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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 黃楓婷 | zh_TW |
| dc.contributor.author | 杜婉菁 | zh_TW |
| dc.contributor.author | Wan-Ching Tu | en |
| dc.date.accessioned | 2021-07-10T21:58:08Z | - |
| dc.date.available | 2024-07-29 | - |
| dc.date.copyright | 2019-07-29 | - |
| dc.date.issued | 2019 | - |
| dc.date.submitted | 2002-01-01 | - |
| dc.identifier.citation | Abbas, T., & Dutta, A. (2009). p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer, 9(6), 400-414. doi:10.1038/nrc2657
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77360 | - |
| dc.description.abstract | 缺乏運動和肥胖與提高罹患大腸直腸癌的風險之間具有相當密切的關聯，研究也顯示運動可以降低罹患大腸直腸癌的機率並延緩癌症的進程。然而，運動如何預防癌症發展的機制尚不清楚。近年的研究發現，irisin是一種運動時肌肉細胞所分泌出來的肌肉激素，irisin會作用於白色脂肪細胞並促進脂肪細胞的褐化以減少肥胖的情況。研究發現irisin會抑制多種類癌細胞的細胞侵襲、遷移和增生的能力。因此本篇論文的研究目的為探討irisin對於不同時期的人類大腸直腸癌細胞的影響及其分子機制。在本篇研究中，以大腸桿菌和酵母菌來表現人類irisin重組蛋白質，並探討irisin對於人類大腸直腸癌細胞的影響。我們的結果顯示irisin會降低大腸直腸癌細胞的增生能力，但不影響正常大腸細胞的增生，irisin也會抑制大腸直腸癌細胞的侵襲能力，但不影響細胞遷移。Irisin會藉由誘導週期蛋白依賴性激酶 (CDK) 的抑制劑p21的表現和抑制細胞週期調控因子cdc2的活化，以促使大腸直腸癌細胞的細胞週期停滯於S和G2期，進而降低細胞的增生能力。接著我們進一步探討irisin如何透過分子機制來調控對於癌細胞生理功能的影響，我們的結果顯示irisin會結合到大腸直腸癌細胞表面，並進一步抑制兩個在整合素 (integrin) 所觸發的信息傳導路徑中的重要分子FAK和AKT的磷酸化。而結果亦顯示irisin可能會結合到細胞表面的integrin β4，並藉由integrin β4來調控對於大腸直腸癌細胞增生能力的影響。此外我們也利用轉錄體學分析來鑑定出irisin所調控的基因，並藉由小分子干擾RNA (siRNA) 來抑制所篩選出的基因表現以評估該基因所參與調控的生理功能，結果顯示irisin會藉由誘導癌細胞轉移抑制因子 (metastasis suppressor) NDRG1的表現來抑制大腸直腸癌細胞的侵襲能力。總結上述的結果，本篇論文提議irisin可以延緩大腸直腸癌惡化的進程，並且具有發展為用於大腸直腸癌治療藥物的潛力。 | zh_TW |
| dc.description.abstract | Insufficient physical activity and obesity are strongly linked to the increased risk of colorectal cancer (CRC). Epidemiological studies also indicate that exercise can reduce the risk of CRC and delay cancer progression. However, the underlying mechanism of how exercise prevents cancer development is still unclear. Recently, irisin is discovered as a myokine released from muscle cells during exercise. Irisin targets white adipocytes and promotes browning of adipocytes to reduce obesity. Several studies found that irisin inhibits cell invasion, migration and proliferation in various types of cancer cells. Thus, the research purpose of this thesis is to study the effect and the molecular mechanism of irisin on different stages of human CRC cells. In this research, recombinant human irisin was produced in E.coli and Pichia pastoris, and its effects on CRC cells were investigated. Our results showed that irisin reduced cell proliferation of CRC cells, but did not affect normal colon cells. Irisin also inhibited cell invasion of CRC cells, but did not affect cell migration. Irisin induced the expression of p21 and inhibited the activation of cdc2, a cell cycle regulator, and further contributed to S and G2 phase arrest of cell cycle in CRC cells to reduce cell proliferation. We further investigated the molecular mechanism of how irisin mediates effects on cancer cells. Our results showed irisin bound to the cell surface of CRC cells and further inhibited phosphorylation of FAK and AKT which are key components of the signal transduction pathway triggered by integrins. Irisin might bind to integrin β4 on the cell surface and mediate effects on CRC cells. Moreover, transcriptome NGS analysis was performed to identify irisin-regulated genes, and the biological function of the selected gene was assessed by siRNA knockdown. The results showed that irisin inhibited cell invasion of CRC cells by inducing the expression of NDRG1 which is known as a metastasis suppressor. In conclusion, we proposed that irisin could delay CRC progression and might be a potential target of CRC treatment. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-10T21:58:08Z (GMT). No. of bitstreams: 1 ntu-108-R06b22021-1.pdf: 6217842 bytes, checksum: 891549917f24d87d1e7bd03c7f903fbc (MD5) Previous issue date: 2019 | en |
