximal GATA-binding sites are essential for human HSD3B1 gene transcription in the placenta. Scientific reports 7: 4271. LaPorte SL, Juo ZS, Vaclavikova J, Colf LA, Qi X, Heller NM, Keegan AD, Garcia KC. 2008. Molecular and Structural Basis of Cytokine Receptor Pleiotropy in the Interleukin-4/13 System. Cell 132: 259-272. Lawrence T, Bebien M, Liu GY, Nizet V, Karin M. 2005. IKKalpha limits macrophage NF-kappaB activation and contributes to the resolution of inflammation. Nature 434: 1138-1143. Lee SO, Lou W, Nadiminty N, Lin X, Gao AC. 2005. Requirement for NF-(kappa)B in interleukin-4-induced androgen receptor activation in prostate cancer cells. The Prostate 64: 160-167. Li BH, Yang XZ, Li PD, Yuan Q, Liu XH, Yuan J, Zhang WJ. 2008. IL-4/Stat6 activities correlate with apoptosis and metastasis in colon cancer cells. Biochemical and biophysical research communications 369: 554-560. Liu KL, Yang YC, Yao HT, Chia TW, Lu CY, Li CC, Tsai HJ, Lii CK, Chen HW. 2016. Docosahexaenoic acid inhibits inflammation via free fatty acid receptor FFA4, disruption of TAB2 interaction with TAK1/TAB1 and downregulation of ERK-dependent Egr-1 expression in EA.hy926 cells. Molecular nutrition & food research 60: 430-443. Liu W, Reinmuth N, Stoeltzing O, Parikh AA, Tellez C, Williams S, Jung YD, Fan F, Takeda A, Akagi M et al. 2003. Cyclooxygenase-2 is up-regulated by interleukin-1 beta in human colorectal cancer cells via multiple signaling pathways. Cancer Res 63: 3632-3636. Liu Y, Shepherd EG, Nelin LD. 2007. MAPK phosphatases--regulating the immune response. Nature reviews Immunology 7: 202-212. Margalef P, Fernandez-Majada V, Villanueva A, Garcia-Carbonell R, Iglesias M, Lopez L, Martinez-Iniesta M, Villa-Freixa J, Mulero MC, Andreu M et al. 2012. A truncated form of IKKalpha is responsible for specific nuclear IKK activity in colorectal cancer. Cell reports 2: 840-854. Martin LJ, Taniguchi H, Robert NM, Simard J, Tremblay JJ, Viger RS. 2005. GATA factors and the nuclear receptors, steroidogenic factor 1/liver receptor homolog 1, are key mutual partners in the regulation of the human 3beta-hydroxysteroid dehydrogenase type 2 promoter. Molecular endocrinology (Baltimore, Md) 19: 2358-2370. Mattioli I, Sebald A, Bucher C, Charles RP, Nakano H, Doi T, Kracht M, Schmitz ML. 2004. Transient and selective NF-kappa B p65 serine 536 phosphorylation induced by T cell costimulation is mediated by I kappa B kinase beta and controls the kinetics of p65 nuclear import. Journal of immunology (Baltimore, Md : 1950) 172: 6336-6344. McCormick SM, Heller NM. 2015. Commentary: IL-4 and IL-13 receptors and signaling. Cytokine 75: 38-50. Merga YJ, O'Hara A, Burkitt MD, Duckworth CA, Probert CS, Campbell BJ, Pritchard DM. 2016. Importance of the alternative NF-kappaB activation pathway in inflammation-associated gastrointestinal carcinogenesis. American journal of physiology Gastrointestinal and liver physiology 310: G1081-1090. Miller WL, Auchus RJ. 2011. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev 32: 81-151. Mor A, Philips MR. 2006. Compartmentalized Ras/MAPK signaling. Annual review of immunology 24: 771-800. Mueller M, Cima I, Noti M, Fuhrer A, Jakob S, Dubuquoy L, Schoonjans K, Brunner T. 2006. The nuclear receptor LRH-1 critically regulates extra-adrenal glucocorticoid synthesis in the intestine. The Journal of experimental medicine 203: 2057-2062. Napetschnig J, Wu H. 2013. Molecular basis of NF-kappaB signaling. Annual review of biophysics 42: 443-468. Nelms K, Keegan AD, Zamorano J, Ryan JJ, Paul WE. 1999. The IL-4 receptor: signaling mechanisms and biologic functions. Annual review of immunology 17: 701-738. Noti M, Corazza N, Mueller C, Berger B, Brunner T. 2010a. TNF suppresses acute intestinal inflammation by inducing local glucocorticoid synthesis. The Journal of experimental medicine 207: 1057-1066. Noti M, Corazza N, Tuffin G, Schoonjans K, Brunner T. 2010b. Lipopolysaccharide induces intestinal glucocorticoid synthesis in a TNFalpha-dependent manner. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24: 1340-1346. Parker KL, Rice DA, Lala DS, Ikeda Y, Luo X, Wong M, Bakke M, Zhao L, Frigeri C, Hanley NA et al. 2002. Steroidogenic factor 1: an essential mediator of endocrine development. Recent progress in hormone research 57: 19-36. Patel M, Horgan PG, McMillan DC, Edwards J. 2018. NF-kappaB pathways in the development and progression of colorectal cancer. Translational research : the journal of laboratory and clinical medicine 197: 43-56. Payne AH, Clarke TR, Bain PA. 1995. The murine 3 beta-hydroxysteroid dehydrogenase multigene family: structure, function and tissue-specific expression. The Journal of steroid biochemistry and molecular biology 53: 111-118. Payne AH, Hales DB. 2004. Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocrine reviews 25: 947-970. Peng L, Huang Y, Jin F, Jiang SW, Payne AH. 2004. Transcription enhancer factor-5 and a GATA-like protein determine placental-specific expression of the Type I human 3beta-hydroxysteroid dehydrogenase gene, HSD3B1. Molecular endocrinology (Baltimore, Md) 18: 2049-2060. Pierce JW, Schoenleber R, Jesmok G, Best J, Moore SA, Collins T, Gerritsen ME. 1997. Novel inhibitors of cytokine-induced IkappaBalpha phosphorylation and endothelial cell adhesion molecule expression show anti-inflammatory effects in vivo. The Journal of biological chemistry 272: 21096-21103. Pradere JP, Hernandez C, Koppe C, Friedman RA, Luedde T, Schwabe RF. 2016. Negative regulation of NF-kappaB p65 activity by serine 536 phosphorylation. Science signaling 9: ra85. Pritchard AL, Hayward NK. 2013. Molecular pathways: mitogen-activated protein kinase pathway mutations and drug resistance. Clinical cancer