請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/44749完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 鄭永銘 | |
| dc.contributor.author | Yun-Chu Wang | en |
| dc.contributor.author | 王韻筑 | zh_TW |
| dc.date.accessioned | 2021-06-15T03:54:06Z | - |
| dc.date.available | 2010-09-09 | |
| dc.date.copyright | 2010-09-09 | |
| dc.date.issued | 2010 | |
| dc.date.submitted | 2010-06-29 | |
| dc.identifier.citation | 1. El-Serag H & Rudolph K (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132(7):2557-2576.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/44749 | - |
| dc.description.abstract | 許多microRNA (miRNA) 於人類癌症中常受抑制，如let-7 miRNA 家族。let-7 miRNA 家族除了調節癌細胞的自體更新(self-renewal)及腫瘤形成能力(tumorigenecity)外，於胚胎發育中也扮演重要角色。最近研究發現RNA結合蛋白(RNA-binding protein) Lin-28及Lin-28B會透過let-7的前趨物(precursor)於末端之尿嘧啶化(uridylation)並使之分解，以致let-7生合成減少。在肝癌細胞中，我們發現只有Lin-28B會高度表現，而Lin-28並沒有此現象。此外，Lin-28B較常表現於高度表現α胎兒蛋白並且分級(grade)較高的肝癌。於肝癌細胞株中，Hep3B及HCC36所表現的Lin-28B量最多，因此我們選擇這兩株細胞株為研究之用。我們利用RNA干擾的方式將其Lin-28B 敲減(knockdown)。利用轉殖Lin-28B載體，使Lin-28B過度表現於HA22T。Lin-28B被knockdown的細胞株Hep3B及HCC36在體外增生的速度降低。Lin-28B敲減的Hep3B細胞株在免疫不全小鼠(NOD/SCID mice)生成腫瘤的速率也下降。相反地，Lin-28B過度表現的HA22T細胞生長速度較快，且生成腫瘤的能力也較高。我們也發現過度表現Lin-28B的HA22T會引起上皮-間質轉化(Epithelial-mesenchymal transition)，而使其侵犯(invasion)及移動(migration)能力皆提高。由於Lin-28B與let-7 miRNA的密切關係，我們以大規模即時PCR陣列(Large-scale real-time PCR array)進一步研究，分析顯示Lin-28B所調節最主要的miRNA是let-7/mir-98家族。Lin-28B過度表現會使let-7所抑制的基因c-myc及HMGA2表現量增加； Lin-28B過度表現也會使受let-7控制的第一型類胰島素成長因子受體(IGF1R)表現量上升。我們的研究結果顯示，透過共同抑制let-7/mir-98家族及許多致癌基因途徑，Lin-28B於肝癌腫瘤形成及轉移扮演著重要的角色。 | zh_TW |
| dc.description.abstract | In human cancers, multiple members of microRNAs (miRNA) are often repressed, such as the let-7 family miRNA. The let-7 family regulates self-renewal and tumorigenicity of cancer cells, and plays critical roles in embryonic development. The RNA binding proteins Lin-28 and Lin-28B are recently demonstrated to negatively regulate let-7 biogenesis by inducing terminal uridylation and degradation of the let-7 precursors. In this study, we showed that in hepatocellular carcinoma (HCC), only Lin-28B but not Lin-28 was highly expressed. Lin-28B expression in HCC was more frequently found in high grade tumors with high α-fetoprotein levels. Among the HCC cell lines, Hep3B and HCC36 expressed higher levels of Lin-28B than the other cell lines, and were chosen for gene knockdown of Lin-28B. HA22T cell line which had very low level or undetectable Lin-28B, was chosen for ectopic expression of Lin-28B. Knockdown of Lin-28B by RNA interference in the Hep3B and HCC36 led to suppressed proliferation in vitro and reduced in vivo tumor growth in NOD/SCID mice. In contrast, overexpression of Lin-28B in HA22T enhanced proliferation and tumorigenecity. Moreover, overexpression of Lin-28B induced epithelial-mesenchymal transition in HA22T cells, accompanied by increased invasion and migration capacity. To further delineate the role of Lin-28B in the expression of miRNA family, we did a large-scale real-time PCR array analysis. The results revealed that only let-7/mir-98 family members were regulated by Lin-28B. Lin-28B overexpression enhanced the expression of the known let-7 targets c-myc and HMGA2. In this study, we also found that Lin-28B enhanced the expression of type 1 insulin-like growth factor receptor (IGF1R) in a let-7-dependent manner. These findings highlight the important role for Lin-28B in tumor formation and invasion in HCC, through coordinated repression of the let-7/mir-98 family and induction of multiple oncogenic pathways. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T03:54:06Z (GMT). No. of bitstreams: 1 ntu-99-R97444008-1.pdf: 5207538 bytes, checksum: 638660603bb1f5f0d5e3010235f6f425 (MD5) Previous issue date: 2010 | en |
| dc.description.tableofcontents | 誌謝 II