| dc.description.tableofcontents | 謝辭 i
中文摘要 ii Abstract iii Abbreviations v Table of contents vi Chapter 1 Introduction 1 1.1 Colorectal cancer 1 1.2 Exercise and colorectal cancer 2 1.3 Exercise-induced cytokines and myokines 2 1.4 Irisin 3 1.4.1 Characteristics and biological functions of irisin 3 1.4.2 The role of irisin in cancer 4 1.5 Cell cycle regulators 4 1.6 Integrins and downstream signaling 6 1.7 N-myc downstream-regulated gene 1 (NDRG1) 8 1.8 Research purpose 9 Chapter 2 Material and methods 11 2.1 Recombinant protein preparation 11 2.1.1 E.coli BL21(DE3) expression system 11 2.1.2 Protein induction 11 2.1.3 Purification and condensation 11 2.1.4 Endotoxin removal and quantification 12 2.1.5 Protein induction and purification from Pichia pastoris expression system 13 2.2 Cell culture 13 2.2.1 HCT 116 cell line 13 2.2.2 DLD-1 cell line 14 2.2.3 SW480 cell line 14 2.2.4 CCD841 CoN cell line 14 2.3 Transwell invasion assay 14 2.4 Transwell migration assay 15 2.5 Cell proliferation analysis 15 2.6 Apoptosis analysis 16 2.7 Cell cycle analysis 16 2.8 FITC-protein binding assay 17 2.8.1 Labeling FITC to irisin 17 2.8.2 Binding of FITC-labeled irisin to cell 17 2.8.3 Quantification of FITC-labeled irisin bound cells by flow cytometry 17 2.9 Flow cytometry analysis on cell surface integrin expression 18 2.10 Cellular protein extraction 19 2.11 Electrophoresis and western blotting 19 2.12 Transcriptome analysis 20 2.12.1 RNA sample preparation 20 2.12.2 Next generation sequencing 20 2.12.3 Bioinformatics analysis 20 2.13 RNA interference 21 2.14 Statistical analysis 21 Chapter 3 Results 22 3.1 Recombinant human irisin preparation 22 3.2 Irisin inhibited cell invasion of colorectal cancer cells 22 3.3 Irisin inhibited cell proliferation of colorectal cancer cells 23 3.4 Irisin reduced colorectal cancer cell proliferation by inducing cell cycle alteration 24 3.4.1 Irisin affected cell cycle distribution 24 3.4.2 Irisin induced p21 expression in a p53-independent manner and might cause cell cycle regulation in HCT 116 and DLD-1 cells 25 3.4.3 Irisin increased the phosphorylation level of cdc2 in SW480 cells 26 3.5 Irisin bound to the cell surface of colorectal cancer cells 26 3.6 Irisin seemed not to mediate effects on colorectal cancer cells via integrin αVβ5 28 3.7 Irisin might mediate effects on colorectal cancer cells via integrin β4 29 3.8 Irisin inhibited FAK and AKT signaling pathways 31 3.9 Identification of other pathways and genes regulated by irisin by transcriptome analysis 32 3.10 Irisin induced the protein expression of heme oxygenase-1 33 3.11 The role of NDRG1 in irisin-induced effects on colorectal cancer cells 34 Chapter 4 Discussion 36 4.1 Irisin induced cell cycle arrest of colorectal cancer cells 36 4.2 The possible irisin receptors on cancer cells and the downstream signaling pathway affected by irisin 37 4.3 The transcriptome analysis of irisin-treated colorectal cancer cells 39 4.4 The role of heme oxygenase-1 