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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/38584完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 鄭永銘 | |
| dc.contributor.author | Hsieh-Cheng Chen | en |
| dc.contributor.author | 陳協成 | zh_TW |
| dc.date.accessioned | 2021-06-13T16:38:13Z | - |
| dc.date.available | 2016-10-07 | |
| dc.date.copyright | 2011-10-07 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-07-18 | |
| dc.identifier.citation | Reference
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/38584 | - |
| dc.description.abstract | SIRT1是一個依賴菸鹼腺嘌呤雙核苷酸催化的去乙醯酵素，它在許多生物功能扮演重要的角色，包括對壓力的回應、凋亡、細胞內代謝機制、卡路里限制的適應、老化和癌化現象。我們發現SIRT1蛋白在肝癌中有過度表現的現象。SIRT1表現量多的樣本其腫瘤分級較高、腫瘤分期較晚期並且病人預後較差。SIRT1蛋白量上升並不是因為SIRT1 mRNA的上升。SIRT1蛋白表現量較高的肝癌細胞株其SIRT1蛋白半衰期較長。我們進而證實SIRT1的降解是經由依賴ubiquitin方式之26S蛋白酶的作用。SIRT1的過度表現會促進癌化現象和抵抗化學治療藥物的效力。此外，我們找到ㄧ些可能為SIRT1新標靶的蛋白質，包括視網膜脫氫酶1、核磷酸蛋白、熱休克同源蛋白71、熱休克蛋白60、異質核的核醣核蛋白K和異質核的核醣核蛋白H。我們發現抑制SIRT1活性會減少ALDH1酵素活性。 | zh_TW |
| dc.description.abstract | SIRT1 is a NAD+-dependent deacetylase that plays crucial roles in many biological processes, including stress response, apoptosis, cellular metabolism, adaptation to calorie restriction, aging, and tumorigenesis. We find that SIRT1 protein is overexpressed in hepatocellular carcinoma. High level of SIRT1 correlates with higher tumor grade and stage and predicts poor long-term survival. The elevated SIRT1 protein is not attributable to elevation of mRNA level. The half-life of SIRT1 protein is longer in cell lines with high expression of SIRT1. We further demonstrate that SIRT1 is degraded by the 26S proteasome in an ubiquitin-dependent manner. Overexpression of SIRT1 promotes tumorigenesis and resists chemotherapeutical agent. In addition, we find some candidate proteins to be novel targets of SIRT1, including retinal dehydrogenase 1, nucleophosmin, heat shock cognate 71, heat shock protein 60, stress-70, heterogeneous nuclear ribonucleoprotein K, and heterogeneous nuclear ribonucleoprotein H. We find inhibition of SIRT1 might reduce ALDH1 enzymatic activity. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T16:38:13Z (GMT). No. of bitstreams: 1 ntu-100-R98444001-1.pdf: 3674661 bytes, checksum: 48ca28a62e664e3bae1877a3ae24a54e (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | Contents
Page 口試委員審定書 I 謝辭 II 中文摘要 III Abstract IV Contents V 1. Introduction 1 1.1 Hepatocellular carcinoma 1 1.2 Sirtuins 1 1.3 SIRT1 is a longevity gene 2 1.4 Regulation of SIRT1 in stresses 5 1.5 SIRT1 involves in DNA damage repair and cellular apoptosis 6 1.6 SIRT1 and metabolism 8 1.7 SIRT1 and disease 9 1.8 SIRT1 acts as a tumor promoter 11 1.9 SIRT1 serves as a tumor suppressor 13 1.10 The specific aims 14 2. Materials and Methods 15 2.1 Cell culture 15 2.2 Plasmids, cotransfection, and retroviral infection 15 2.3 Immunohistochemical stain 16 2.4 Western blot 17 2.5 Protein half-life and degradation measurement 18 2.6 Immunoprecipitation 18 2.7 RNA isolation 19 2.8 RT-PCR 20 2.9 Real-Time RT-PCR 21 2.10 Anchorage-independent growth assay 21 2.11 Focus formation assay 22 2.12 Trypan blue assay 22 2.13 RNA interference 23 2.14 Tumor xenograft assay 23 2.15 2-D gel electrophoresis 24 2.16 In-gel digestion for protein identification 25 2.17 Mass spectrometry analysis 26 2.18 Detection of subG1 fraction 26 2.19 ALDEFLUOR assay 27 3. Results 28 3.1 SIRT1 was overexpressed in HCC and other types of cancer 28 3.2 Clinicopathologic significance of SIRT1 expression in HCC patients 28 3.3 The elevation of