中文摘要 III ABSTRACT V CONTENTS VII 1. INTRODUCTION 1 1.1 Hepatocellular carcinoma (HCC) 1 1.2 MicroRNA 5 1.3 Let-7/mir-98 family miRNA 6 1.4 Lin-28 and Lin-28B 8 1.5 Epithelial-mesenchymal transition or transformation (EMT) 11 2. MATERIAL AND METHODS 13 2.1 Cell culture 13 2.2 Construction of the Lin28B vector 13 2.3 Transfection and viral infection 14 2.4 RNA interference 14 2.5 RNA isolation 15 2.6 RT-PCR 15 2.7 Western Blot 16 2.8 In vitro Boyden chamber Invasion Assay 18 2.9 Cell proliferation assay (MTT assay) 18 2.10 Soft agar assay 19 2.11 Tumorigenecity assay 19 2.12 Wound-healing Assay 20 3. RESULTS 21 3.1 Lin-28B but not Lin-28 is overexpressed in HCC 21 3.2 Lin-28B is highly expressed in Hep3B and HCC36 21 3.3 Knockdown of Lin-28B in Hep3B and HCC36 reduced proliferation rate, anchorage-independent growth and tumorigenecity. 22 3.4 Lin-28B-overexpressing HA22T enhanced proliferation, anchorage- independent growth ability and tumorigenecity. 23 3.5 Lin-28B-overexpressing HA22T has morphology change. 24 3.6 Lin-28B enhances epithelial-mesenchymal transition and tumor invasion. 25 3.7 In HCC, let-7/mir-98 family is the major target of Lin-28B. 26 3.8 Lin-28B activates several oncogenic pathways through the reduction of let-7 family. 27 4. DISCUSSION AND CONCLUSIONS 29 5. FIGURES AND TABLE 35 Text-Figure 1. The model for the biogenesis and post-transcriptional processing of microRNAs and small interfering RNAs. 35 Text-Figure 2. The amino acid sequence and structure of Lin-28 and Lin-28B 36 Figure 1. Measurement of Lin-28 and Lin-28B mRNA expression in HCC by RT-PCR. 37 Table 1. Clinicopathologic significance of Lin-28B expression in HCC 39 Figure 2. Lin-28B expression in the tumor did not affect the survival of HCC patients. 40 Figure 3. Measurements of Lin-28B expression in HCC cell lines by RT-PCR and Western blot. 41 Figure 4. Knockdown of Lin-28B in HCC cell lines using the small hairpin RNA (shRNA) in lentiviral vector pLKO.1 against different Lin-28B sequences. 43 Figure 5. Cell proliferation ability of Hep3B was determined using MTT assay. 44 Figure 6. The soft agar assay for Hep3B cells. 45 Figure 7. The tumorigenecity of Hep3B implanted subcutaneously to NOD/SCID mice. 48 Figure 8. Cell proliferation ability of HCC36 was determined using MTT assay. 49 Figure 9. Knockdown of Lin-28B in Huh7-vgh also decrease anchorage independent growth ability and the in vivo tumorigenecity. 51 Figure 10. Knockdown of Lin-28B in SK-Hep1 also decrease proliferation rate, anchorage independent growth ability and the tumorigenecity. 54 Figure 11. Determination of the percentage of CD44 positive cells by flow cytometry. 55 Figure 12. Lin-28B overexpression in HA22T. 56 Figure 13. Cell proliferation ability of HA22T was determined using MTT assay. 57 Figure 14. The soft agar assay for HA22T. 58 Figure 15. The tumorigenecity of HA22T implanted subcutaneously to NOD/SCID mice. 60 Figure 16. Morphology change of Lin-28B-overexpressing HA22T. 62 Figure 17. Western blot analysis of EMT markers. 63 Figure 18. Lin-28B overexpresion in MB231 also enhances vimentin expression. 64 Figure 19. Wound-healing assay 65 Figure 20. Boyden chamber assay 67 Figure 21. Large-scale real-time PCR array analyzed the miRNA expression profile of HA22T cells with Lin-28B and vector control. 68 Figure 22. Western blot analysis of the targets of let-7. 69 Figure 23. Luciferase assay reveals only site 1 and 3 were enhanced by Lin-28B overexpression. 70 Figure 24. The RTK array analysis of HA22T overexpressing Lin-28B. 71 Figure 25. Aberrant expression of Lin-28B in HCC enhances tumor growth, EMT, and invasion. 72 6. REFERENCE 73 | |
| dc.language.iso | en | |
| dc.subject | 侵犯 | zh_TW |
| dc.subject | 肝細胞癌 | zh_TW |
| dc.subject | let-7 | zh_TW |
| dc.subject | Lin-28B | zh_TW |
| dc.subject | 轉形 | zh_TW |
| dc.subject | Hepatocellular carcinoma(HCC) | en |
| dc.subject | transformation | en |
| dc.subject | Lin-28B | en |
| dc.subject | let-7 | en |
| dc.subject | invasion | en |
| dc.title | Lin-28B表現會引起肝細胞癌的轉形及侵犯 | zh_TW |
| dc.title | Lin-28B expression promotes transformation and invasion in human hepatocellular carcinoma | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 98-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 許輝吉,張?仁,葉秀慧,周涵怡 | |
| dc.subject.keyword | 肝細胞癌,let-7,Lin-28B,轉形,侵犯, | zh_TW |
| dc.subject.keyword | Hepatocellular carcinoma(HCC),let-7,Lin-28B,transformation,invasion, | en |
| dc.relation.page | 82 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2010-06-30 | |
| 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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