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DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 黃敏銓 | zh_TW |
dc.contributor.advisor | Min-Chuan Huang | en |
dc.contributor.author | 陳柏達 | zh_TW |
dc.contributor.author | Po-Da Chen | en |
dc.date.accessioned | 2024-02-22T16:47:16Z | - |
dc.date.available | 2024-02-23 | - |
dc.date.copyright | 2024-02-22 | - |
dc.date.issued | 2024 | - |
dc.date.submitted | 2024-01-24 | - |
dc.identifier.citation | 1.Villanueva, A., Hepatocellular Carcinoma. N Engl J Med, 2019. 380(15): p. 1450-1462.
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Hepatol Commun, 2022. 6(4): p. 652-664. 7.Zhang, J., et al., Identifying cancer-associated fibroblasts as emerging targets for hepatocellular carcinoma. Cell Biosci, 2020. 10(1): p. 127. 8.Becchetti, A. and A. Arcangeli, Integrins and ion channels in cell migration: implications for neuronal development, wound healing and metastatic spread. Adv Exp Med Biol, 2010. 674: p. 107-23. 9.Ozaki, I., et al., Differential expression of laminin receptors in human hepatocellular carcinoma. Gut, 1998. 43(6): p. 837-42. 10.Fu, B.H., Z.Z. Wu, and C. Dong, Integrin beta1 mediates hepatocellular carcinoma cells chemotaxis to laminin. Hepatobiliary Pancreat Dis Int, 2004. 3(4): p. 548-51. 11.Fu, B.H., Z.Z. Wu, and J. Qin, Effects of integrin alpha6beta1 on migration of hepatocellular carcinoma cells. Mol Biol Rep, 2011. 38(5): p. 3271-6. 12.Marsico, G., et al., Glycosylation and Integrin Regulation in Cancer. 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Schetters, and Y. van Kooyk, The tumour glyco-code as a novel immune checkpoint for immunotherapy. Nat Rev Immunol, 2018. 18(3): p. 204-211. 20.Bydlinski, N., et al., The contributions of individual galactosyltransferases to protein specific N-glycan processing in Chinese Hamster Ovary cells. J Biotechnol, 2018. 282: p. 101-110. 21.Chen, J., et al., Expression of Notch signaling pathway genes in mouse embryos lacking beta4galactosyltransferase-1. Gene Expr Patterns, 2006. 6(4): p. 376-82. 22.Giannini, S., et al., beta4GALT1 controls beta1 integrin function to govern thrombopoiesis and hematopoietic stem cell homeostasis. Nat Commun, 2020. 11(1): p. 356. 23.Sato, T., et al., Molecular cloning of a human cDNA encoding beta-1,4-galactosyltransferase with 37% identity to mammalian UDP-Gal:GlcNAc beta-1,4-galactosyltransferase. 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Xie, B4GalT1 Regulates Apoptosis and Autophagy of Glioblastoma In Vitro and In Vivo. Technol Cancer Res Treat, 2020. 19: p. 1533033820980104. 30.Ren, Z., et al., High expression of B4GALT1 is associated with poor prognosis in acute myeloid leukemia. Front Genet, 2022. 13: p. 882004. 31.Chen, X., et al., Gene expression patterns in human liver cancers. Mol Biol Cell, 2002. 13(6): p. 1929-39. 32.Roessler, S., et al., A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients. Cancer Res, 2010. 70(24): p. 10202-12. 33.Huang, W., et al., ITGBL1 promotes cell migration and invasion through stimulating the TGF-beta signalling pathway in hepatocellular carcinoma. Cell Prolif, 2020. 53(7): p. e12836. 34.Kim, Y.R., M.R. Byun, and J.W. Choi, Integrin alpha6 as an invasiveness marker for hepatitis B viral X-driven hepatocellular carcinoma. 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FEBS Open Bio, 2020. 10(12): p. 2750-2760. 41.Cai, X., et al., The importance of N-glycosylation on beta(3) integrin ligand binding and conformational regulation. Sci Rep, 2017. 