research : an official journal of the American Association for Cancer Research 19: 2301-2309. Prokopchuk O, Liu Y, Henne-Bruns D, Kornmann M. 2005. Interleukin-4 enhances proliferation of human pancreatic cancer cells: evidence for autocrine and paracrine actions. British journal of cancer 92: 921-928. Richards ML, Katz DH. 1997. Analysis of the promoter elements necessary for IL-4 and anti-CD40 antibody induction of murine Fc epsilon RII (CD23): comparison with the germline epsilon promoter. Journal of immunology (Baltimore, Md : 1950) 158: 263-272. Roca H, Craig MJ, Ying C, Varsos ZS, Czarnieski P, Alva AS, Hernandez J, Fuller D, Daignault S, Healy PN et al. 2012. IL-4 induces proliferation in prostate cancer PC3 cells under nutrient-depletion stress through the activation of the JNK-pathway and survivin up-regulation. Journal of cellular biochemistry 113: 1569-1580. Roux PP, Shahbazian D, Vu H, Holz MK, Cohen MS, Taunton J, Sonenberg N, Blenis J. 2007. RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. The Journal of biological chemistry 282: 14056-14064. Sasaki CY, Barberi TJ, Ghosh P, Longo DL. 2005. Phosphorylation of RelA/p65 on serine 536 defines an I{kappa}B{alpha}-independent NF-{kappa}B pathway. The Journal of biological chemistry 280: 34538-34547. Sater AK. 2012. TAK1: Kinase at the Crossroads. Biochemistry & Analytical Biochemistry 1: 1-3. Senftleben U, Cao Y, Xiao G, Greten FR, Krahn G, Bonizzi G, Chen Y, Hu Y, Fong A, Sun SC et al. 2001. Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science (New York, NY) 293: 1495-1499. Shen CH, Stavnezer J. 1998. Interaction of stat6 and NF-kappaB: direct association and synergistic activation of interleukin-4-induced transcription. Molecular and cellular biology 18: 3395-3404. Sidler D, Renzulli P, Schnoz C, Berger B, Schneider-Jakob S, Fluck C, Inderbitzin D, Corazza N, Candinas D, Brunner T. 2011. Colon cancer cells produce immunoregulatory glucocorticoids. Oncogene 30: 2411-2419. Simard J, Ricketts M-L, Gingras Sb, Soucy P, Feltus FA, Melner MH. 2005. Molecular Biology of the 3β-Hydroxysteroid Dehydrogenase/Δ5-Δ4 Isomerase Gene Family. Endocrine Reviews 26: 525-582. Sunami Y, Wirth T. 2011. Intestinal carcinogenesis: IKK can go all the way. The Journal of clinical investigation 121: 2551-2553. Takeda K, Kishimoto T, Akira S. 1997. STAT6: its role in interleukin 4-mediated biological functions. Journal of molecular medicine (Berlin, Germany) 75: 317-326. Tergaonkar V, Correa RG, Ikawa M, Verma IM. 2005. Distinct roles of IkappaB proteins in regulating constitutive NF-kappaB activity. Nature cell biology 7: 921-923. Thomas JL, Duax WL, Addlagatta A, Brandt S, Fuller RR, Norris W. 2003. Structure/function relationships responsible for coenzyme specificity and the isomerase activity of human type 1 3 beta-hydroxysteroid dehydrogenase/isomerase. The Journal of biological chemistry 278: 35483-35490. Todaro M, Alea MP, Di Stefano AB, Cammareri P, Vermeulen L, Iovino F, Tripodo C, Russo A, Gulotta G, Medema JP et al. 2007. Colon Cancer Stem Cells Dictate Tumor Growth and Resist Cell Death by Production of Interleukin-4. Cell Stem Cell 1: 389-402. Todaro M, Lombardo Y, Francipane MG, Alea MP, Cammareri P, Iovino F, Di Stefano AB, Di Bernardo C, Agrusa A, Condorelli G et al. 2008. Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4. Cell death and differentiation 15: 762-772. Todaro M, Zerilli M, Ricci-Vitiani L, Bini M, Perez Alea M, Maria Florena A, Miceli L, Condorelli G, Bonventre S, Di Gesu G et al. 2006. Autocrine production of interleukin-4 and interleukin-10 is required for survival and growth of thyroid cancer cells. Cancer Res 66: 1491-1499. Tu Y, Perdue MH. 2006. CD23-mediated transport of IgE/immune complexes across human intestinal epithelium: role of p38 MAPK. American journal of physiology Gastrointestinal and liver physiology 291: G532-538. Ul-Haq Z, Naz S, Mesaik MA. 2016. Interleukin-4 receptor signaling and its binding mechanism: A therapeutic insight from inhibitors tool box. Cytokine & Growth Factor Reviews 32: 3-15. Wang S, Liu Z, Wang L, Zhang X. 2009. NF-kappaB signaling pathway, inflammation and colorectal cancer. Cellular & molecular immunology 6: 327-334. Waskiewicz AJ, Flynn A, Proud CG, Cooper JA. 1997. Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. The EMBO journal 16: 1909-1920. Wills-Karp M, Finkelman FD. 2008. Untangling the complex web of IL-4- and IL-13-mediated signaling pathways. Science signaling 1: pe55. Yu M, Qi X, Moreno JL, Farber DL, Keegan AD. 2011. NF-kappaB signaling participates in both RANKL- and IL-4-induced macrophage fusion: receptor cross-talk leads to alterations in NF-kappaB pathways. Journal of immunology (Baltimore, Md : 1950) 187: 1797-1806. Zhang Q, Lenardo MJ, Baltimore D. 2017. 30 Years of NF-kappaB: A Blossoming of Relevance to Human Pathobiology. Cell 168: 37-57. Zhao HF, Wang J, Tony To SS. 2015. The phosphatidylinositol 3-kinase/Akt and c-Jun N-terminal kinase signaling in cancer: Alliance or contradiction? (Review). International journal of oncology 47: 429-436. 洪珮瑜. 2017. Interleukin-4誘導HT-29人類大腸癌細胞HSD3B1基因表現. in Graduate Institute of Physiology, National Taiwan University. | - |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78970 | - |
dc.description.abstract | 類固醇荷爾蒙主要由腎上腺、性腺或胎盤所分泌。近年發現,腸道也會表現類固醇生成基因,並局部性地合成糖類皮質素,調節腸道免疫恆定。類固醇荷爾蒙的生成需仰賴3beta-hydroxysteroid dehydrogenase/△5-△4 isomerase (3beta-HSD) 的作用,其為HSD3B基因的產物。人類有HSD3B1與HSD3B2兩種基因,前者主要於胎盤、周邊組織與腫瘤細胞中表現,後者則在腎上腺與性腺中表現。過去研究顯示,周邊組織中的HSD3B1在interlukin-4 (IL-4) 的刺激下會增加表現,而我們先前於人類大腸癌細胞HT-29發現,IL-4能誘導HSD3B1大量表現且此現象受PI3K/Akt/GSK3訊息傳遞路徑所調控。本論文則更深入探討其他可能參與調控的因子。結果顯示,STAT6抑制劑AS1517499能大量抑制IL-4誘導的HSD3B1表現,且IL-4會促進STAT6磷酸化,也能提升STAT6與HSD3B1啟動子結合的能力,說明IL-4會活化STAT6路徑來增加HSD3B1在HT-29細胞中表現。