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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 莊立民(Lee-Ming Chuang) | |
dc.contributor.author | Emily Yun-Chia Chang | en |
dc.contributor.author | 張芸嘉 | zh_TW |
dc.date.accessioned | 2021-06-16T23:25:32Z | - |
dc.date.available | 2012-09-18 | |
dc.date.copyright | 2012-09-18 | |
dc.date.issued | 2012 | |
dc.date.submitted | 2012-07-31 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/65110 | - |
dc.description.abstract | 前列腺素還原酶PTGR2是一種可將15-keto-PGE2代謝成為13,14-dihydro-15- keto-PGE2的酵素。在我們之前已發表的研究中發現15-keto-PGE2是PTGR2的受質,且也是PPARγ的天然配體,而PPARγ本身可受配體調控進而影響脂肪的代謝與細胞分化。目前除已知PTGR2可抑制PPARγ活性與脂肪細胞分化外,對PTGR2的生化功能了解極為有限。目前許多研究證實前列腺素與其相關合成酵素與胃癌腫瘤的發育和轉移有關。而前列腺素與其代謝產物皆是PPARγ的配體且經由其交互作用可在腫瘤形成與轉移扮演一定角色。因此是否PTGR2也與癌症有關是一個待研究的有趣課題。
本論文中我們針對PTGR2在胃癌中的功能特性與機制做探討。透過慢病毒感染方式,我們建立了PTGR2剃除與PTGR2過度表現之胃癌細胞株AGS與SNU-16。 體外分析發現PTGR2剃除之胃癌細胞株其貼附性與非貼附性細胞生長以及貼附性細胞在半固狀的凝膠中懸浮生長能力皆受到抑制,而體內腫瘤異種移植老鼠研究中也顯示腫瘤生長較慢。 在機制方面,PTGR2剃除之胃癌細胞株可改變線粒體的功能,並產生了較高的活性氧自由基(ROS),因而導致ERK1/2和caspase3的活化與增加Bcl-2和抑制Bax的表現量,因而誘導細胞死亡,和PTGR2過度表現之胃癌細胞株呈現相反的對比。用PTGR2抑制劑以及冷凍乾燥後微脂粒重組的PTGR2代謝產物13,14-dihydro-15-keto-PGE2,我們發現PTGR2的致癌潛能是依賴它酵素本身的催化活性。為了尋找PTGR2其他的致癌途徑及受它調控的分子, 微陣列分析中也顯示PTGR2在對於腫瘤細胞遷移的功能也有潛在作用。最後,臨床免疫病理染色也發現PTGR2在胃癌檢體腫瘤區中相較鄰近非腫瘤區域有顯著性表現,且其和腸道型胃癌患者存活率亦有相關性。此外,剃除PTGR2之胃癌細胞株對於胃癌化學療法常用藥物cisplatin和5-fluorouracil更為敏感。基於以上的結果,我們的研究不僅提供PTGR2在胃癌中扮演的功能和機制的證據,臨床觀察也肯定PTGR2對胃癌病變有重要角色,所以設立PTGR2為未來治療目標是值得進一步評估。 | zh_TW |
dc.description.abstract | Prostaglandin reductase 2 (PTGR2) is an enzyme that catalyses the NADPH- dependent reduction of 15-keto-PGE2 into the downstream metabolite 13,14-dihydro- 15-keto-PGE2. Previously, 15-keto-PGE2 was demonstrated to act as a natural ligand for peroxisome proliferator-activated receptor γ (PPARγ), which plays a distinct role in mediating differentiation of adipocytes and regulating lipid metabolism. The suppressive effect of PTGR2 on PPARγ activity and adipocyte differentiation were characterized. However, there is still very little knowledge on the biological role of PTGR2. It is well established that different prostanoids & their synthases play an important role in gastric cancer. Many of these prostaglandin metabolites also serve as natural ligands for PPARγ. Thus, whether PTGR2 plays a distinct role in cancer biology is of interest.
