Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/20207
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dc.contributor許美鈴zh_TW
dc.contributor.author吳昇懋zh_TW
dc.contributor.authorWu, Sheng-Maoen_US
dc.contributor.other生物醫學研究所zh_TW
dc.date2012en_US
dc.date.accessioned2014-06-06T07:12:09Z-
dc.date.available2014-06-06T07:12:09Z-
dc.identifierU0005-0207201212223700en_US
dc.identifier.citationAbdel-Latif, M.M.M., Windle, H.J., Homasany, B.S.E., Sabra, K., and Kelleher, D. (2009). Caffeic acid phenethyl ester modulates Helicobacter pylori-induced nuclear factor-kappa B and activator protein-1 expression in gastric epithelial cells. British Journal of Pharmacology 146, 1139-1147. Brzezinski, A. (1997). Melatonin in Humans. The New England Journal of Medicine 336, 186-195. Chang, Y.J. (2004). Induction of Cyclooxygenase-2 Overexpression in Human Gastric Epithelial Cells by Helicobacter pylori Involves TLR2/TLR9 and c-Src-Dependent Nuclear Factor- B Activation. Molecular Pharmacology 66, 1465-1477. Chen, H., Libertini, S.J., Wang, Y., Kung, H.J., Ghosh, P., and Mudryj, M. (2009). ERK Regulates Calpain 2-induced Androgen Receptor Proteolysis in CWR22 Relapsed Prostate Tumor Cell Lines. Journal of Biological Chemistry 285, 2368-2374. Chen, J. (2005). C/EBP and Its Binding Element Are Required for NF B-induced COX2 Expression Following Hypertonic Stress. Journal of Biological Chemistry 280, 16354-16359. Chen, J.J. (2005). Transcriptional Regulation of Cyclooxygenase-2 in Response to Proteasome Inhibitors Involves Reactive Oxygen Species-mediated Signaling Pathway and Recruitment of CCAAT/Enhancer-binding Protein and CREB-binding Protein. Molecular Biology of the Cell 16, 5579-5591. Chun-Ying (2005). Helicobacter pylori promote gastric cancer cells invasion through a NF-κB and COX-2-mediated pathway. World Journal of Gastroenterology 11, 3197-3203. Daniela (2008). Immunohistochemical expression of the cyclooxygenase-2 (COX-2) in gastric cancer. The correlations with the tumor angiogenesis and patients'' survival. Romanian Journal of Morphology and Embryology 49, 371–379. Deng, W.-G. (2006). Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p52 acetylation and binding. Blood 108, 518-524. Eibl, G. (2008). The Role of PPAR-γ and Its Interaction with COX-2 in Pancreatic Cancer. PPAR Research 2008, 1-6. Goll, D.E. (2003). The Calpain System. Physiological Reviews 83, 731–801. Hahm, K.B. (2003). Chemoprevention of Helicobacter pylori-associated Gastric Carcinogenesis in a Mouse Model; Is It Possible? Journal of Biochemistry and Molecular Biology 36, 82-94. Hsu, K.W., Hsieh, R.H., Wu, C.W., Chi, C.W., Lee, Y.H.W., Kuo, M.L., Wu, K.J., and Yeh, T.S. (2009). MBP-1 Suppresses Growth and Metastasis of Gastric Cancer Cells through COX-2. Molecular Biology of the Cell 20, 5127-5137. Jang, S.H. (2009). β-carotene Inhibits Helicobacter Pylori-induced Expression of Inducible Nitric Oxide Synthase and Cyclooxygenas-2 in Human Gastric Epithelial AGS Cells. Journal of Physiology and Pharmacology 60, 131-137. Jung, B., and Ahmad, N. (2006). Melatonin in Cancer Management: Progress and Promise. Cancer Research 66, 9789-9793. Jung-Hynes, B., Schmit, T.L., Reagan-Shaw, S.R., Siddiqui, I.A., Mukhtar, H., and Ahmad, N. (2010). Melatonin, a novel Sirt1 inhibitor, imparts antiproliferative effects against prostate cancer in vitro in culture and in vivo in TRAMP model. Journal