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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 賴亮全(Liang-Chuan Lai) | |
| dc.contributor.author | En-Yu Li | en |
| dc.contributor.author | 李恩宇 | zh_TW |
| dc.date.accessioned | 2021-06-16T16:24:14Z | - |
| dc.date.available | 2018-03-04 | |
| dc.date.copyright | 2013-03-04 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-01-24 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/63131 | - |
| dc.description.abstract | 研究觀察發現腫瘤細胞缺氧會造成其治療上的抗性增強，並有更多預後不良的狀況，因此腫瘤的缺氧現象在過去十幾年被深度的研究探討。先前我們實驗室發現N-myc downstream-regulated gene 1 (NDRG1)在缺氧刺激下會大量表現，並且在腫瘤適應周遭氧濃度變動的過程中可能扮演重要角色。然而在缺氧狀況下，調控NDRG1轉錄的機制仍然不明。因此，本篇研究的目的在於鑑定出新的轉錄因子，能夠調控NDRG1在周遭氧濃度變化刺激下的轉錄。首先，利用生物資訊工具MatInspector和MatchTM 1.0去搜尋NDRG1啟動子(-783 ~ +312 鹼基對)上的轉錄因子結合位點，並根據分析結果中所有候選轉錄因子的序列相似度和其結合位點的數量，發現芳香烴受體(AHR)具有最高的潛力，故挑選出來做後續的實驗驗證。由西方墨點法的結果發現在缺氧或氯化鈷模擬缺氧之下，細胞核內的芳香烴受體的量增加。而在冷光酶報導基因分析法的結果當中，可知在擬缺氧環境下，位於NDRG1啟動子內-402 ~ -398鹼基對的芳香烴受體結合位點扮演調控其轉錄的關鍵角色。更進一步，在利用小片段干擾核糖核酸機制抑制芳香烴受體表現之後，擬缺氧誘發NDRG1的表現也隨之降低。總的來說，在這些結果中我們首度發現芳香烴受體能透過啟動子中，一個由軟體預判的芳香烴受體結合位點，正調控NDRG1在擬缺氧誘發下的轉錄，未來也許可以藉此發現而拓展出特定的治療方法，以避免腫瘤在缺氧下更趨惡性。 | zh_TW |
| dc.description.abstract | Hypoxia has been intensively investigated over the past decades based on the observations that hypoxic tumors were more resistant to therapy and had a worse prognosis. Previously, our lab identified that N-myc downstream-regulated gene 1 (NDRG1) was strongly up-regulated under hypoxia and may play an important role in tumor adaptation to fluctuation of oxygen concentrations. However, the regulatory mechanism of NDRG1 under hypoxia remains elusive. Therefore, the purpose of this study is to identify the novel transcription factors that regulate NDRG1 upon changes in oxygen concentrations. First of all, bioinformatic tools, MatInspector and MatchTM 1.0, were used to search the DNA binding sites of transcription factors in the promoter of NDRG1. Based on the similarities and numbers of transcription factor binding sites existing in the NDRG1 promoter (-783 ~ +312 bp), aryl hydrocarbon receptor (AHR) was identified as the most potential candidate and herein chosen for further validation. Western blotting showed that nuclear AHR was up-regulated in the presence of cobalt and hypoxia. Luciferase reporter assays showed that binding site of AHR at -402 ~ -398 bp played a crucial role in regulating NDRG1 under hypoxia-mimicking conditions. Moreover, hypoxia-mimetic induction of NDRG1 by was attenuated by knockdown of AHR expression using short interfering RNA. In summary, these results showed for the first time that AHR positively regulates NDRG1 transcription through a putative AHR binding site in the promoter by hypoxia-mimetic signaling, which may lead to development of a specific therapeutic regime to prevent tumor malignancy under hypoxia. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T16:24:14Z (GMT). No. of bitstreams: 1 ntu-102-R99441005-1.pdf: 1155868 bytes, checksum: cfebe77e290aaf16249ef1885d721767 (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | Index
中文摘要 ii Abstract iii Chapter 1 Introduction 1 1.1 Hypoxia in solid tumor and its metal mimics 1 1.2 Relationship between NDRG1 and hypoxia 2 1.3 Cross-talk between AHR and hypoxia 4 1.4 Motivations and aims 5 Chapter 2 Materials and Methods 7 2.1 Cell culture and reagents 7 2.2 NDRG1 promoter constructs 7 2.3 Site-directed mutagenesis 9 2.4 Luciferase reporter assay 10 2.5 Western blot analysis 10 2.6 Quantitative real-time RT-PCR 11 2.7 RNA interference via lentivirus 12 2.8 Conservation analysis 12 2.9 Prediction of transcription factor binding sites 13 Chapter 3 Results 14 3.1 In silico analysis of transcription factor binding site in the human NDRG1 promoter region 14 3.2 Conservation analysis of the predicted AHR/ARNT binding sites among several species 18 3.3 Endogenous expression of AHR under hypoxia and hypoxia-mimetic conditions 20 3.4 Identification of the regulatory relationship between AHR and the NDGR1 promoter through the predicted binding sites 21 3.5 Effect of AHR knockdown on NDRG1 expression 26 Chapter 4 Discussion 28 4.1 Hypoxia-inducible NDRG1 promoter activity via binding of transcription factors 28 4.2 Ligand-dependent versus ligand-independent activation of the AHR 30 4.3 Induction of NDRG1 underlying cross-talk between AHR and hypoxia pathway 32 4.4 Accuracy of promoter analysis and its limitations 34 4.5 Alterations of morphology in the viral-infected MCF7 cells expressing AHR-specific shRNA#3 35 4.6 AHR and carcinogenesis 36 4.7 Summary and further works 37 References 38 Supplementary Data 49 | |
| dc.language.iso | en | |
| dc.subject | 冷光?報導基因分析法 | zh_TW |
| dc.subject | 轉錄因子結合位點 | zh_TW |
| dc.subject | 啟動子 | zh_TW |
| dc.subject | 生物資訊工具 | zh_TW |
| dc.subject | 缺氧 | zh_TW |
| dc.subject | NDRG1 | zh_TW |
| dc.subject | 芳香烴受體 | zh_TW |
| dc.subject | luciferase reporter assays | en |
| dc.subject | NDRG1 | en |
| dc.subject | hypoxia | en |
| dc.subject | bioinformatic tools | en |
| dc.subject | promoter | en |
| dc.subject | transcription factor binding sites | en |
| dc.subject | aryl hydrocarbon receptor | en |
| dc.title | 芳香烴受體於擬缺氧狀況下調控NDRG1基因的轉錄 | zh_TW |
| dc.title | Aryl Hydrocarbon Receptor Regulates NDRG1 Transcription under Hypoxia Mimic Conditions | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 胡孟君(Meng-Chun Hu),莊曜宇(Eric Y. Chuang),蔡孟勳(Mong-Hsun Tsai) | |
| dc.subject.keyword | 芳香烴受體,NDRG1,缺氧,生物資訊工具,啟動子,轉錄因子結合位點,冷光?報導基因分析法, | zh_TW |
| dc.subject.keyword | aryl hydrocarbon receptor,NDRG1,hypoxia,bioinformatic tools,promoter,transcription factor binding sites,luciferase reporter assays, | en |
| dc.relation.page | 50 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2013-01-24 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生理學研究所 | zh_TW |
| 顯示於系所單位： | 生理學科所 | |
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