In this thesis, functional and mechanistic analyses on the impact of PTGR2 in gastric cancer are presented. Downregulation or overexpression of PTGR2 was performed by lentiviral technology in AGS and SNU-16 gastric cancer cell lines. In contrast to overexpressing PTGR2, in vitro analysis showed that PTGR2 knockdown resulted in decreased proliferation rate and colony formation, and in vivo xenograft models showed slower growth of tumors. Mechanistically, PTGR2 knockdown induced cell death, altered mitochondrial function, and produced higher reactive oxygen species (ROS), which lead to the activation of ERK1/2 and caspase 3, with increased Bcl-2 and suppressed Bax expressions. Furthermore, treatment of AGS cells with synthetic PTGR2 inhibitors as well as lyophilized lipids reconstituted with 13,14-dihydro-15- keto-PGE2 showed the dependency of PTGR2 on its catalytic activity in its oncogenic potency. To investigate additional oncogenic pathways and molecules in which PTGR2 act on, microarray was also performed and identified potential role of PTGR2 in cancer cell migration. Lastly, clinical immunopathological staining showed strong PTGR2 expression in the gastric tumor portion relative to nearby non-tumor areas, and its expression negatively correlated with the survival of patients with intestinal type gastric cancer. Furthermore, PTGR2-knockdown cells were more sensitive to cisplatin and 5-fluorouracil. Taken together, our findings not only provide functional and mechanistic evidence of the involvement of PTGR2 in gastric cancer, but also clinical observations affirm the significance of PTGR2 in gastric cancer and suggest PTGR2-target based therapy is worth further evaluation. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T23:25:32Z (GMT). No. of bitstreams: 1 ntu-101-F95448014-1.pdf: 3356964 bytes, checksum: 9f1e3d9f137459410566a9a9e0cb4c62 (MD5) Previous issue date: 2012 | en |
dc.description.tableofcontents | Acknowledgements I
中文摘要 III Abstract V Table of contents VII Introduction: Background Overview & Experimental Rational 1 1.1 Gastric cancer 1 1.2 Prostaglandins and Gastric Cancer 2 1.3 Peroxisome Proliferator-Activated Receptor γ (PPARγ) and Gastric Cancer 2 1.4 Prostaglandin Reductase 2 (PTGR2) 3 1.5 Cancer Cell Biology: Hallmarks of Cancer Cells 4 1.6 Apoptosis and Necrosis 5 1.7 Mitochondria, Bcl-2 Family Proteins, and Cell Death Signaling 6 1.8 Mitochondria, ROS, and Cell Death Signaling 6 1.9 Cancer Cells: Energy Utilization and Warburg Effect 7 1.10 Cell Migration and the uPAR Signaling 8 1.11 Plasminogen activator inhibitor type 2 9 1.12 Vitronectin 10 1.13 Experimental Rational 11 Materials and Methods 13 2.1 Cell Culture 13 2.2 Lentiviral Transduction 13 2.3 Immunoblotting 14 2.4 Cell Proliferation Assay 15 2.5 Soft Agar Colony Formation Assay 16 2.6 Xenograft Tumor Models 16 2.7 Flow Cytometric Cell Cycle and Cell Death Analysis 17 2.8 Assessment of Oxygen Consumption Rates (OCR) and Extracellular Acidification Rates (ECAR) 18 2.9 Measurement of ROS Production 19 2.10 RNA Extraction and Quantitative Reverse Transcription-PCR (qRT-PCR) 19 2.11 Cell Viability 20 2.12 Quantification of 13,14-dihydro-15-keto-PGE2 Production 21 2.13 Reconstitution of Lyophilized Lipids with 13,14-dihydro-15-keto-PGE2 21 2.14 Effect of 13,14-dihydro-15-keto-PGE2 on Cell Growth 22 2.15 Gene Expression Microarray and Ingenuity Pathways Analysis 23 2.16 Transwell migration assay 23 2.17 Human Tissue Immunopathological Studies and Clinical Outcomes 24 2.18 Chemosensitivity Assay 25 2.19 Statistical Analysis 26 Results 27 3.1 PTGR2 levels affect the oncogenic potency of gastric cancer cells in vitro and in vivo 27 3.2 PTGR2 affects gastric cancer cell growth by altering the susceptibility towards cell death 29 3.3 The effect of PTGR2 on cell death is through modulating mitochondrial function and ROS production 30 3.4 PTGR2 modulates mitochondrial apoptotic signaling through both the ERK1/2-caspase 3 pathway and the Bcl-2-family proteins 32 3.5 The catalytic activity of PTGR2 may be involved in its oncogenic potency 33 3.6 Biological activities of 13,14-dihydro-15-keto-PGE2 support the importance of PTGR2 catalytic activity in its oncogenic potency 34 3.7 15-keto-PGE2 affects cell viability via PPARγ-dependent pathway 35 3.8 Gene expressing profiling further supports the functional importance of PTGR2 in cancer cell metabolism and cell death, and revealed additional potential in regulating cellular movement 36 3.9 Clinical significance and immunopathological analysis of PTGR2 expression in human gastric cancer tissues 38 3.10 Involvement of PTGR2 in chemotherapeutic response 39 Discussion 41 Tables 60 Figures 72 References 101 Appendix 118 | |
dc.language.iso | en | |
dc.title | 第二型前列腺素還原酶在胃癌中的角色:功能與機制之探討 | zh_TW |
dc.title | Role of prostaglandin reductase 2 in gastric cancer: functional and mechanistic studies | en |
dc.type | Thesis | |
dc.date.schoolyear | 100-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 呂勝春(Sheng-Chung Lee),王惠鈞(Andrew H-J Wang),吳明賢(Ming-Shiang Wu),張明富(Ming-Fu Chang) | |
dc.subject.keyword | 前列腺素還原酶,PTGR2,前列腺素新陳代謝,胃癌,線粒體,細胞計畫性的死亡, | zh_TW |
dc.subject.keyword | PTGR2,prostaglandin metabolism,gastric cancer,mitochondria,apoptosis, | en |
dc.relation.page | 118 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2012-08-01 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
顯示於系所單位: | 分子醫學研究所 |
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