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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 黃敏銓 | |
| dc.contributor.author | Chiung-Hui Liu | en |
| dc.contributor.author | 劉烱輝 | zh_TW |
| dc.date.accessioned | 2021-06-07T23:47:37Z | - |
| dc.date.copyright | 2014-10-09 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-05-07 | |
| dc.identifier.citation | [1] Roderick N. M. MacSween PPA, Peter J. Scheuer, Alastair D. Burt, Bernard C. Portmann. Pathology of the Liver. 2002;3 Sub edition:711–775.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/16838 | - |
| dc.description.abstract | 細胞醣基化的改變是癌症的一項重要特徵。然而控制粘蛋白型O-聚醣合成的醣類轉換酵素core 1 β1,3-galactosyltransferase（C1GALT1）在癌症的重要性卻長期被忽略與低估。在此篇研究中我們發現C1GALT1的 mRNA和蛋白質經常在肝細胞癌（HCC）的腫瘤組織中過度表達，它的過量表現與腫瘤的高度分期、癌細胞轉移、與不良的預後呈正相關。
細胞實驗發現，強制表達C1GALT1可以提高癌細胞增生能力，而C1GALT1的核酸干擾可以抑制在體外和體內的細胞增殖。值得注意的是，在肝癌細胞中降低C1GALT1的表現可以抑制肝細胞生長因子（HGF）引發的MET激酶磷酸化，而C1GALT1過量表達可增強MET磷酸化。 使用MET抑制劑「PHA665752」可以抑制C1GALT1所增強的細胞活性。為了支持細胞實驗結果，我們分析肝癌檢體並且發現MET磷酸化和C1GALT1表達量呈現正相關。分子機轉研究顯示，毛苕子凝集素和花生凝集素的結合實驗顯示MET帶有粘蛋白型O-聚醣。此外，C1GALT1所調控的O-聚醣可以提高HGF所誘導的MET二聚化與活化。 我們進一步發現，C1GALT1的表達增強肝癌細胞粘附到細胞外基質（ECM）、細胞移動、與細胞侵襲等能力。而且C1GALT1的核酸干擾可以抑制細胞的這些表型。我們使用小鼠異種移植模型證明C1GALT1對肝癌細胞轉移有促進的作用。分子機轉的研究顯示，C1GALT1所增強的細胞粘附、移動和侵襲等能力均被細胞外基質接受器(integrin β1)的阻斷性抗體所抑制。此外，我們發現C1GALT1能夠修飾integrin β1上的粘蛋白型O-聚醣並且調控integrin β1的活性與訊息傳遞。 以上結果顯示C1GALT1在肝細胞癌中過度表達改變了癌細胞中MET與integrin β1的O-聚醣，因而增強了HGF的訊息與integrin β1的活性。此研究提供了粘蛋白型O-聚醣在肝細胞癌中新的機制與見解。 | zh_TW |
| dc.description.abstract | Glycosylation plays a crucial role in tumor progression. The core 1 β1,3-galactosyltransferase (C1GALT1) controls the formation of mucin-type O-glycans. However, the role of C1GALT1 in cancer has long been underestimated and overlooked in the past.
In this study, we identified C1GALT1 mRNA and protein were frequently overexpressed in hepatocellular carcinoma (HCC) tumors compared with non-tumor liver tissues. C1GALT1 expression correlated with advanced tumor stage, metastasis, and poor survival in HCC. Knockdown of C1GALT1 in HA22T and PLC5 cells suppressed cell growth in vitro and decreased tumor growth in vivo. Conversely, overexpression of C1GALT1 enhanced cell growth. Interestingly, we found that C1GALT1 enhanced hepatocyte growth factor (HGF)-mediated phosphorylation of MET in HCC cells, and MET blockade with PHA665752 inhibited C1GALT1-enhanced cell viability. The expression level of phospho-MET was significantly associated with that of C1GALT1 in primary HCC tissues. Mechanistic investigation showed that MET was decorated with O-glycans. Moreover, C1GALT1 modified the O-glycosylation on MET and enhanced HGF-induced dimerization. In addition, we found that overexpression of C1GALT1 enhanced HCC cell adhesion, migration, and invasion, whereas RNAi-mediated knockdown of C1GALT1 suppressed these phenotypes. In animal models, C1GALT1 significantly promoted lung metastasis of HCC cells. Mechanistic investigations showed that the C1GALT1-enhanced adhesion, migration, and invasion were significantly suppressed by anti-integrin β1 blocking antibody. Moreover, C1GALT1 was able to modify O-glycans on integrin β1 and regulate integrin β1 activity as well as FAK signaling. Together, our results suggested that C1GALT1 contributed to the malignant growth of HCC cells and regulated MET and integrin β1 O-glycosylation and activation. This study provided new insights into how O-glycosylation drives HCC pathogenesis. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-07T23:47:37Z (GMT). No. of bitstreams: 1 ntu-103-D99446005-1.pdf: 1909063 bytes, checksum: c5cc35ad994c5d7021baa8f7016801da (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | Contents
