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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 郭明良(Min-Liang Kuo) | |
dc.contributor.author | Shih-Huan Tseng | en |
dc.contributor.author | 曾士桓 | zh_TW |
dc.date.accessioned | 2021-05-17T09:15:05Z | - |
dc.date.available | 2017-07-01 | |
dc.date.available | 2021-05-17T09:15:05Z | - |
dc.date.copyright | 2012-09-19 | |
dc.date.issued | 2012 | |
dc.date.submitted | 2012-08-13 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/6596 | - |
dc.description.abstract | 癌症 (惡性腫瘤)一直以來都是國人十大死因之首,其中,得到肺癌的比例也都居高不下,因此肺癌的治療是相當重要的課題。根據的研究指出,癌細胞的代謝已經被認為是一個用做藥物設計治療癌症的新方向。在此篇研究中,我們企圖去呈現一個與血管新生相關的蛋白:血管相似素1可能能夠藉由改變癌細胞的代謝而抑制了肺癌的進程。首先,我們利用了代謝體學的方法分析了CL1-5肺癌細胞株在血管相似素1過量表現的與原本細胞株的差異,進而發現了過量表現血管相似素1的CL1-5肺癌細胞可能由麩醯胺酸酶2 (Glutaminase 2)改變細胞內麩醯胺酸 (glutamine)的表現量。而且,我們更進一步的發現在抑制了麩醯胺酸酶2的mRNA表現後,會增加其原本血管相似素1所抑制的癌症進程如侵犯力 (invasion)、移動力 (migration)以及細胞的非貼附性生長 (anchorage independent growth)等。為了證明我們的觀察是否也會在活體內發生,我們利用了免疫不全 (SCID)的小鼠做了原位模式 (orthotropic model)的動物實驗進行應證,發現了與原本細胞實驗有類似的結果。進一步的,我們想探討血管相似素1可能會透過什麼樣的機制誘導了麩醯胺酸酶2的表現。因為血管相似素1是分泌型的蛋白,於是我們推測血管相似素1可能會透過一系列的訊息傳遞來達到誘導麩醯胺酸酶2的表現,然而在麩醯胺酸酶2的啟動子區(promoter region) 找到了轉錄因子FOXOs的同源辨認位 (cognate recognition site),進而發現了血管相似素1是透過了磷酸化的Erk路徑來調控FOXO家族中的FOXO3a而影響麩醯胺酸酶2的表現。再者,為了證明血管相似素1與麩醯胺酸酶2在臨床上是否也具有相關性,也想探討這2個蛋白與存活率的關係,於是我們針對了82位肺癌病人的組織切片做免疫組織染色,經過統計後發現血管相似素1與麩醯胺酸酶2呈正相關且這2種蛋白的表現都和存活率有顯著的正相關性。以上的研究指出了血管相似素1可能透過改變了麩醯胺酸酶2的代謝角色造成了癌症的進程受到抑制。未來希望能夠透過此篇的研究結果,能發展出肺癌治療的新方法或新的藥物,增加肺癌病人的存活率以及治癒率。 | zh_TW |
dc.description.abstract | Cancer is the most deadly disease in Taiwan. Among all type of cancer, lung cancer is one of the most lethal types. Therefore, searching the cures of lung cancer is an important issue. According to recent research, cancer cells metabolism are considered as a new direction of drug design for cancer therapy. In this study, we present a new biological function of an anti- angiogenesis protein, Angiopoietin-like 1(ANGPTL1), can influence lung cancer progression via affecting lung cancer cells metabolism. We use LC/MS to analyze the whole metabolites in overexpression ANGPTL1 and wild type cells. The profile indicates that intracellular glutamine is lower in overexpression ANGPTL1 cells. After screen some glutamine-related enzymes, we found that the level of intracellular glutamine changed through the glutamine catabolic enzyme Glutaminase 2 (GLS2). Then, we evaluated the function of ANGPTL1. The results showed that ANGPTL1 can inhibit the invasion, migration and anchorage independent abilities. Further, knockdown GLS2 will restore those abilities which are inhibited by ANGPTL1. In animal model, we found that ANGPTL1 can repress intra-pulmonary metastasis and nodules numbers but knockdown ANGPTL1-induced GLS2 can regain lung cancer intra-pulmonary metastasis in vivo and increase the nodules. We further investigated the possible mechanism of how ANGPTL1 can induce GLS2. The data showed that ANGPTL1-inhibited mobility and anchorage independent ability of lung cancer cells were found to required upregulation of GLS2 through inhibiting phospho-Erk/FOXO3a pathway. Clinically, we found that ANGPTL1 is positive correlation with GLS2 and their expression are inversely correlated with poor clinical outcomes. Above data suggested that ANGPTL1 has a new role in glutamine catabolism and can inhibit tumor progression by inducing GLS2. In conclusion, our findings provide a potential role of ANGPTL1 involved in regulation of tumor metabolism pathway that further to affect tumor progression in lung cancer. | en |