of Pineal Research 50, 140-149. Karnezis, T., Shayan, R., Caesar, C., Roufail, S., Harris, Nicole C., Ardipradja, K., Zhang, You F., Williams, Steven P., Farnsworth, Rae H., Chai, Ming G. (2012). VEGF-D Promotes Tumor Metastasis by Regulating Prostaglandins Produced by the Collecting Lymphatic Endothelium. Cancer Cell 21, 181-195. Kim, H.J., Chung, H., Yoo, Y.G., Kim, H., Lee, J.Y., Lee, M.O., and Kong, G. (2007). Inhibitor of DNA Binding 1 Activates Vascular Endothelial Growth Factor through Enhancing the Stability and Activity of Hypoxia-Inducible Factor-1 Molecular Cancer Research 5, 321-329. Kim, S.J., Choi, I.J., Cheong, T.C., Lee, S.J., Lotan, R., Park, S.H., and Chun, K.H. (2010). Galectin-3 Increases Gastric Cancer Cell Motility by Up-regulating Fascin-1 Expression. Gastroenterology 138, 1035-1045.e1032. Konturek (2008). Tryptophan Free Diet Delays Healing of Chronic Gastric Ulcers in Rat. Journal of Physiology and Pharmacology 59, 53-65. Lekstrom-Himes, J. (1998). Biological Role of the CCAAT/Enhancer-binding Protein Family of Transcription Factors. THE JOURNAL OF BIOLOGICAL CHEMISTRY 273, 28545-28548. Lim, J.W. (2002). Expression of Ku70 and Ku80 Mediated by NF-kappa B and Cyclooxygenase-2 Is Related to Proliferation of Human Gastric Cancer Cells. Journal of Biological Chemistry 277, 46093-46100. Lin, A.M.Y. (2009). Melatonin inhibits arsenite-induced peripheral neurotoxicity. Journal of Pineal Research 46, 64-70. Lin, M.T. (2005). Cyr61 Induces Gastric Cancer Cell Motility/Invasion via Activation of the Integrin/Nuclear Factor- B/Cyclooxygenase-2 Signaling Pathway. Clinical Cancer Research 11, 5809-5820. Ma, X.-M. (2009). Peroxisome proliferator-activated receptor-gamma is essential in the pathogenesis of gastric carcinoma. World Journal of Gastroenterology 15, 3874-3883. Mao, L., Yuan, L., Slakey, L.M., Jones, F.E., Burow, M.E., and Hill, S.M. (2010). Inhibition of breast cancer cell invasion by melatonin is mediated through regulation of the p38 mitogen-activated protein kinase signaling pathway. Breast Cancer Research 12, R107. Matsumoto, S. (1997). Induction of ulceration and severe gastritis in Mongolian gerbil by Helicobacter pylori infection. J Med Microbiol 46, 391-397. Merrell, D.S., Whitmire, J.M., and Jones, K.R. (2010). A Tale of Two Toxins: Helicobacter Pylori CagA and VacA Modulate Host Pathways that Impact Disease. Frontiers in Microbiology 1, 115. Mifflin, R.C. (2001). Regulation of COX-2 expression in human intestinal myofibroblasts: mechanisms of IL-1-mediated induction. American Journal Of Physiology-Cell Physiology 282, C824-C834. Mustafa, A., and Kruger, W.D. (2008). Suppression of Tumor Formation by a Cyclooxygenase-2 Inhibitor and a Peroxisome Proliferator-Activated Receptor Agonist in an In vivo Mouse Model of Spontaneous Breast Cancer. Clinical Cancer Research 14, 4935-4942. Nagy, T.A., Wroblewski, L.E., Wang, D., Piazuelo, M.B., Delgado, A., Romero–Gallo, J., Noto, J., Israel, D.A., Ogden, S.R., Correa, P. (2011). β-Catenin and p120 Mediate PPARδ-Dependent Proliferation Induced by Helicobacter pylori in Human and Rodent Epithelia. Gastroenterology 141, 553-564. Negi, G. (2011). Melatonin modulates neuroinflammation and oxidative stress in experimental diabetic neuropathy: effects on NF-κB and Nrf2 cascades. Journal of Pineal Research 50, 124-131. Pai, V.P., Marshall, A.M., Hernandez, L.L., Buckley, A.R., and