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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/9781完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 李明學(Ming-Shyue Lee) | |
| dc.contributor.author | Ying-Chieh Lu | en |
| dc.contributor.author | 盧盈潔 | zh_TW |
| dc.date.accessioned | 2021-05-20T20:40:58Z | - |
| dc.date.available | 2011-10-05 | |
| dc.date.available | 2021-05-20T20:40:58Z | - |
| dc.date.copyright | 2011-10-05 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-08-09 | |
| dc.identifier.citation | 1. Kumar-Sinha, C., Tomlins, S.A., and Chinnaiyan, A.M. 2008. Recurrent gene fusions in prostate cancer. Nature Reviews Cancer 8:497-511.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/9781 | - |
| dc.description.abstract | 攝護腺癌的致死率在西方男性世界中排名第二位；在台灣，攝護腺癌的發生率以及死亡率亦有逐年增加的趨勢。有些研究指出發炎與攝護腺癌的產生以及惡化有關。希樂葆 (Celebrex) 是一種亞型環氧化酶 (Cyclooxygenase-2, COX-2) 抑制物，近年研究指出希樂葆具有抗發炎、抗癌以及預防癌症產生 (chemoprevention) 的功能。然而，希樂葆是如何抑制攝護腺癌細胞侵襲的分子機制尚未清楚了解。在本篇研究裡，我們建立了攝護腺癌細胞侵襲能力進化的細胞模式 (PC-3以及M2I2 PC-3細胞)，並發現幾個發炎相關蛋白，亞型環氧化酶、磷酸化JUN激酶以及第一型介白素在M2I2 PC-3細胞的表現量增加。進而檢測了希樂葆對於攝護腺癌PC-3細胞的生長、移動與侵襲的影響。實驗結果指出希樂葆可有效地抑制攝護腺癌細胞的生長、移動與侵襲能力。為了更進一步研究希樂葆抑制攝護腺癌細胞移動與侵襲的分子機制，我探討希樂葆對於間質蛋白酶 (Matriptase) 可能的影響。間質蛋白酶是第二型嵌膜絲胺酸蛋白酶，近年來研究指出異常活化的間質蛋白酶與許多癌症的演進有相關聯，包括攝護腺癌。本篇實驗結果指出，希樂葆可以降低間質蛋白酶的表現以及釋出到細胞外的量；此量的降低，主要藉由抑制間質蛋白酶基因的表達以降低其表現量。更進一步地，在兩株不具亞型環氧化酶的攝護腺癌DU-145和LNCaP細胞中，希樂葆一樣可以藉由降低間質蛋白酶活化及表現量來抑制這兩種癌細胞的移動與侵襲能力。同時發現，在所有市面上可購得的非類固醇抗炎藥物中，希樂葆是最具潛力的藥物可抑制攝護腺癌細胞的間質蛋白酶活化。同時亞型環氧化酶主要產物PGE2可刺激間質蛋白酶的活化。為了更進一步了解PGE2如何促進間質蛋白酶的活化，我使用不同的EP接受器抑制物並發現EP1接受器可能參與間質蛋白酶的活化。整體來說，本論文實驗結果指出希樂葆具有抑制間質蛋白酶功能以及壓抑攝護腺癌細胞侵襲的能力。因此希樂葆是一個未來具有潛力的藥物，可用以抗攝護腺癌或預防此癌症的產生。 | zh_TW |
| dc.description.abstract | Prostate cancer is the second leading cause of cancer-related death in men of the western world. In Taiwan, the incidence and mortality of prostate cancer (PCa) have been rising progressively in recent years. Several studies have showed that inflammation is involved in the development and progression of PCa. Celebrex, a COX-2 specific inhib¬itor, has been shown with anti-inflammatory, anti-carcinogenic, and chemopreventive effects. However, the molecular mechanism how celebrex suppresses PCa cell invasion is not well understood. In this study, we established a PC-3 cell invasion progression model (parental and M2I2 PC-3 cells) and found that several inflammation-associated proteins, COX-2, p-JNK and IL-1β were up-regulated in M2I2 PC-3 cells. The results showed that celebrex could significantly suppress PCa cell migration and invasion, at least in part, due to down regulation of a tumor-promoting serine protease matriptase at the gene expression and activation levels. Similarly, celebrex also can execute its anti-cancer properties in two COX-2-null PCa DU-145 and LNCaP cells, via a similar mechanism as shown in PC3 cells. Furthermore, PGE2, a main product of COX-2, could induce matriptase activation and its EP1 receptor was identified to be involved in matriptase activation in PCa cells. Taken together, the data indicated that celebrex exhibits a suppressive effect on PCa cell migration and invasion, at least in part, by down-regulating matriptase function. | en |
| dc.description.provenance | Made available in DSpace on 2021-05-20T20:40:58Z (GMT). No. of bitstreams: 1 ntu-100-R98442014-1.pdf: 8312287 bytes, checksum: 4402d54448c6af17b8c655648e71642c (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | 致謝 i
