請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77892完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| 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.
Bakker, W. J., et al. (2007). FOXO3a is activated in response to hypoxic stress and inhibits HIF1-induced apoptosis via regulation of CITED2. Molecular Cell, 28(6), 941-953. Bertaggia, E., et al. (2012). Posttranslational modifications control FoxO3 activity during denervation. American Journal of Physiology-Cell Physiology, 302(3), C587-C596. Boehm, A. M., et al. (2012). FoxO is a critical regulator of stem cell maintenance in immortal Hydra. Proceedings of the National Academy of Sciences, 109(48), 19697-19702. Bonnet, D., & Dick, J. E. (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Medicine, 3, 730-737. Brenkman, A. B., et al. (2008). Mdm2 induces mono-ubiquitination of FOXO4. PLoS One, 3(7), e2819. Brunet, A., et al. (1999). Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor. Cell, 96(6), 857–868. Brunet, A., et al. (2004). Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase. Science, 303(5666), 2011-2015. Calnan, D. R., & Brunet, A. (2008). The FoxO code. Oncogene, 27(16), 2276-2788. Chakrabarty, A., et al. (2012). Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Proceedings of the National Academy of Sciences, 109(8), 2718-2723. Chandarlapaty, S., et al. (2011). AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell, 19(1), 58-71. Cheung, C. C., et al. (2016). MicroRNA-183 suppresses cancer stem-like cell properties in EBV-associated nasopharyngeal carcinoma. BMC Cancer, 16, 495. Daitoku, H., et al. (2004). Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proceedings of the National Academy of Sciences, 101(27), 10042-10047. Dansen, T. B., & Burgering, B. M. (2008). Unravelling the tumor-suppressive functions of FOXO proteins. Trends in Cell Biology, 18(9), 421-429. Dudgeon, C., et al. (2010). PUMA induction by FoxO3a mediates the anticancer activities of the broad-range kinase inhibitor UCN-01. Molecular Cancer Therapeutics, 9(11), 2893-2902. Dull, T., et al. (1998). A third-generation lentivirus vector with a conditional packaging system. Journal of Virology, 72(11), 8463-8471. Eijkelenboom, A., & Burgering, B. M. (2013). FOXOs: signalling integrators for homeostasis maintenance. Nature Reviews Molecular Cell Biology, 14(2), 83-97. Essers, M. A., et al. (2004). FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. The EMBO Journal, 23(24), 4802–4812. Ferber, E. C., et al. (2012). FOXO3a regulates reactive oxygen metabolism by inhibiting mitochondrial gene expression. Cell Death and Differentiation, 19(6), 968-979. Fernandez de Mattos, S., et al. (2008). FOXO3a mediates the cytotoxic effects of cisplatin in colon cancer cells. Molecular Cancer Therapeutics, 7(10), 3237-3246. Fu, W., et al. (2009). MDM2 acts downstream of p53 as an E3 ligase to promote FOXO ubiquitination and degradation. The Journal of Biological Chemistry, 284(21), 13987-14000. Furuyama, T., et al. (2000). Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues. Biochemical Journal, 349(2), 629-634. Gao, F., & Wang, W. (2015). MicroRNA-96 promotes the proliferation of colorectal cancer cells and targets tumor protein p53 inducible nuclear protein 1, forkhead box protein O1 (FOXO1) and FOXO3a. Molecular Medicine Reports, 11(2), 1200-1206. Gopinath, S. D., et al. (2014). FOXO3 promotes quiescence in adult muscle stem cells during the process of self-renewal. Stem Cell Reports, 2(4), 414-426. Greer, E. L., et al. (2007). The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. The Journal of Biological Chemistry, 282(41), 30107-30119. Guo, Y., et al. (2003). MRP8, ATP-binding cassette C11 (ABCC11), is a cyclic nucleotide efflux pump and a resistance factor for fluoropyrimidines 2',3'-dideoxycytidine and 9'-(2'-phosphonylmethoxyethyl)adenine. The Journal of Biological Chemistry, 278(32), 29509-29514. Haraguchi, N., et al. (2006). Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells, 24(3), 506-513. Hecht, A., et al. (1995). Histone H3 and H4 N-termini interact with SIR3 and SIR4 proteins: a molecular model for the formation of heterochromatin in yeast. Cell, 80(4), 583-592. Hillion, J., et al. (1997). AF6q21, a novel partner of the MLL gene in t(6;11)(q21;q23), defines a forkhead transcriptional factor subfamily. Blood, 90(9), 3714-3719. Hosaka, T., et al. (2004). Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. Proceedings of the National Academy of Sciences, 101(9), 2975-2980. Hu, Y., & Smyth, G. K. (2009). ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. Journal of Immunological Methods, 347(1-2), 70-78. Huang, H., et al. (2006). CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage. Science, 314(5797), 294-297. Hui, R. C., et al. (2008). Doxorubicin activates FOXO3a to induce the expression of multidrug resistance gene ABCB1 (MDR1) in K562 leukemic cells. Molecular Cancer Therapeutics, 7(3), 670-678. Kenyon, C., et al. (1993). A C. elegans mutant that lives twice as long as wild type. Nature, 366(6454), 461-464. Kops, G. J. P. L., et al. (2002). Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature, 419, 316-321. Kouri, F. M., et al. (2015). miR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma. Genes & Development, 29, 732-745. Kress, T. R., et al. (2011). The MK5/PRAK kinase and Myc form a negative feedback loop that is disrupted during colorectal tumorigenesis. Molecular Cell, 41(4), 445-457. Liu, P., et al. (2008). CDK1 promotes cell proliferation and survival via phosphorylation and inhibition of FOXO1 transcription factor. Oncogene, 27(34), 4733-4744. Luo, H., et al. (2013). PTEN-regulated AKT/FoxO3a/Bim signaling contributes to reactive oxygen species-mediated apoptosis in selenite-treated colorectal cancer cells. Cell Death & Disease, 4, e481. Matkar, S., et al. (2015). An epigenetic pathway regulates sensitivity of breast cancer cells to HER2 inhibition via FOXO/c-Myc axis. Cancer Cell, 28(4), 472-485. Matsuoka, S., et al. (2007). ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage. Science, 316(5828), 1160-1166. Matsuzaki, H., et al. (2005). Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation. Proceedings of the National Academy of Sciences, 102(32), 11278-11283. Michan, S., & Sinclair, D. (2007). Sirtuins in mammals: insights into their biological function. Biochemical Journal, 404(1), 1-13. Motta, M. C., et al. (2004). Mammalian SIRT1 represses forkhead transcription factors. Cell, 116(4), 551-563. Naka, K., et al. (2010). TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature, 463(7281), 676-680. Nilsen, T. W. (2007). Mechanisms of microRNA-mediated gene regulation in animal cells. Trends in Genetics, 23(5), 243-249. O'Brien, C. A., et al. (2007). A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature, 445(7123), 106-110. Paik, J. H., et al. (2007). FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell, 128(2), 309-323. Pratt, S., et al. (2005). The multidrug resistance protein 5 (ABCC5) confers resistance to 5-fluorouracil and transports its monophosphorylated metabolites. Molecular Cancer Therapeutics, 4(5), 855-863. Rappa, G., et al. (2008). Growth of cancer cell lines under stem cell-like conditions has the potential to unveil therapeutic targets. Experimental Cell Research, 314(10), 2110-2122. Renault, V. M., et al. (2009). FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell, 5(5), 527-539. Ricci-Vitiani, L., et al. (2007). Identification and expansion of human colon-cancer-initiating cells. Nature, 445(7123), 111-115. Rodriguez, M. S., et al. (2000). Multiple C-terminal lysine residues target p53 for ubiquitin-proteasome-mediated degradation. Molecular and Cellular Biology, 20(22), 8458-8467. Scharenberg, C. W., et al. (2002). The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors. Blood, 99(2), 507-512. Shiota, M., et al. (2010). Foxo3a expression and acetylation regulate cancer cell growth and sensitivity to cisplatin. Cancer Science, 101(5), 1177-1185. Siegel, R. L., et al. (2017). Cancer Statistics, 2017. CA: A Cancer Journal for Clinicians, 67(1), 7-30. Storz, P., et al. (2009). FOXO3a promotes tumor cell invasion through the induction of matrix metalloproteinases. Molecular and Cellular Biology, 29(18), 4906-4917. Sykes, S. M., et al. (2011). AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias. Cell, 146(5), 697-708. Tenbaum, S. P., et al. (2012). β-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer. Nature Medicine, 18(6), 892-902. Testa, U. (2012). Colon Cancer Stem Cells. In R. Scatena, A. Mordente, & B. Giardina (Eds.), Advances in Cancer Stem Cell Biology (pp. 155-179). Tothova, Z., et al. (2007). FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell, 128(2), 325-339. Tran, H., et al. (2002). DNA Repair Pathway Stimulated by the Forkhead Transcription Factor FOXO3a Through the Gadd45 Protein. Science, 296(5567), 530-534. Urbanek, P., & Klotz, L. O. (2017). Posttranscriptional regulation of FOXO expression: microRNAs and beyond. British Journal of Pharmacology, 174(12), 1514-1532. Valent, P., et al. (2012). Cancer stem cell definitions and terminology: the devil is in the details. Nature Review Cancer, 12(11), 767-775. van der Horst, A., et al. (2006). FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP. Nature Cell Biology, 8(10), 1064-1073. van der Horst, A., et al. (2004). FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). The Journal of Biological Chemistry, 279(28), 28873-28879. van der Vos, K. E., & Coffer, P. J. (2008). FOXO-binding partners: it takes two to tango. Oncogene, 27(16), 2289-2299. van der Vos, K. E., & Coffer, P. J. (2011). The extending network of FOXO transcriptional target genes. Antioxidants & redox signaling, 14(4), 579-592. Wang, F., et al. (2012). Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation. Oncogene, 31(12), 1546-1557. Wang, Y., et al. (2013). FoxO3a contributes to the reprogramming process and the differentiation of induced pluripotent stem cells. Stem Cells and Development, 22(22), 2954-2963. Xie, Q., et al. (2012). Lysine methylation of FOXO3 regulates oxidative stress-induced neuronal cell death. EMBO Reports, 13(4), 371-377. Yamagata, K., et al. (2008). Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt. Molecular Cell, 32(2), 221-231. Yang, J. Y., et al. (2008). ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nature Cell Biology, 10(2), 138-148. | |
| 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.subject | 後轉譯修飾 | zh_TW |
| dc.subject | 大腸癌 | zh_TW |
| dc.subject | 癌幹細胞 | zh_TW |
| dc.subject | 自我更新 | zh_TW |
| dc.subject | FOXO3 | zh_TW |
| dc.subject | FOXO3 | en |
| dc.subject | cancer stem cell | en |
| dc.subject | colorectal cancer | en |
| dc.subject | self-renewal | en |
| dc.subject | posttranslational modifications | 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 |
| 顯示於系所單位： | 生化科技學系 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-106-R04b22001-1.pdf 未授權公開取用 | 8.25 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。