Horseman, N.D. (2009). Altered serotonin physiology in human breast cancers favors paradoxical growth and cell survival. Breast Cancer Research 11, R81. Panzer (1997). The validity of melatonin as an oncostatic agent. Journal of Pineal Research 22, 184-202. Park, S.H., Choi, H.J., Yang, H., Do, K.H., Kim, J., Lee, D.W., and Moon, Y. (2010). Endoplasmic Reticulum Stress-activated C/EBP Homologous Protein Enhances Nuclear Factor- B Signals via Repression of Peroxisome Proliferator-activated Receptor. The Journal of Biological Chemistry 285, 35330-35339. Peterson, A.J., Menheniott, T.R., O''Connor, L., Walduck, A.K., Fox, J.G., Kawakami, K., Minamoto, T., Ong, E.K., Wang, T.C., Judd, L.M. (2010). Helicobacter pylori Infection Promotes Methylation and Silencing of Trefoil Factor 2, Leading to Gastric Tumor Development in Mice and Humans. Gastroenterology 139, 2005-2017. Polk, D.B., and Peek, R.M. (2010). Helicobacter pylori: gastric cancer and beyond. Nature Reviews Cancer 10, 403-414. RAMJI, D.P. (2002). CCAAT/enhancer-binding proteins : structure, function and regulation. Biochem J 365, 561-575. Ravindra, T. (2005). Melatonin in pathogenesis and therapy of cancer. Indian J Med Sci 60, 523-535. Regalo, G., Resende, C., Wen, X., Gomes, B., Durães, C., Seruca, R., Carneiro, F., and Machado, J.C. (2010). C/EBPα expression is associated with homeostasis of the gastric epithelium and with gastric carcinogenesis. Laboratory Investigation 90, 1132-1139. Sato, H. (2000). Expression of peroxisome proliferator-activated receptor (PPAR)g in gastric cancer and inhibitory effects of PPARg agonists. British Journal of Cancer 83, 1394-1400. Sethi, S. (2008). C-terminal domains within human MT1 and MT2 melatonin receptors are involved in internalization processes. Journal of Pineal Research 45, 212-218. Siddiqui, E.J., Shabbir, M.A., Mikhailidis, D.P., Mumtaz, F.H., and Thompson, C.S. (2006). The effect of serotonin and serotonin antagonists on bladder cancer cell proliferation. BJU International 97, 634-639. Storr, S.J., Carragher, N.O., Frame, M.C., Parr, T., and Martin, S.G. (2011). The calpain system and cancer. Nature Reviews Cancer 11, 364-374. Thor, P.J. (2007). Melatonin and Serotonin Effects on Gastrointestinal Motility. Journal of Physiology and Pharmacology 58, 97-105. Wang, Y., Nangia-Makker, P., Balan, V., Hogan, V., and Raz, A. (2010). Calpain activation through galectin-3 inhibition sensitizes prostate cancer cells to cisplatin treatment. Cell Death and Disease 1, e101. Watanabe, T. (1998). Helicobacter pylori Infection Induces Gastric Cancer in Mongolian Gerbils. Gastroenterology 115, 642-648. Xu, L., and Deng, X. (2006). Suppression of Cancer Cell Migration and Invasion by Protein Phosphatase 2A through Dephosphorylation of - and m-Calpains. The Journal of Biological Chemistry 281, 35567-35575. Yamamoto, K. (1995). Transcriptional Roles of Nuclear Factor kB and Nuclear Factor-Interleukin-6 in the Tumor Necrosis Factor a-Dependent Induction of Cyclooxygenase-2 in MC3T3-E1 Cells. The Journal of Biological Chemistry 270, 31315-31320. Yin, Y., Grabowska, A.M., Clarke, P.A., Whelband, E., Robinson, K., Argent, R.H., Tobias, A., Kumari, R., Atherton, J.C., and Watson, S.A. (2010). Helicobacter pylori potentiates epithelial:mesenchymal transition in gastric cancer: links to soluble HB-EGF, gastrin and matrix metalloproteinase-7. Gut 59, 