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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77892Full metadata record
| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 陳彥榮 | |
| dc.contributor.author | Chao-Wei Hsu | en |
| dc.contributor.author | 許兆瑋 | zh_TW |
| dc.date.accessioned | 2021-07-11T14:36:50Z | - |
| dc.date.available | 2022-08-31 | |
| dc.date.copyright | 2017-08-31 | |
| dc.date.issued | 2017 | |
| dc.date.submitted | 2017-08-15 | |
| dc.identifier.citation | Alison, M. R., et al. (2012). Cancer stem cells: in the line of fire. Cancer Treatment Reviews, 38, 589-598.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77892 | - |
| dc.description.abstract | 癌幹細胞具有較強的抗藥性和轉移能力，而且會促進腫瘤的進程。FOXO3 為一轉錄因子。由於它會抑制細胞週期和促進細胞凋亡，所以 FOXO3 一直以來被視為抑癌基因。然而有些研究卻發現 FOXO3 也有助於腫瘤，而且 FOXO3 負責維持成體幹細胞的自我更新能力。目前還不清楚為何 FOXO3 在癌症裡有矛盾的功能，也不清楚 FOXO3 對於癌幹細胞的影響。在這篇研究裡，我發現缺乏特定轉譯後修飾的 FOXO3 會促進癌幹細胞的特性。相比於癌細胞而言，癌幹細胞的 FOXO3 的表現量較高。抑制 FOXO3 表現會降低癌幹細胞的特性，證明了 FOXO3 的確對癌幹細胞很重要。而且，本篇研究還發現了癌幹細胞裡 FOXO3 的功能會受到特定後轉譯修飾調控。轉譯後修飾會調控 FOXO3 對目標基因的專一性。失去特定修飾型態的 FOXO3 會促進自我更新、抗藥性和轉移能力，而有此轉譯後修飾的 FOXO3 則沒有這樣的功能。而且，基因表現分析結果發現缺乏此轉譯後修飾的 FOXO3 可能還會增進氧化自由基的清除和 DNA 修復能力，而有此轉譯後修飾的 FOXO3 則可能會促使細胞凋亡。因此，我們的結果證明了，FOXO3 的確會維持癌幹細胞的特性，而且 FOXO3 的不同功能會受到蛋白質的後轉譯修飾調控。FOXO3 的後轉譯修飾酵素在未來也許可以當作癌症標靶治療的目標。這篇研究顯示著在癌症裡基因的重要性並不能只由表現量決定，還跟蛋白質的後轉譯修飾有關。 | zh_TW |
| dc.description.abstract | Cancer stem cells (CSCs) are responsible for tumor progression, drug resistance and metastasis in malignant diseases. FOXO3, a transcription factor, has been regarded as a tumor suppressor due to its cell-cycle arrest and apoptosis-inducing abilities. Nevertheless, some studies indicated that FOXO3 may be an oncogene and FOXO3 maintains self-renewal in adult stem cells. The paradoxical roles of FOXO3 in cancers and the roles of FOXO3 in CSCs remain to be clarified. Here I show that without specific posttranslational modifications, FOXO3 promotes colorectal CSC properties. Higher FOXO3 expression was observed in CSCs and inhibition of FOXO3 reduced CSC properties, suggesting that FOXO3 is essential for colorectal CSCs. Moreover, I discovered that the functions of FOXO3 in CSCs are regulated by posttranslational modifications. Posttranslational modifications on FOXO3 regulated its target specificity. Without specific posttranslational modifications, FOXO3 promoted self-renewal, drug resistance and migration, while modified FOXO3 could not. Also, different gene expression profiles showed that without specific posttranslational modifications, FOXO3 might enhance ROS detoxification and DNA repair, while modified FOXO3 might induce apoptosis. Therefore, my results suggest that FOXO3 is indispensable for the maintenance of CSCs and the differential functions of FOXO3 in CSCs are regulated by protein modifications. Specific FOXO3 modulating enzymes could be target molecules for cancer therapy in the future. This study shows that the roles of genes in cancers could not be determined only by gene expression levels but also their protein posttranslational modifications. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T14:36:50Z (GMT). No. of bitstreams: 1 ntu-106-R04b22001-1.pdf: 8448317 bytes, checksum: 45aca9192de571addd45b267c4bf01fe (MD5) Previous issue date: 2017 | en |
| dc.description.tableofcontents | 中文摘要 i
