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研究生:曾國彰
研究生(外文):Kuo-Chang Tseng
論文名稱:探討 forkhead box protein O3A 於大腸癌幹細胞中所扮演之角色
論文名稱(外文):Characterization of the role played by forkhead box protein O3A in colon cancer stem cell
指導教授:陳彥榮
指導教授(外文):Yen-Rong Chern
口試委員:黃楓婷華國泰張玉芳
口試委員(外文):Feng-Ting HuangKuo-Tai HuaYu-Fang Chang
口試日期:2015-07-23
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:生化科技學系
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:英文
論文頁數:71
中文關鍵詞:大腸癌癌幹細胞細胞休眠自我更新球體生成轉錄因子 FOXO3A
外文關鍵詞:colon cancerCSCquiescenceself-renewsphere formationFOXO3A
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癌幹細胞往往是造成癌症轉移及復發的主因之一。如同正常的幹細胞,癌幹細胞所具有的自我更新、細胞休眠以及抵抗外來壓力的能力也讓研究推測它與正常幹細胞使用許多共同的因子。不過,因為純化及研究癌幹細胞的困難,加上目前較少針對癌幹細胞進行的全面研究,使得那些重要的因子尚未明瞭。在本研究中,我探討在正常幹細胞中扮演重要角色的轉錄因子 forkhead box protein O3A (FOXO3A) 是否也對於大腸癌幹細胞也有著同樣地位。藉由分析細胞休眠的族群顯示:FOXO3A knock-down 的大腸癌細胞株中細胞休眠的族群較低。此外,由較低的球體 (sphere) 生成數目也可得知,FOXO3A 表現降低會影響癌細胞自我更新的能力。因為 FOXO3A 可以促進自我更新及細胞休眠,所以確定了 FOXO3A 對於大腸癌幹細胞的維持扮演著不可或缺的角色。實驗結果也顯示 FOXO3A 在大腸癌細胞中始終保持著活化的狀態,並且不受到 AKT/PI3K 以及 TGF/SMAD 調控路徑影響,顯示 FOXO3A 的活性可能不取決於表現量。因此,我推測 FOXO3A 能藉由開啟與先前研究不同甚至是全新的基因來維持癌幹細胞型細胞自的能力。

Cancer stem cell (CSC) is one of the main reasons leading to the recurrence and the metastasis of several cancers. While having abilities as self-renew, quiescence and stress resistance as a normal stem cell, CSC is believed to share many key factors with a normal stem cell. However, due to the less of comprehensive researches and the difficulty in isolation and investigation of CSC, the factors which are essential to the CSC are not yet clear. In this thesis, I tested whether the transcription factor forkhead box protein O3A (FOXO3A), which is known as a necessary factor for normal stem cells, plays an important role in colon CSCs. Through analysis of quiescence population, the knock-down of FOXO3A in colon cancer cell lines decrease the quiescent population of cancer cells. Through sphere forming assay, I also show that the decrease of FOXO3A in cancer cells eliminates the self-renew ability since sphere numbers become significant lower than control. I confirmed that FOXO3A is critical for the maintenance of colon CSCs by promoting self-renew and quiescence. I also show that FOXO3A is constantly activated in colon cancer and independent to AKT/PI3K and TGF/SMAD pathways. Therefore FOXO3A may function in a dose-independent manner. Furthermore, these results indicate that FOXO3A may activate different or even novel gene sets during self-renew in colon CSCs.

摘要 i
Abstract ii
Table of contents iv
1. Introduction 1
1.1. Colon cancer 1
1.2. CSC theory and the characteristics of CSCs 2
1.2.1. Self-renew and CSCs 2
1.2.2. Quiescence and CSCs 3
1.2.3. Stress-resistance and CSCs 4
1.2.4. Isolation of CSCs 5
1.2.5. Important genes and pathways of CSCs 6
1.3. FOXO3A and its roles in CSCs 8
1.3.1. Introduction of FOXO3A 8
1.3.2. Different modifications of FOXO3A 8
1.3.3. Binding partners of FOXO3A 10
1.3.4. Normal stem cells and FOXO3A 11
1.3.5. FOXO3A and cancer cells or CSCs 11
1.4. Motivation and Aim 13
2. Materials and Methods 14
2.1. Cell culture 14
2.2. Lentivirus knock-down system 14
2.3. Side population (SP) analysis 15
2.4. Quiescent population analysis 16
2.5. Sphere formation culture 17
2.6. Cellular RNA extraction 18
2.7. Quantitative reverse transcription polymerase chain reaction (qRTPCR) 19
2.8. Cellular protein extraction 19
2.9. Western blotting 20
2.10. Cell immunofluorescence staining 21
3. Results 22
3.1. Generation and basic characterization of siFOXO3A cell lines. 22
3.2. Down regulation of FOXO3A decreases the quiescent population of colon cancer. 23
3.3. Down regulation of FOXO3A eliminates the self-renewal ability of colon CSC. 25
3.4. The regulation of FOXO3A in colon cancer is independent to AKT/PI3K and TGF/SMAD pathways. 26
3.5. FOXO3A may change its binding affinity and its transcription profile during self-renew. 29
4. Discussion 31
4.1. The state transition in CSCs 32
4.2. FOXO3A is critical to CSCs by promoting self-renew and quiescence 33
4.3. FOXO3A may have a distinct transcription profile in CSCs 36
5. Figures 39
Figure 1. Basic characteristics of FOXO3A knock-down cell lines. 40
Figure 2. Down-regulation of FOXO3A decreases the quiescent population of colon cancer. 43
Figure 3. Down-regulation of FOXO3A hampers the self-renewal ability of colon CSC. 45
Figure 4. The regulation of FOXO3A in colon cancer is independent to AKT/PI3K and TGF/SMAD pathways. 48
Figure 5. FOXO3A may change its binding affinity and thus transcription profile during self-renew. 50
6. Tables 51
Table 1. The gene list for epigenetic study. 51
7. References 52
8. Appendix 69
8.1. List of the primers 69
8.2. List of the antibodies 71


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