dc.description.provenance | Made available in DSpace on 2021-05-17T09:15:05Z (GMT). No. of bitstreams: 1 ntu-101-R98447005-1.pdf: 1751963 bytes, checksum: b7e8ae3868b7e04fd763a653d6cbbcdb (MD5) Previous issue date: 2012 | en |
dc.description.tableofcontents | 口試委員會審定書……………………………………………………………………..........Ⅰ
誌謝…………………………………………………………………………………………………Ⅱ 中文摘要……………………………………………………………………………………………Ⅲ 英文摘要……………………………………………………………………………………………Ⅳ INTRODUCTION 1 1-1 LUNG CANCER 1 1-2 THE CHARACTERISTICS OF CANCER AND CANCER METABOLISM 1 1-3 METABOLOMICS AND CANCER 3 1-4 ANGIOPOITIN-LIKE PROTEINS AND METABOLISM 4 1-5 THE FOXOS FAMILY AND METABOLISM 5 1-6 THE MOTIVATION OF THIS STUDY 5 MATERIALS AND METHODS 6 2-1 CELL CULTURE 6 2-2 IMMUNOHISTOCHEMISTRY 6 2-3 WESTERN BLOTTING ANALYSIS 7 2-4 TRANSFECTION AND LENTIVIRUS INFECTION 8 2-5 MTT PROLIFERATION ASSAY 8 2-6 RNA ISOLATION AND REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION 9 2-7 MOUSE MODEL FOR TUMORIGENESIS 9 2-8 ANCHORAGE-INDEPENDENT GROWTH ASSAY 10 2-9 INVASION AND MIGRATION ABILITY ASSAY 10 2-10 METABOLOMIC SAMPLES PREPARATION 11 2-11 PRINCIPAL COMPONMENT ANALYSIS (PCA), LC/MS AND METABOLOMIC ANALYSIS 11 2-12 STATISTICAL ANALYSIS 12 RESULTS 13 3-1 ANGPTL1 INDUCED GLS2 ALTERED THE GLUTAMINE LEVEL IN LUNG CANCER CELL LINES 13 3-2 ANGPTL1- INDUCED GLS2 DID NOT AFFECT CELL PROLIFERATION BUT INVASION, MIGRATION AND ANCHORAGE INDEPENDENT ABILITY 14 3-3 ANGPTL- INDUCED GLS2 CHANGED THE LUNG CANCER CELL PROGRESSION IN VIVO 15 3-4 GLS2 WAS INDUCED BY ANGPTL1 THROUGH MEK1-FOXO3A SIGNALING 15 3-5 THE CLINICAL CORRELATION BETWEEN ANGPTL1 AND GLS2 17 DISCUSSION 19 REFERENCE 21 FIGURES AND FIGURE LEGENDS 27 FIG. 1 METABOLOMIC PROFILE AND GLUTAMINE METABOLISM IS CHANGED BY GLUTAMINASE 2. 29 FIG. 2 ANGPTL1 INHIBITED THE INVASION, MIGRATION, AND ANCHORAGE INDEPENDENT ABILITY IN LUNG CANCER CELLS VIA INDUCING GLS2. 34 FIG. 3 ANGPTL1-INDUCED GLS2 CHANGES THE CELL MOBILITY AND TUMORGENISITY IN VIVO. 36 FIG. 4 SIGNAL TRANSDUCTION MECHANISM INVOLVED IN ANGPTL1 MEDIATED GLS2 UPREGULATION IN CL1-5 LUNG CANCER CELL. 41 FIG. 5. GLS2 IS EXPRESSED IN CANCERS AND INVERSELY CORRELATES WITH SURVIVAL OF CANCER PATIENTS. 43 TABLE 44 TABLE. 1 UNIVARIANTS AND MULTIVARIATE ANALYSIS OF POTENTIAL PROGNOSTIC VARIABLES 44 TABLE. 2 CORRELATION BETWEEN LEVEL OF ANGPTL1 AND GLS2 EXPRESSION IN LUNG CANCER 45 | |
dc.language.iso | en | |
dc.title | 探討血管生成相似素1在肺癌中參與腫瘤代謝的分子機制 | zh_TW |
dc.title | The role of Angiopoietin-like 1 in lung cancer progression via altering metabolism | en |
dc.type | Thesis | |
dc.date.schoolyear | 100-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 林明燦(Ming-Tsan Lin),蕭宏昇(Michael Hong-Shen Hsiao),嚴孟祿(Men-Luh Yen) | |
dc.subject.keyword | 肺癌,血管新生,血管相似素1,麩醯胺酸,癌細胞代謝, | zh_TW |
dc.subject.keyword | Lung cancer,Angiogenesis,Angiopoietin-like 1,Glutamine,Cancer cell metabolism, | en |
dc.relation.page | 45 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2012-08-13 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 毒理學研究所 | zh_TW |
顯示於系所單位: | 毒理學研究所 |
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