口試委員審定書 i 誌謝 ii 中文摘要 iii 英文摘要 iv Chapter I: General Introduction 1 1.1 Significance of Hepatocellular carcinoma 2 1.2 Glycosylayion in HCC 3 1.3 Mucin-type O-glycosylation in HCC 4 1.4 Biological function of C1GALT1 6 Chapter II: Hypothesis and Specific Aims 7 2.1 Hypothesis 8 2.2 Specific Aims 8 Chapter III: Materials and Methods 9 3.1 Ethics Statement 10 3.2 Human tissue samples 10 3.3 Cell culture 10 3.4 Reagents and antibodies 11 3.5 Tissue array and immunohistochemistry 12 3.6 cDNA synthesis and quantitative real-time PCR 12 3.7 Transfection 13 3.8 RNA interference 13 3.9 Western blotting 14 3.10 Phospho- receptor tyrosine kinase (RTK) array 14 3.11 Cell viability, proliferation, and cell cycle 15 3.12 Cell migration and invasion assay 15 3.13 Cell adhesion assay 16 3.14 Flow cytometry assays 17 3.15 De-glycosylation, lectin pull down, and immunoprecipitation 17 3.16 Tumor growth in immunodeficient mice 18 3.17 Dimerization of MET 18 3.18 Statistical analysis 19 Chapter IV: Results 20 4.1 C1GALT1 is up-regulated in HCC and associated with advanced tumor stage, metastasis, and poor overall survival 21 4.2 Expression of C1GALT1 modifies mucin-type O-glycans on HCC cells 22 4.3 Expression of C1GALT1 regulates proliferation of HCC cell in vitro and in vivo 24 4.4 C1GALT1 modulates activation of MET 25 4.5 Mucin type O-glycans on MET 26 4.6 C1GALT1 modifies MET glycosylation and HGF-induced dimerization 27 4.7 Expression of C1GALT1 promotes HCC cell adhesion, migration, and, invasion. 28 4.8 C1GALT1 regulates HCC cell metastasis in NOD/SCID mice 29 4.9 Integrin β1 mediates the C1GALT1-induced migration, invasion, and adhesion in HCC cells 30 4.10 C1GALT1 modifies integrin β1 glycosylation and activation 31 Chapter V: Disscusion 34 5.1 Summary 35 5.2 Short mucin-type O-glycans in HCC 35 5.3 O-glycans on MET 36 5.4 O-glycans on integrin β1 38 5.5 Conclusion 40 Reference 42 Figures and legends 48 Tables 78 Appendix 80 Figures Figure 1. Biosynthesis of core 1 O-glycans 48 Figure 2. Expression of C1GALT1 in human HCC 49 Figure 3. Statistic result of C1GALT1 expression in two independent groups of patient 50 Figure 4. Kaplan-Meier analysis of the probabilities of overall survival for patients 51 Figure 5. Expression of C1GALT1 in normal liver tissues and HCC cell lines 52 Figure 6. C1GALT1 knockdown or overexpression in HCC cells 53 Figure 7. Effects of C1GALT1 on O-glycans of hepatocellular carcinoma cell surface 55 Figure 8. C1GALT1 modulates O-glycan structures on cell surfaces of HCC cells 56 Figure 9. C1GALT1 regulates hepatocellular carcinoma cell proliferation in vito 58 Figure 10. C1GALT1 regulates cell cycle 59 Figure 11. Establishment of stable transfectants of C1GALT1 knockdown cells 60 Figure 12. Effects of C1GALT1 on hepatocellular carcinoma tumor growth in SCID mouse model 61 Figure 13. Cell proliferation in the Xenograft tumors 62 Figure 14. Human phospo-RTK array 63 Figure 15. C1GALT1 modulates HGF-induced signaling in HCC cells 64 Figure 16. Effects of MET inhibitor, PHA665752, on C1GALT1-enhanced cell viability 65 Figure 17. Expression of C1GALT1 and p-MET in hepatocellular carcinoma tissues 66 Figure 18. c-MET is decorated with short O-glycans 67 Figure 19. C1GALT1 modifies O-glycosylation of MET in HCC cells 68 Figure 20. C1GALT1 regulates dimerization of MET in HCC cells 69 Figure 21. C1GALT1 regulates cell adhesion, migration, and invasion 70 Figure 22. C1GALT1 regulates lung metastasis of HCC cells in NOD/SCID mice 72 Figure 23. Expression of integrin family genes in HCC cell lines 73 Figure 24. C1GALT1 induces HCC cell adhesion, migration and invasion through integrin β1 74 Figure 25. C1GALT1 modifies O-glycans on integrin β1 75 Figure 26. C1GALT1 regulates integrin β1 activity 76 Figure 27. C1GALT1 regulated integrin β1-induced FAK activation 77 | |
| dc.language.iso | en | |
| dc.title | 醣類轉換酵素C1GALT1在肝細胞癌的功能 | zh_TW |
| dc.title | The role of C1GALT1 in hepatocellular carcinoma | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 吳耀銘,李明學,賴逸儒,陳?豪 | |
| dc.subject.keyword | 肝細胞癌,醣類轉換酵素,粘蛋白型O-聚醣,肝細胞生長因子,細胞外基質接受器, | zh_TW |
| dc.subject.keyword | hepatocellular carcinoma,C1GALT1,O-glycosylation,MET,integrin β1,metastasis, | en |
| dc.relation.page | 80 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2014-05-07 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 解剖學暨細胞生物學研究所 | zh_TW |
| 顯示於系所單位： | 解剖學暨細胞生物學科所 | |
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