1037-1045. Yuan, C.J. (2000). Transcriptional Regulation of Cyclooxygenase-2 Gene Expression: Novel Effects of Nonsteroidal Anti-Inflammatory Drugs. Cancer Research 60, 1084-1091. Zahnow, C.A. (2002). CCAAT/enhancer binding proteins in normal mammary development and breast cancer. Breast Cancer Research 4, 113-121. Zeng, L., Geng, Y., Tretiakova, M., Yu, X., Sicinski, P., and Kroll, T.G. (2008). Peroxisome Proliferator-Activated Receptor- Induces Cell Proliferation by a Cyclin E1-Dependent Mechanism and Is Up-regulated in Thyroid Tumors. Cancer Research 68, 6578-6586. Zhu, D.M. (2000). Calpain Inhibitor II Induces Caspase-dependent Apoptosis in Human Acute Lymphoblastic Leukemia and Non-Hodgkin''s Lymphoma Cells as Well as Some Solid Tumor Cells. Clinical Cancer Research 6, 2456-2463.en_US
dc.identifier.urihttp://hdl.handle.net/11455/20207-
dc.description.abstract內質網壓力所導致的細胞凋亡以及抑制腫瘤在腹膜中的擴散已知與 癌症的發展有密切的關係。褪黑激素是由大腦內的松果體所分泌的一種荷爾蒙。過去的研究指出褪黑激素具有清除自由基和抗氧化的活性,並且也可能具有抑制腫瘤的功用。然而,褪黑激素是否能抑制胃癌生長以及癌細胞在腹膜中擴散的情況,目前還是未知且尚待釐清的。本篇研究使用了各種活體內、活體外及生物體外等實驗系統,來多方驗證褪黑激素抑制腫瘤生長以及腫瘤在腹膜中擴散的效用。從活體外的實驗結果我們發現褪黑激素能有效抑制癌細胞增生、細胞群簇的形成、細胞的移動能力和金屬蛋白酶的活性等。在裸鼠腫瘤異體移植試驗中,褪黑激素明顯抑制了腫瘤生長,而使用正子電腦斷層掃描(PET/CT)也清楚驗證褪黑激素有效的減少腫瘤在腹膜中的擴散轉移。此外,使用小鼠皮下matrigel plug 技術、大鼠主動脈環實驗和人類臍靜脈內皮細胞血管新生實驗,也都發現褪黑激素能有效抑制血管新生。從電泳遷移率實驗(EMSA)和染色質免疫沉澱法(CHIP assay)的實驗結果我們更進一步證實褪黑激素能有效降低轉錄因子NFκB 和C/EBPβ的轉錄作用並減少兩個蛋白間的交互作用。另一方面,褪黑激素能夠造成內質網壓力並增加細胞中Calpain 的蛋白表現和活性,造成其他蛋白質的降解。在使用了Calpain 的抑制劑和轉染siRNA 後發現,褪黑激素所抑制的NFκB 和C/EBPβ調控的COX-2 的表現會被有效的逆轉。這些實驗結果說明了褪黑激素能有效的抑制胃癌細胞生長及在腹膜中的擴散轉移,提供其在治療胃癌上具有高度應用的潛力。zh_TW
dc.description.abstractEndoplasmic reticulum stress-regulated cell apoptosis and dampened peritoneal dissemination is implicated in the progression of cancer. Melatonin (N-acetyl-5 methoxytryptamine), a hormone produced in the brain by the pineal gland, has previously been reported to antioxidant activity and oncostatic properties in a wide variety of tumors. Whether Melatonin inhibits the tumor growth and peritoneal dissemination of gastric cancer remains enigma. We tested the effects of Melatonin on antitumor activity and peritoneal dissemination using in vivo, ex vivo and in vitro assay systems. In vitro study, we found that Melatonin inhibited proliferation, colony formation, migration and gelatin zymography were observed. In xenograft gastric tumor mouse model, Melatonin significantly inhibited tumor burden and peritoneal dissemination detected by PET/CT technique. Melatonin also effectively inhibited the angiogenesis determined by mouse matrigel plug assay, rat aortic ring endothelial cell sprouting assay, and endothelial cell tube formation assay. Furthermore, Melatonin efficiently abolished physical interaction and mutual functional between C/EBPβ and NFκB by EMSA or CHIP assay, which was simultaneously correlated with the up-regulation of the activity and protein expression of calapin, result in protein reduction. Calpain inhibitor and siRNA transfection significantly reversed the Melatonin-increased cleavage of C/EBPβ and NFκB regulated COX-2 expression and ER stress marker. These findings suggest that Melatonin is a novel and potent inhibitor for tumor growth and peritoneal dissemination of gastric cancer, which supports the application potential of Melatonin on gastric cancer therapy.en_US