另外,我們亦發現,ERK抑制劑PD98059和p38 MAPK抑制劑SB202190能降低50 ~ 70% IL-4誘導的HSD3B1表現量,可是IL-4似乎不會影響細胞內ERK與p38 MAPK磷酸化的程度。此外,NF-κB抑制劑Bay117082約減少50% 的HSD3B1表現,且我們發現IL-4能增加NF-κB p65 Ser536的磷酸化,並促進NF-κB與HSD3B1啟動子的結合,說明IL-4會活化NF-κB來增加HSD3B1的表現。接著,IKK抑制劑 BMS345541與TPCA-1以及其激酶TAK-1抑制劑5Z-7-oxozeaenol皆能降低約90% 的HSD3B1蛋白質量,但IKK knockdown並不影響IL-4誘導的HSD3B1表現,說明IKK可能並非調控NF-κB活化的因子。BMS345541、TPCA-1以及5Z-7-oxozeaenol的作用機制尚需更多的研究。綜合所有結果,本論文發現IL-4能透過多條訊息傳遞路徑調控HSD3B1於HT-29細胞表現,包括:STAT6、NF-κB、ERK與p38 MAPK。 | zh_TW |
dc.description.abstract | In humans, most of steroid hormones are produced by adrenal glands, gonads and placenta. Recently, intestine has also been found to express steroidogenic genes and has the ability to locally synthesize glucocorticoid (GC) for maintenance of intestinal immune homeostasis. The 3beta-hydroxysteroid dehydrogenase (3beta-HSD), which is encoded by HSD3B gene, is essential for the biosynthesis of steroid hormones. There are two HSD3B genes in human. HSD3B1 is predominantly expressed in the placenta, peripheral tissues and tumor cells, while HSD3B2 is expressed in the adrenals and gonads. Previous studies indicated that interleukin-4 (IL-4) induces the expression of HSD3B1 in several peripheral tissues and tumor cells. Our recent data demonstrated that IL-4 dramatically increased the protein and mRNA levels of HSD3B1 in HT-29 human colon cancer cells. In addition, PI3K/Akt/GSK3 signaling pathway is critical for IL-4-stimulated HSD3B1 expression. In this study, we further investigate whether additional signaling factors induced by IL-4 that mediate the HSD3B1 expression. Our data revealed that IL-4-induced HSD3B1 expression was markedly decreased by STAT6 inhibitor AS1517499. The results showed that IL-4 induced the phosphorylation of STAT6 and enhanced the binding of STAT6 to the proximal region of HSD3B1 promoter, suggesting that IL-4 increased HSD3B1 expression via STAT6 activation. Additionally, we found that MEK inhibitor PD98059 and p38 MAPK inhibitor SB202190 suppressed IL-4 induced HSD3B1 by 50~70%. However, IL-4 treatment had no effect on the phosphorylation level of ERK and p38 in HT-29 cells. Moreover, NF-κB inhibitor Bay117082 attenuated HSD3B1 protein by 50%. We found that IL-4 increased the level of NF-κB p65 Ser536 phosphorylation and enhanced the binding of NF-κB to the HSD3B1 promoter, demonstrating that NF-κB is involved in IL-4-induced HSD3B1 expression. Furthermore, treatment with IKK inhibitors (BMS345541 and TPCA-1) and TAK-1 (kinase for IKK) inhibitor 5Z-7-oxozeaenol resulted in ~90% decrease in IL-4-induced HSD3B1 protein in HT-29 cells. However, knockdown of IKK alpha and IKK beta had no effect on IL-4-mediated HSD3B1 expression, implying that IKKs may not be the upstream regulator of NF-κB. As for the inhibition mechanism of BMS345541, TPCA-1 and 5Z-7-oxozeaenol, more research is need. In summary, our finding demonstrated that IL-4 induces HSD3B1 expression in HT-29 cells via multiple signaling pathways, including STAT6, NF-κB, ERK and p38 MAPK. | en |