中文摘要 iii Abstract iv Chapter 1. Introduction 1 1.1 Prostate cancer 2 1.2 Inflammation in prostate carcinogenesis 2 1.3 Cyclooxygenase-2 and cancer progression 3 1.4 Non-steroidal anti-inflammatory drugs (NSAIDs) 4 1.5. Celebrex (Celecoxib) 5 1.6 Matriptase 7 1.7 Research motivation 14 Chapter 2. Materials and methods 16 2.1 Materials 17 2.2 Methods 21 2.3 Buffer 30 Chapter 3. Results 32 3.1 Correlation of inflammation-associated protein expression and matriptase activation in a PC-3 cell invasion progression model 33 3.2 Effect of celebrex on the cell viability of PC-3 cells 34 3.3 Inhibitory effect of celebrex on PC-3 cell growth. 35 3.4 Celebrex inhibited the motility and invasion of PC-3 cells. 35 3.5 Celebrex reduced matriptase and HAI-1 shedding and protein expression in PC-3 cells. 36 3.6 Celebrex down-regulated gene expression of matriptase and HAI-1 in PC-3 cells. 37 3.7 Celebrex decreased MMPs activity in PC-3 cells. 38 3.8 Prostaglandin E2 (PGE2) increased the motility and invasion of PC-3 cells. 38 3.9 PGE2 induced the levels of matriptase activation and HAI-1 but reduced the shedding of matriptase and HAI-1 in PC-3 cells. 39 3. 10 Effect of EP antagonists on matriptase shedding and protein expression. 40 3.11 Celebrex down-regulated matriptase expression and activation partly via COX-2-independent pathway in PC-3 cells. 40 3.12 Effect of celebrex on the cytotoxicity of non-COX-2 expressed prostate cancer cells, DU-145 and LNCaP cells. 41 3.13 Inhibitory effects of celebrex on cell motility and invasion in DU-145 cells via down-regulating matriptase. 42 3.14 Inhibitory effects of celebrex on LNCaP cell migration and invasion via suppressing the total and activated levels of matriptase. 43 3.15 Effect of celebrex and other NSAIDs on matriptase expression and activation in LNCaP cells. 44 3.16 Role of matriptase on PC-3 cell migration and invasion. 44 3.17 Inhibitory effect of celebrex on matriptase-overexpressing PC-3 cell migration, invasion and matriptase activation. 45 Chapter 4. Discussion 46 Chapter 5. Figures 52 Figure 1. Establishment of prostate cancer PC-3 cell progression model and analysis of inflammation biomarkers and matriptase expression in these cells. 54 Figure 2. Effect of celebrex on the cell viability of PC-3 cells. 55 Figure 3. Effect of celebrex on PC-3 cell growth, migration and invasion. 57 Figure 4. Effect of celebrex on matriptase and HAI-1 expression and shedding in PC-3 cells. 60 Figure 5. Analysis of the celebrex effect on MMPs activity by gelatin zymography. 62 Figure 6. Effect of PGE2 on PC-3 cell migration and invasion. 64 Figure 7. Effect of PGE2 on matriptase and HAI-1 expression and shedding in PC-3 cells. 66 Figure 9. Analysis of the of PGE2 and celebrex effect on matriptase in PC-3 cells. 70 Figure 10. Examination of COX-2 expression in PC-3, DU-145 andLNCaP cells and the effect of celebrex on the cell viability of DU-145 and LNCaP cells. 72 Figure 11. Effect of celebrex on DU-145 cell migration, invasion and on the expression of matriptase and HAI-1. 74 Figure 12. Effect of celebrex on LNCaP cell migration, invasion and on the expression and shedding of matriptase and HIA-1. 76 Figure 13. Effect of different NSAIDs on matriptase expression and activation in LNCaP cells. 78 Figure 14. Establishment of MTX-overexpressing PC-3 cells and the effect of celebrex on MTX-overexpressing PC-3 cell migration, invasion and matriptase activation. 80 Chapter 6. References 82 | |
| dc.language.iso | en | |
| dc.title | 探討希樂葆在攝護腺癌細胞移動、侵襲以及間質蛋白酶活化的影響 | zh_TW |
| dc.title | Suppression of prostate cancer cell migration and invasion by celebrex through down-regulating matriptase activity | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 99-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 符文美(Wen-Mei Fu),呂紹俊(Shao-Chun Lu),鄧述諄(Shu-Chun Teng) | |
| dc.subject.keyword | 希樂葆,間質蛋白酶,攝護腺癌, | zh_TW |
| dc.subject.keyword | celebrex,matriptase,prostate cancer, | en |
| dc.relation.page | 91 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2011-08-09 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
| 顯示於系所單位： | 生物化學暨分子生物學科研究所 | |
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