dc.description.tableofcontents中文摘要.........................................................i 英文摘要........................................................ii 目次.......................................................iii 圖目次........................................................vi 第一章、 前言.........................................................1 一、 褪黑激素(Melatonin) .....................................................................1 二、 胃癌(Gastric cancer)........................................................................1 (一) 流行病學.................................................................................1 1. 遺傳因素............................................................................1 2. 性別與年齡........................................................................2 3. 飲食生活習慣....................................................................2 4. 惡性貧血............................................................................2 5. 胃部病變及胃切除手術....................................................2 6. 幽門螺旋桿菌感染............................................................2 (二) 治療方式.................................................................................2 三、 COX-2 (Cyclooxygenase-2) ...........................................................3 (一) COX 的結構與功能................................................................3 (二) COX-2與癌症.........................................................................3 四、 C/EBP-beta (CCAAT enhancer binding protein beta)....................4 (一) C/EBP family..........................................................................4 (二) C/EBPβ....................................................................................5 (三) C/EBPβ與癌症........................................................................5 五、 內質網壓力(Endoplasmic Reticulum Stress).................................6 (一) ER Stress 的分子機轉.............................................................6 (二) ER Stress 和Calpain................................................................7 六、 研究方向與動機.............................................................................7 第二章、 材料與方法.........................................................8 一、 實驗儀器.........................................................................................8 二、 實驗材料.........................................................................................8 (一) 常用緩衝溶液: 附表一..........................................................8 (二) 實驗試劑: 附表二..................................................................8 (三) 實驗藥品: 附表三..................................................................8 (四) 實驗抗體: 附表四..................................................................8 (五) PCR Primer: 附表五...............................................................8 三、 實驗方法.........................................................................................8 (一) 細胞培養(Cell culture)............................................................8 (二) 人類臍靜脈內皮細胞初代培養(Primary HUVEC culture)...9 (三) 蛋白質萃取(Protein extraction)..............................................9 (四) 西方墨點法(Western Blot)......................................................9 (五) 核酸萃取(RNA extraction)...................................................10 (六) 反轉錄聚合酶連鎖效應(Reverse Transcription-PCR)........10 (七) 聚合酶連鎖效應(Polymerase Chain Reaction)....................10 (八) 免疫螢光染色(Immunofluorescence stain)...........................11 (九) 免疫組織染色(Immunohistochemistry stain).......................11 (十) 瓊膠生長實驗(Colony Formation Assay).............................11 (十一) 流氏細胞儀分析(Flowcytometry)...................................12 (十二) 人類臍靜脈內皮細胞血管新生實驗(HUVEC Tube Formation).....................................................................12 (十三) 大鼠主動脈環試驗(Rat Aorta Ring Assay)....................12 (十四) 酶譜分析(Gelatin Zymography)......................................12 (十五) 酵素活性分析(Enzyme Activity)....................................13 (十六) 細胞增生試驗(MTT Assay)............................................13 (十七) 細胞核質蛋白分離萃取(Nuclear/ Cytosol protein extraction)....................................................................13 (十八) 免疫沉澱法(Immunoprecipitation)..................................13 (十九) 核酸干擾技術(RNA interference)...................................14 (二十) 傷口癒合試驗(Wound Healing Assay)...........................14 (二十一) 動物實驗(Animal experiment)..................................14 (二十二) 動物組脂蛋白萃取....................................................15 (二十三) 電泳移動率試驗(Electrophoretic Mobility Shift Assay, EMSA).........................................................15 (二十四) 染色質免疫沉澱法(Chromatin Immunoprecipitation, CHIP Assay)........................................................15 第三章、 實驗結果.........................................17 一、 致癌物質MNNG 顯著增加小鼠胃部組織中COX-2 和C/EBPβ 的蛋白表現量..............................................17 二、 Melatonin 在轉錄層次上透過NFκB 及C/EBPβ有效抑制胃癌細 胞中COX-2 的轉錄表現..............................................................17 三、 Melatonin 有效抑制NFκB-p65 和C/EBPβ在胃癌細胞中的內生 性交互作用...................................................................................18 四、 Melatonin 降低COX-2 和C/EBPβ蛋白在胃癌細胞中的表現....18 五、 Melatonin 誘導胃癌細胞內質網壓力的形成...............................18 六、 Melatonin 活化不論是in vitro 或in vivo 中胃癌細胞內Calpain的蛋白表現及活性...................................19 七、 Calpain 抑制劑可以有效恢復胃癌細胞中由Melatonin 所減少之COX-2 和C/EBPβ的表現...................................20 八、 以PET/CT 影像觀察Melatonin 抑制胃癌細胞在裸鼠體內生長和 擴散之情形...................................................................................20 九、 Melatonin 有效抑制胃癌細胞在裸鼠皮下及體外試驗之生長...21 十、 Melatonin 抑制胃癌細胞增生並促進細胞走向死亡...................21 十一、 Melatonin 降低胃癌細胞中基質金屬蛋白酶(MMP)的活性.22 十二、 Melatonin 有效抑制胃癌細胞的移動性和血管新生作用.....22 十三、 總結........................................................23 第四章、 討論....................................................... 24 第五章、 參考文獻........................................................28 結果圖表........................................................33 附錄表........................................................58 附錄圖........................................................65zh_TW
dc.language.isozh_TWen_US
dc.publisher生物醫學研究所zh_TW
dc.relation.urihttp://www.airitilibrary.com/Publication/alDetailedMesh1?DocID=U0005-0207201212223700en_US
dc.subject胃癌zh_TW
dc.subjectgastric canceren_US
dc.subject褪黑激素zh_TW
dc.subjectCalpainzh_TW
dc.subjectNFκBzh_TW
dc.subjectC/EBPβzh_TW
dc.subject腹膜轉移zh_TW
dc.subjectMelatoninen_US
dc.subjectcalpainen_US
dc.subjectC/EBPβen_US
dc.subjectNFκBen_US
dc.subjectperitoneal disseminationen_US
dc.title褪黑激素抑制胃癌生長及腹膜轉移機轉之探討zh_TW
dc.titleThe Mechanism of Melatonin Inhibits Tumor Growth and Peritoneal Dissemination in Gastric Cancer Cellsen_US
dc.typeThesis and Dissertationzh_TW
item.languageiso639-1zh_TW-
item.openairetypeThesis and Dissertation-
item.cerifentitytypePublications-
item.grantfulltextnone-
item.fulltextno fulltext-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
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