7(1): p. 4656. 42.Gu, J. and N. Taniguchi, Regulation of integrin functions by N-glycans. Glycoconj J, 2004. 21(1-2): p. 9-15. 43.Isaji, T., et al., N-glycosylation of the I-like domain of beta1 integrin is essential for beta1 integrin expression and biological function: identification of the minimal N-glycosylation requirement for alpha5beta1. J Biol Chem, 2009. 284(18): p. 12207-16. 44.Nagae, M., et al., 3D Structure and Function of Glycosyltransferases Involved in N-glycan Maturation. Int J Mol Sci, 2020. 21(2). 45.Wu, Y., et al., Targeting integrins in hepatocellular carcinoma. Expert Opin Ther Targets, 2011. 15(4): p. 421-37. 46.Torimura, T., et al., Coordinated expression of integrin alpha6beta1 and laminin in hepatocellular carcinoma. Hum Pathol, 1997. 28(10): p. 1131-8. 47.Fu, B.H., Z.Z. Wu, and J. Qin, Effects of integrins on laminin chemotaxis by hepatocellular carcinoma cells. Mol Biol Rep, 2010. 37(3): p. 1665-70. 48.Lv, G., et al., RNA interference targeting human integrin alpha6 suppresses the metastasis potential of hepatocellular carcinoma cells. Eur J Med Res, 2013. 18(1): p. 52. 49.Patman, G., Liver: loss of integrin beta1 impairs liver regeneration and HCC progression. Nat Rev Gastroenterol Hepatol, 2014. 11(7): p. 392. 50.Hou, W., et al., Integrin subunit beta 8 contributes to lenvatinib resistance in HCC. Hepatol Commun, 2022. 6(7): p. 1786-1802. 51.Slack, R.J., et al., Emerging therapeutic opportunities for integrin inhibitors. Nat Rev Drug Discov, 2022. 21(1): p. 60-78. 52.Dhaliwal, D. and T.G. Shepherd, Molecular and cellular mechanisms controlling integrin-mediated cell adhesion and tumor progression in ovarian cancer metastasis: a review. Clin Exp Metastasis, 2022. 39(2): p. 291-301. | - |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/91801 | - |
dc.description.abstract | Beta1,4-半乳糖轉移酶(B4GALTs)在各種疾病中扮演關鍵角色,包括癌症。其中,B4GALT1在肝臟中高度表達,而患有B4GALT1基因突變的人通常會罹患肝病。然而,B4GALT1對肝癌的影響長期以來一直未明確。在這項研究中,我們發現相對於相鄰的正常肝組織,肝細胞癌組織中B4GALT1明顯下降。此外,我們還發現低B4GALT1表現與肝細胞癌患者的血管侵犯性增加以及整體存活率下降有關。進一步的研究顯示,B4GALT1的沉默或缺失增加了體外肝細胞癌細胞的遷移和侵犯性,並在小鼠中促使肺轉移。值得注意的是,我們的研究揭示了B4GALT1影響肝細胞癌細胞與laminin層黏蛋白的黏附之間的聯繫。B4GALT1的沉默或缺失增加了細胞的黏附,而B4GALT1的過度表達則產生了相反的效應。通過質譜和Griffonia simplicifolia凝集素II(GSL-II)拉下實驗,我們確定了integrin整合素α6和β1是B4GALT1的主要蛋白質受質,B4GALT1通過修改它們的N-glycan進行調控。由於B4GALT1下調,導致細胞遷移和侵犯性增強,這種效應可以通過使用抗α6或抗β1整合素的阻斷抗體明顯逆轉。這些發現表明B4GALT1的下調導致N-glycan修飾的改變,提高了整合素α6和β1對層黏蛋白的結合能力,從而促進了肝細胞癌細胞的侵犯性。整體而言,我們的研究增加了對B4GALT1在肝細胞癌轉移的作用的理解,並指出針對B4GALT1表達下降的肝細胞癌患者,以層黏蛋白-整合素作為潛在治療策略的重要性。 | zh_TW |
dc.description.abstract | Beta-1,4-galactosyltransferases, particularly B4GALT1, are crucial enzymes implicated in various diseases, including cancer. B4GALT1''s high expression in the liver and its association with liver diseases is established, but its role in liver cancer has been uncertain. This investigation reveals that B4GALT1 is significantly underexpressed in hepatocellular carcinoma (HCC) compared to non-cancerous liver tissue. This downregulation correlates with more pronounced vascular invasion and a poorer overall survival rate for those affected by HCC. Experimentally, B4GALT1 inhibition or elimination heightened HCC cell migratory and invasive behavior in vitro, and also increased the occurrence of lung metastases in animal models. Furthermore, B4GALT1 was found to be intricately linked to cell adhesion to laminin; reductions in B4GALT1 facilitated cellular adhesion, while its overexpression reduced it. Integrins