in cancer cells 39 4.5 The role of NDRG1 in cancer cells 40 Chapter 5 Summary and future prospects 41 Chapter 6 Reference list 43 Figures 48 Figure 1. The purified recombinant human irisin produced by E.coli BL21(DE3) and Pichia pastoris expression system 49 Figure 2. Irisin inhibited cell invasion ability of colorectal cancer cells 53 Figure 3. Irisin did not affect cell migration of colorectal cancer cells 55 Figure 4. Irisin inhibited cell proliferation of colorectal cancer cells, but did not affect normal cells 57 Figure 5. Irisin did not affect cell apoptosis of colorectal cancer cells 59 Figure 6. Irisin induced S and G2/M phase arrest of cell cycle in colorectal cancer cells 64 Figure 7. The protein levels of cell cycle regulatory proteins in irisin-treated HCT 116 cells 68 Figure 8. The protein levels of cell cycle regulatory proteins in irisin-treated DLD-1 cells 71 Figure 9. The protein levels of cell cycle regulatory proteins in irisin-treated SW480 cells 74 Figure 10. Irisin bound to the cell surface of colorectal cancer cells 77 Figure 11. Quantification of FITC-labeled irisin bound to cell surface of colorectal cancer cells 78 Figure 12. Irisin seemed not to mediate effects on colorectal cancer cells via integrin αvβ5 80 Figure 13. The expression levels of integrins on colorectal cancer cells and normal cells 84 Figure 14. Irisin might mediate effects of colorectal cancer cells via integrin β4 88 Figure 15. Irisin decreased phosphorylation levels of FAK and AKT 91 Figure 16. Gene expression pattern of colorectal cancer cells with irisin treatment by transcriptome analysis 93 Figure 17. Gene ontology analysis of colorectal cancer cells with irisin treatment 96 Figure 18. Irisin induced the protein expression of heme oxygenase-1 in HCT 116 cells 98 Figure 19. The effects of irisin on cell proliferation and invasion of NDRG1-knockdown HCT 116 cells 101 Figure 20. Proposed model of the molecular mechanisms of irisin-regulated effects on colorectal cancer cells 102 Appendixes 103 1. Antibodies 104 2. The Silencer® Select siRNA duplex (Ambion) sequences 104 3. mRNA expression levels of integrin encoded genes 105 | - |
| dc.language.iso | en | - |
| dc.subject | 大腸直腸癌 | zh_TW |
| dc.subject | irisin | zh_TW |
| dc.subject | 細胞增生 | zh_TW |
| dc.subject | 細胞週期停滯 | zh_TW |
| dc.subject | 細胞侵襲 | zh_TW |
| dc.subject | irisin | en |
| dc.subject | colorectal cancer | en |
| dc.subject | cell invasion | en |
| dc.subject | cell cycle arrest | en |
| dc.subject | cell proliferation | en |
| dc.title | 探討 Irisin 對人類大腸直腸癌之影響與其分子機制 | zh_TW |
| dc.title | Study the Effect and the Molecular Mechanism of Exercise-Induced Irisin on Human Colorectal Cancer | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 107-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 周綠蘋;冀宏源;廖憶純;陳彥榮 | zh_TW |
| dc.contributor.oralexamcommittee | ;;; | en |
| dc.subject.keyword | 大腸直腸癌,irisin,細胞增生,細胞週期停滯,細胞侵襲, | zh_TW |
| dc.subject.keyword | colorectal cancer,irisin,cell proliferation,cell cycle arrest,cell invasion, | en |
| dc.relation.page | 105 | - |
| dc.identifier.doi | 10.6342/NTU201901756 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2019-07-22 | - |
| dc.contributor.author-college | 生命科學院 | - |
| dc.contributor.author-dept | 生化科技學系 | - |
| 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-107-2.pdf 未授權公開取用 | 6.07 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。