SIRT1 protein was not attributed to increased SIRT1 mRNA level 28 3.4 The half-life of SIRT1 protein was longer in cell lines with high SIRT1 expression 29 3.5 SIRT1 was degraded by the 26S proteasome in an ubiquitin-dependent manner 29 3.6 CDC4, an E3 ubiquitin ligase, was not responsible for SIRT1 degradation 30 3.7 SIRT1 knockdown did not change the ability of anchorage-independent growth and tumor xenograft growth 31 3.8 Overexpression of SIRT1 in HCC cell line promoted tumorigenesis 31 3.9 Overexpression of SIRT1 in HCC cell line reduced drug sensitivity through decreasing apoptosis 32 3.10 Identification of new targets for SIRT1 33 3.11 Inhibition of SIRT1 might decrease ALDH1 enzyme activity. 34 4. Discussion 35 5. Conclusion 45 6. Figures and Tables 47 Figure 1. Immunohistochemical stain of SIRT1 expression in representative hepatocellular carcinoma specimens. 47 Figure 2. Immunohistochemical stain of SIRT1 expression in various cancers specimens. 49 Figure 3. Kaplan-Meir analysis showed SIRT1 expression correlated with poor survival. 50 Figure 4. Detection of SIRT1 expression in tumor specimens and hepatocellular carcinoma cell lines using Western Blot, RT-PCR, and Real-Time RT-PCR. 52 Figure 5. The half-life of SIRT1 protein was longer in cell lines with highly expressed SIRT1. 54 Figure 6. Inhibition of SIRT1 protein degradation by proteasome inhibitor. 56 Figure 7. SIRT1 protein was ubiquitinated. 57 Figure 8. CDC4, an E3 ubiquitin ligase, was not a target for SIRT1. 58 Figure 9. Knockdown of SIRT1 in Hep3B cells did not alter anchorage-independent growth ability. 60 Figure 10. Knockdown of SIRT1 in SK-Hep1 cells did not alter anchorage-independent growth ability and tumor xenograft growth. 62 Figure 11. Knockdown of SIRT1 in A549 cells did not alter anchorage-independent growth ability and tumor xenograft growth. 64 Figure 12. Overexpression of SIRT1 increased focus formation. 66 Figure 13. Overexpression of SIRT1 by using lentiviral system also increased focus formation. 68 Figure 14. SIRT1 overexpression increased resistance to chemotherapy. 70 Figure 15. SIRT1 overexpression in other expression system also increased resistance to chemotherapy. 72 Figure 16. Overexpressioin of SIRT1 reduced the subG1 population inducing by treating doxorubicin. 74 Figure 17. Flow chart for searching the new targets for SIRT1 using proteomic assay. 76 Figure 18. Separation of proteins using two-dimensional (2D) gel electrophoresis and detection of acetylated protein using western blot. 77 Figure 19. SIRT1 specific inhibitor, EX-527, decreased ALDEFLOUR-positive population in Huh7-Wu cells. 80 Table 1. Univariate analysis of SIRT1 expression and clinicopathologic risk factors in patients with unifocal HCC. 51 Table 2. MASCOT search results 79 7. Reference 82 | |
| dc.language.iso | en | |
| dc.title | SIRT1在肝癌中過度表現並促進其癌化現象和抗藥性 | zh_TW |
| dc.title | SIRT1 overexpression in hepatocellular carcinoma promotes tumorigenesis and resistance to chemotherapy | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 99-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 林佼穎,張正琪,黃祥博 | |
| dc.subject.keyword | 肝癌,癌化現象,SIRT1,ubiquitin和ALDH1A1, | zh_TW |
| dc.subject.keyword | hepatocellular carcinoma,tumorigenesis,SIRT1,ubiquitin and ALDH1A1, | en |
| dc.relation.page | 91 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2011-07-18 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 病理學研究所 | zh_TW |
| 顯示於系所單位： | 病理學科所 | |
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