α6 and β1 were pinpointed as primary substrates altered by B4GALT1 via N-glycosylation, a process discernible through mass spectrometry and lectin pull-down assays. Counteracting the effects of reduced B4GALT1 on cell movement and invasiveness was possible by employing antibodies against integrins α6 or β1. Overall, the study posits that diminished B4GALT1 expression contributes to the invasive potential of HCC cells by affecting the N-glycosylation and hence the binding dynamics of integrin-laminin. Consequently, this research not only advances our understanding of B4GALT1''s role in HCC metastasis but also highlights targeting integrin-laminin interactions as a promising therapeutic avenue for HCC patients with low B4GALT1 expression. | en |
dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2024-02-22T16:47:16Z No. of bitstreams: 0 | en |
dc.description.provenance | Made available in DSpace on 2024-02-22T16:47:16Z (GMT). No. of bitstreams: 0 | en |
dc.description.tableofcontents | 口試委員會審定書 i
誌謝 ii 中文摘要 iii Abstract iv List of Figures vii List of Tables viii Chapter 1. Introduction 1 1.1 Current predicament of hepatocellular carcinoma 1 1.2 The role of extracellular matrix in hepatocellular carcinoma 1 1.3 Abnormal glycosylation and B4GALT1 in hepatocellular carcinoma 2 Chapter 2. Materials and Methods 4 2.1 Clinical samples 4 2.2 Immunohistochemistry (IHC) 4 2.3 Cell lines and cell culture 5 2.4 Transfection and plasmid construction 6 2.5 Utilizing CRISPR/Cas9 system to knockout B4GALT1 knockout in PLC5 cells 7 2.6 Mass spectrometric analysis 8 2.7 Antibodies and reagents 9 2.8 Western blot analysis 10 2.9 Experimental NOD/SCID mice model formetastasis 11 2.10 MTT assay 12 2.11 Migration (transwell) and Invasion (Matrigel) assays 13 2.12 Flow cytometry 14 2.13 Lectin pull-down assay 14 2.14 Cell adhesion assay 15 2.15 Statistical analyses 16 Chapter 3. Results 17 3.1 Lower expression levels of B4GALT1 are associated with a decline in survival outcomes for hepatocellular carcinoma patients. 17 3.2 B4GALT1 influences the oncogenic properties of HCC cells. 19 3.3 B4GALT1 impacts on the metastatic progression of HCC cells in Mice Models. 20 3.4 Systematic glycoproteomics reveals integrin β1 and α6 as protein targets of B4GALT1. 21 3.5 Involvement of B4GALT1 in the adhesive function of HCC Cells to ECM 23 3.6 Integrins β1 and α6 are central to the enhanced migration and invasion of HCC cells prompted by the suppression or elimination of B4GALT1. 25 Chapter 4. Discussion 27 Reference 32 | - |
dc.language.iso | en | - |
dc.title | B4GALT1 調節基質-整合素相互作用以控制肝細胞癌轉移 | zh_TW |
dc.title | B4GALT1 regulates the extracellular matrix-integrin interaction to control metastasis of hepatocellular carcinoma | en |
dc.type | Thesis | - |
dc.date.schoolyear | 112-1 | - |
dc.description.degree | 博士 | - |
dc.contributor.coadvisor | 吳耀銘 | zh_TW |
dc.contributor.coadvisor | Yao-Ming Wu | en |
dc.contributor.oralexamcommittee | 陳啟豪;劉炯輝;王淑慧 | zh_TW |
dc.contributor.oralexamcommittee | Chi-Hau Chen;Chiung-Hui Liu;Shu-Hui Wang | en |
dc.subject.keyword | 整合素,侵犯性,醣基化反應, | zh_TW |
dc.subject.keyword | integrin,invasion,glycosylation, | en |
dc.relation.page | 60 | - |
dc.identifier.doi | 10.6342/NTU202400222 | - |
dc.rights.note | 同意授權(全球公開) | - |
dc.date.accepted | 2024-01-24 | - |
dc.contributor.author-college | 醫學院 | - |
dc.contributor.author-dept | 解剖學暨細胞生物學研究所 | - |
顯示於系所單位: | 解剖學暨細胞生物學科所 |
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