Abstract iii I. Introduction 3 i. Colorectal cancer & Cancer stem cells 3 1、 Colorectal cancer 3 2、 Cancer stem cells 3 ii. FOXO3 5 1、 Introduction of FOXO3 5 2、 FOXO3 maintained self-renewal in stem cells 6 3、 FOXO3 was regarded as a tumor suppressor 7 4、 FOXO3 was also an oncogene 8 iii. FOXO3 posttranslational modifications 10 1、 Phosphorylation of FOXO3 10 2、 Ubiquitination of FOXO3 11 3、 Methylation of FOXO3 12 4、 Acetylation of FOXO3 12 II. Material and Methods 15 i. Cell culture 15 ii. Construction of pCDH/pLAS3w.Pneo-FOXO3-WT/3KR/3KQ FOXO3 plasmid 15 iii. Lentivirus plasmids 16 iv. Virus production 17 v. Virus titer measurement 18 vi. Virus infection 19 vii. Cellular mRNA extraction and reverse transcription 19 viii. Quantitative polymerase chain reaction (qPCR) 19 ix. Cellular protein extraction 20 x. Immunoprecipitation 21 xi. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting 22 xii. Drug resistance 23 xiii. Transwell migration assay 23 xiv. Sphere formation 24 xv. Side population (SP) analysis and isolation 25 xvi. Statistical analysis 27 III. Results 28 i. Higher FOXO3 expression in CSC-like cells 28 ii. Knockdown and overexpression of FOXO3 disrupted the self-renewal potential of CSCs 29 iii. FOXO3 tended to be deacetylated in CSCs. 29 iv. Construction of acetylated/deacetylated FOXO3 mimics 30 v. Deacetylation of FOXO3 restored its self-renewal-promoting potential 31 vi. Deacetylation of FOXO3 enhanced drug resistance 32 vii. Deacetylation of FOXO3 promoted the migration ability 33 viii. Deacetylated and acetylated FOXO3 induced different target genes 34 IV. Figures 36 Figure 1: FOXO3 expression in colorectal CSC-like cells 37 Figure 2: FOXO3 is essential for but disrupts self-renewal 39 Figure 3: FOXO3 tends to be deacetylated in CSCs 40 Figure 4: Deacetylated FOXO3 mimics restores partial self-renewal potential 43 Figure 5: Deacetylated FOXO3 enhances drug resistance 47 Figure 6: Deacetylated FOXO3 promotes migration 49 Figure 7: Acetylation of FOXO3 regulates its target specificity 53 V. Discussion 54 i. Upstream regulation of expression of FOXO3 in colorectal CSCs 54 ii. Acetylation of FOXO3 protein 56 1、 The paradox of FOXO3 in CSCs 56 2、 Construction of FOXO3-3KR/3KQ 57 3、 FOXO3 may promote self-renewal through BMI1 58 4、 FOXO3 enhanced drug resistance 58 5、 FOXO3 promoted migration 60 6、 FOXO3 contributed to ROS detoxification, DNA repair and apoptosis 60 7、 Differential gene expression by FOXO3-3KR/3KQ 61 VI. References 63 VII. Appendix Tables 68 Appendix Table 1: Primers used in FOXO3 mutation 68 Appendix Table 2: qPCR primers 70 Appendix Table 3: Antibodies 72 | |
| dc.language.iso | en | |
| dc.title | FOXO3 在大腸癌幹細胞之功能研究 | zh_TW |
| dc.title | The Role of FOXO3 in Colorectal Cancer Stem Cells | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 105-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 趙曉梅,黃楓婷,蔡素宜 | |
| dc.subject.keyword | 大腸癌,癌幹細胞,自我更新,FOXO3,後轉譯修飾, | zh_TW |
| dc.subject.keyword | colorectal cancer,cancer stem cell,self-renewal,FOXO3,posttranslational modifications, | en |
| dc.relation.page | 80 | |
| dc.identifier.doi | 10.6342/NTU201703300 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2017-08-15 | |
| 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-R04b22001-1.pdf Restricted Access | 8.25 MB | Adobe PDF |
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