dc.description.provenance | Made available in DSpace on 2021-07-11T15:33:10Z (GMT). No. of bitstreams: 1 ntu-107-R05441005-1.pdf: 4389943 bytes, checksum: ce13d11b42b6ab356c995221e0aa2da8 (MD5) Previous issue date: 2018 | en |
dc.description.tableofcontents | 致謝 I
目錄 II 表次 IV 圖次 V 摘要 VI Abstract VII 第一章 序論 1 一、 類固醇荷爾蒙 1 二、 腸道類固醇荷爾蒙的生成與作用 2 三、 HSD3B簡介 3 1. 人類HSD3B基因 3 2. HSD3B基因的調控 3 四、 IL-4簡介 5 1. IL-4的生理功能 5 2. IL-4的受體 6 3. IL-4的訊息傳遞路徑 6 五、 MAPK訊息傳遞路徑 8 1. ERK訊息傳遞路徑 8 2. p38 MAPK訊息傳遞路徑 9 3. JNK訊息傳遞路徑 9 六、 NF-κB訊息傳遞路徑 10 七、 研究目的 11 第二章 材料與方法 12 一、 藥品 12 二、 細胞培養 12 三、 蛋白質萃取 13 四、 西方墨點法 (Western blot) 15 五、 凝膠電泳遷移 (Electrophoretic mobility shift assay,EMSA) 17 六、 RNA萃取 20 七、 即時性反轉錄聚合酶連鎖反應 (Real-time RT-PCR) 21 八、 shRNA knockdown 22 九、 統計分析 (Statistical analysis) 23 第三章 結果 24 一、 STAT6訊息傳遞路徑參與在IL-4誘導HSD3B1的表現中 24 二、 MAPK訊息傳遞路徑對於IL-4誘導HSD3B1表現之影響 25 三、 NF-κB訊息傳遞路徑牽涉在IL-4誘導HSD3B1的表現中 25 四、 IKK抑制劑 (BMS345541) 會降低IL-4誘導的HSD3B1表現 26 五、 NF-κB、PI3K與IKK抑制劑對於IL-4活化STAT6的影響 27 第四章 討論 28 一、 STAT6訊息傳遞路徑之作用 28 二、 MAPK訊息傳遞路徑之作用 28 三、 NF-κB訊息傳遞路徑之作用 29 四、 IKK訊息傳遞路徑之作用 30 五、 STAT6與NF-κB訊息傳遞路徑之間的關係 30 參考文獻 32 表次 表一、藥品 12 表二、初級抗體 16 表三、次級抗體 17 表四、冷光反應試劑 17 表五、使用之寡核苷酸探針序列 17 表六、Real-time PCR使用之配對引子 21 表七、使用之shRNA 23 圖次 圖一、STAT6抑制劑會降低IL-4誘導HSD3B1在HT-29細胞中的表現 41 圖二、IL-4促進STAT6與HSD3B1啟動子的結合 42 圖三、MEK抑制劑會降低IL-4誘導HSD3B1在HT-29細胞中的表現 43 圖四、p38 MAPK抑制劑會降低IL-4誘導HSD3B1在HT-29細胞中的表現 44 圖五、JNK抑制劑對於IL-4誘導HSD3B1在HT-29細胞中表現的影響 45 圖六、NF-κB抑制劑會降低IL-4誘導HSD3B1在HT-29細胞中的表現 46 圖七、IL-4會促進HT-29細胞中NF-B的活性 47 圖八、IL-4促進NF-B與HSD3B1啟動子的結合 48 圖九、IL-4對於非典型NF-κB路徑中p52活化的影響 49 圖十、IKK與TAK-1抑制劑會降低IL-4誘導HSD3B1在HT-29細胞中表現 50 圖十一、IKK knockdown對於IL-4誘導HSD3B1在HT-29細胞中表現的影響 51 圖十二、NF-κB、PI3K與IKK抑制劑對於IL-4活化STAT6的影響 52 | - |
dc.language.iso | zh_TW | - |
dc.title | Interleukin-4經多條訊息傳遞路徑誘導HSD3B1表現於HT-29人類大腸癌細胞 | zh_TW |
dc.title | HSD3B1 is up-regulated by interleukin-4 in HT-29 human colon cancer cells via multiple signaling pathways | en |
dc.type | Thesis | - |
dc.date.schoolyear | 106-2 | - |
dc.description.degree | 碩士 | - |
dc.contributor.oralexamcommittee | 盧主欽;余佳慧;王致恬 | zh_TW |
dc.contributor.oralexamcommittee | Juu-Chin Lu;Linda Chia-Hui Yu;Chih-Tien Wang | en |
dc.subject.keyword | 介白素-4,HSD3B1,大腸癌,訊息傳遞路徑, | zh_TW |
dc.subject.keyword | Interleukin-4,HSD3B1,colon cancer,signaling pathway, | en |
dc.relation.page | 52 | - |
dc.identifier.doi | 10.6342/NTU201803273 | - |
dc.rights.note | 未授權 | - |
dc.date.accepted | 2018-08-16 | - |
dc.contributor.author-college | 醫學院 | - |
dc.contributor.author-dept | 生理學研究所 | - |
dc.date.embargo-lift | 2028-08-16 | - |
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-106-2.pdf 目前未授權公開取用 | 4.29 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。