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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 陳彥榮 | |
| dc.contributor.author | Teh-Wei Wang | en |
| dc.contributor.author | 王德瑋 | zh_TW |
| dc.date.accessioned | 2021-07-11T14:37:25Z | - |
| dc.date.available | 2022-08-30 | |
| dc.date.copyright | 2017-08-30 | |
| dc.date.issued | 2017 | |
| dc.date.submitted | 2017-08-10 | |
| dc.identifier.citation | Agostini, M., & Knight, R. A. (2014). miR-34 from bench to bedside. Oncotarget, 5(4).
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77920 | - |
| dc.description.abstract | 近年來，許多研究發現癌幹細胞具有自我更新、抗藥性與轉移能力等特性，而癌幹細胞的存在也往往造成大腸癌病患具有較差的預後。表觀遺傳修飾對於維持癌幹細胞特性而言，扮演著相當重要的角色，根據先前的研究，去乙醯酶SIRT1可促進癌細胞增生能力與抗壓能力，它在表觀遺傳上可以針對組蛋白3的賴氨酸9 (histone 3 lysine 9, H3K9) 進行去乙醯化，進而造成染色質形成較緊密的結構並抑制轉錄活性，然而，SIRT1是否能夠透過調控表觀遺傳影響癌幹細胞特性仍然未知。在本研究中，證實SIRT1下游相關路徑能夠促進大腸癌癌幹細胞特性。首先，SIRT1會結合到微小核醣核酸miR-niChe啟動子，藉由去除組蛋白乙醯化降低其轉錄，其次，透過生物資訊工具的預測，發現miR-niChe能夠直接結合大腸癌幹細胞標記基因的mRNA，此結合作用能夠抑制癌幹細胞標記基因轉譯形成蛋白質，進一步地，在大腸癌細胞HT29以及DLD-1中過量表現miR-niChe後，癌幹細胞特性皆有顯著下降，並能利用過量表現癌幹細胞標記基因減緩該影響，證實miR-niChe是透過降低癌幹細胞標記基因表現達到抑制癌幹細胞特性的功能，除此之外，小鼠異體移植實驗中，過量表現miR-niChe的腫瘤大小明顯被抑制。綜上所述，我證明了這個預測的miRNA具有降低癌幹細胞特性的能力，並證實在大腸癌幹細胞中，可以透過表觀遺傳修飾抑制抑癌miRNA表現，進而開啟下游路徑促進癌幹細胞特性。 | zh_TW |
| dc.description.abstract | The cancer stem cell (CSC) properties such as self-renewal, drug resistance, and metastasis have been indicated to be responsible for poor prognosis of patients with colon cancers. In CSC, epigenetic modification plays a crucial role in maintaining CSC properties. According to previous studies, epigenetic regulator SIRT1 as a regulatory hub positively influences cancer related pathways such as proliferation and stress-resistance. It mediates deacetylation of histone H3 lysine 9 (H3K9), which results in repressive chromatin structure and low transcriptional activity. However, the precise mechanisms between CSC properties and abnormal histone modification by SIRT1 are still unknown. In this study, I report that SIRT1 signaling pathway is highly associated with CSC properties. The novel miRNA miR-niChe is predicted by bioinformatics databases with a potential of targeting Colon CSC Marker Gene. Inhibition of SIRT1 by RNA interference leading to elevated H3K9 acetylation in the promoter region of miR-niChe. This epigenetic reprogram results in elevation of miR-niChe expression, which further represses Colon CSC Marker Gene translation through targeting the 3’UTR of Colon CSC Marker Gene mRNA. Meanwhile, the repression of CSC properties caused by miR-niChe can be rescued by overexpression of Colon CSC Marker Gene. In subcutaneous xenograft model, tumors with miR-niChe overexpression reduced the tumor size. Therefore, the potential of the predicted miRNA for inhibiting CSC properties is demonstrated. Overall, these findings reveal how epigenetic regulator modulates gene expression and further CSC properties through repression of tumor-suppressing miRNAs in colon CSCs. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T14:37:25Z (GMT). No. of bitstreams: 1 ntu-106-R04b22012-1.pdf: 2185712 bytes, checksum: 688d13cdf7e8fa31d11e196fd2ef15d3 (MD5) Previous issue date: 2017 | en |
| dc.description.tableofcontents | 中文摘要 i
Abstract ii Table of contents iv Chapter 1. Introduction 1 1.1. Colorectal cancer 1 1.2. Cancer stem cells 1 1.2.1. Cancer stem cell theory 1 1.2.2. Self-renewal of CSCs 2 1.2.3. Drug-resistance of CSCs 3 1.2.4. Metastasis of CSCs 4 1.2.5. Isolation and surface markers of colon CSCs 5 1.3. Sirtuin1 and its role in cancer 5 1.3.1. Introduction of SIRT1 5 1.3.2. Function of SIRT1 in normal stem cells 6 1.3.3. Characteristics of SIRT1 in cancer cells 7 1.4. Abnormal epigenetic regulation in cancers 8 1.4.1. DNA methylation 8 1.4.2. Histone modification status 8 1.4.3. Regulation of miRNA in cancer researches 9 1.5. CD24, a colon CSC marker 10 Chapter 2. Motivation and Aim 12 Chapter 3. Materials and Methods 13 3.1. Cell culture 13 3.2. Lentivirus package vector 13 3.2.1. pLKO_TRC005 system 13 3.2.2. pCDH system 14 3.2.3. pLAS3w.Pneo system 14 3.2.4. Lentivirus production 14 3.2.5. Infection 15 3.3. cDNA of cellular mRNA preparation 15 3.4. cDNA of miRNA preparation 16 3.5. Quantitative reverse transcription polymerase chain reaction (qRTPCR) 16 3.6. Protein extraction 16 3.7. Western blotting 17 3.8. Sphere formation culture 18 3.9. Survival analysis of MTT assay 18 3.10. 5-Fu resistance of colony formation assay 19 3.11. Transwell migration assay 19 3.12. Chromatin immunoprecipitation (ChIP) 20 3.13. Flow cytometry 21 3.14. Side population 22 3.15. Dual-luciferase reporter assay 22 3.16. In vivo xenograft model 23 3.17. Statistical analysis 24 Chapter 4. Results 25 4.1. The expression of SIRT1 was positively correlated with CSC properties 25 4.2. Inhibition of SIRT1 reduced the stemness of colon cancer cells 26 4.3. SIRT1 enhanced CSC properties 27 4.4. CD24 regulated by SIRT1 participated in maintaining CSC properties 28 4.5. SIRT1 repressed a novel miRNA miR1185-1-3p via epigenetic regulation 29 4.6. The miR1185-1-3p downregulated CD24 via directly binding to 3’UTR 30 4.7. The miR1185-1-3p reduced CSC properties through repressing CD24 30 Chapter 5. Conclusion and Discussion 32 Chapter 6. Figures and Tables 36 Table 1. List of qPCR primers 36 Table 2. List of antibodies 37 Table 3. Searching result of predicted miRNAs from miRDB 38 Table 4. Pathway mapping by KEGG 39 Figure 1. Confirmation of correlation between SIRT1 and CSC markers 40 Figure 2. Stemness reduced by nicotinamide (NAM) treatment in colon cancer 41 Figure 3. Association between SIRT1 expression and CSC properties 43 Figure 4. CSC properties altered by CD24 expression 46 Figure 5. CD24 expression induced by SIRT1 47 Figure 6. H3K9 deacetylation by SIRT1 in miR-1185-1-3p promoter region 49 Figure 7. Direct interaction between miR-1185-1-3p and CD24 3’UTR 51 Figure 8. miR-1185-1-3p repressed CSC properties rescued by CD24 54 Figure 9. In vivo xenograft model of miR-1185-1 overexpressed cells 56 Chapter 7. Reference 57 | |
| dc.language.iso | en | |
| dc.subject | SIRT1 | zh_TW |
| dc.subject | 大腸癌幹細胞 | zh_TW |
| dc.subject | 表觀遺傳調控 | zh_TW |
| dc.subject | 微小核糖核酸 | zh_TW |
| dc.subject | colon cancer stem cells | en |
| dc.subject | epigenetic regulation | en |
| dc.subject | miRNA | en |
| dc.subject | SIRT1 | en |
| dc.title | SIRT1促進大腸癌幹細胞之幹細胞特性研究 | zh_TW |
| dc.title | SIRT1 Enhances Cancer Stem Cell Properties in Colon Cancer | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 105-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 蔡素宜,黃楓婷,趙曉梅 | |
| dc.subject.keyword | 大腸癌幹細胞,表觀遺傳調控,微小核糖核酸,SIRT1, | zh_TW |
| dc.subject.keyword | colon cancer stem cells,epigenetic regulation,miRNA,SIRT1, | en |
| dc.relation.page | 66 | |
| dc.identifier.doi | 10.6342/NTU201702941 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2017-08-10 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科技學系 | zh_TW |
| Appears in Collections: | 生化科技學系 | |
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| ntu-106-R04b22012-1.pdf Restricted Access | 2.13 MB | Adobe PDF |
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