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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 郭明良(Min-Liang Kuo) | |
| dc.contributor.author | Chi-Kuan Chen | en |
| dc.contributor.author | 陳啟寬 | zh_TW |
| dc.date.accessioned | 2021-06-07T23:50:47Z | - |
| dc.date.copyright | 2014-02-25 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-01-24 | |
| dc.identifier.citation | 1. Dekervel J, van Pelt J, Verslype C. Advanced unresectable hepatocellular carcinoma: new biologics as fresh ammunition or clues to disease understanding? Curr Opin Oncol 2013;25:409-416.
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Clin Exp Metastasis 2003;20:291-300. 53. Nakopoulou L, Gakiopoulou H, Keramopoulos A, Giannopoulou I, Athanassiadou P, Mavrommatis J, Davaris PS. c-met tyrosine kinase receptor expression is associated with abnormal beta-catenin expression and favourable prognostic factors in invasive breast carcinoma. Histopathology 2000;36:313-325. 54. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol 2003;4:915-925. 55. Trusolino L, Comoglio PM. Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer 2002;2:289-300. 56. Martens T, Schmidt NO, Eckerich C, Fillbrandt R, Merchant M, Schwall R, Westphal M, et al. A novel one-armed anti-c-Met antibody inhibits glioblastoma growth in vivo. Clin Cancer Res 2006;12:6144-6152. 57. Petrelli A, Circosta P, Granziero L, Mazzone M, Pisacane A, Fenoglio S, Comoglio PM, et al. Ab-induced ectodomain shedding mediates hepatocyte growth factor receptor down-regulation and hampers biological activity. Proc Natl Acad Sci U S A 2006;103:5090-5095. 58. Michieli P, Mazzone M, Basilico C, Cavassa S, Sottile A, Naldini L, Comoglio PM. Targeting the tumor and its microenvironment by a dual-function decoy Met receptor. Cancer Cell 2004;6:61-73. 59. Matsumoto K, Nakamura T. NK4 (HGF-antagonist/angiogenesis inhibitor) in cancer biology and therapeutics. Cancer Sci 2003;94:321-327. 60. Yap TA, Sandhu SK, Alam SM, de Bono JS. HGF/c-MET targeted therapeutics: novel strategies for cancer medicine. Curr Drug Targets;12:2045-2058. 61. Christensen JG, Burrows J, Salgia R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett 2005;225:1-26. 62. Ohtomi M, Nagai H, Ohtake H, Uchida T, Suzuki K. Dynamic change in expression of LECT2 during liver regeneration after partial hepatectomy in mice. Biomed Res 2007;28:247-253. 63. Hiraki Y, Inoue H, Kondo J, Kamizono A, Yoshitake Y, Shukunami C, Suzuki F. A novel growth-promoting factor derived from fetal bovine cartilage, chondromodulin II. Purification and amino acid sequence. J Biol Chem 1996;271:22657-22662. 64. Saito T, Okumura A, Watanabe H, Asano M, Ishida-Okawara A, Sakagami J, Sudo K, et al. Increase in hepatic NKT cells in leukocyte cell-derived chemotaxin 2-deficient mice contributes to severe concanavalin A-induced hepatitis. J Immunol 2004;173:579-585. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/16952 | - |
| dc.description.abstract | 肝癌為世界上最常見的癌症之一，因其惡性進程的特性具有高復發率及不良癒後，造成肝癌不易治療且致死率居高的情況。在肝癌惡性進程中血管侵犯被認定為一臨床上重要診斷指標，因此研究調控肝癌惡性進程中血管侵犯之機轉可作為病理診斷的重要指標，並且可以此為治標地發展更有效的肝癌治療藥物。肝細胞所分泌之白血球趨化蛋白2(Leukocyte cell-derived chemotoxin 2, LECT2)為腫瘤抑制因子可以抑制肝癌的血管侵犯及惡性進程，但對於其抑制肝癌的詳細機轉迄今不明。為了更進一步地去了解LECT2抑制肝癌血管侵犯及惡性進程的機轉，我們利用親核性管柱層析法搭配液相層析串聯質譜儀(LC-Mass/Mass)篩選出LECT2可能的作用標的蛋白；在我們的篩選中發現在肝癌中相當重要角色的肝細胞生長因子受體(Hepatocyte growth factor receptor, HGFR/MET)和LECT2有很強的交互作用；在細胞與動物實驗中我們更進一步證實了LECT2和MET的結合會抑制MET的磷酸化反應，而此抑制作用會透過影響酪胺酸磷酸水解酶1B(Protein tyrosine phosphatase 1B)對MET產生結抗肝細胞生長因子(Hepatocyte growth factor receptor, HGF)誘發的MET磷酸化反應，而LECT2所主導的抑制MET磷酸化反應可以抑制肝癌的血管侵犯和轉移等惡性進程的發生；此外，我們更進一步找出LECT2和MET作用的位置位於LECT2蛋白上的HxGxD結構區域，並證明此結構區域對其活性的重要性。由於LECT2是分泌性蛋白，除了透過和MET結合影響腫瘤本身外，另一方面我們也發現LECT2會透過抑制血管內皮細胞上的血管生成因子受體2(Vascular Endothelial Cell Growth Factor Receptor 2/VEGFR2)的磷酸化反應，並進一步抑制血管生成因子(Vascular Endothelial Cell Growth Factor, VEGF)所誘發的血管新生反應，而抑制腫瘤生長。我們的研究發現LECT2透過和MET及VEGFR2的結合抑制兩者的活化可以抑制肝癌的血管侵犯及惡性進程，並同時也透過抑制腫瘤誘發的血管新生抑制腫瘤的生長，而這樣的作用機轉也提供了治療其他MET及血管新生相關癌症一種新的治療方式。 | zh_TW |
| dc.description.abstract | Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. The high mortality of HCC is due to a high frequency of tumor recurrence and malignancy. One of the major factors of recurrence in hepatocellular carcinoma (HCC) treatment is vascular invasion. To investigate the molecular mechanism of vascular invasion in HCC can provide new insight for clinical diagnosis and development of new therapy. Leukocyte cell-derived chemotoxin 2 (LECT2) has been shown to act as a tumor suppressor in hepatocellular carcinoma (HCC). However the underlying mechanism has not completely defined yet. Here we employ a LECT2-affinity column plus LC-ms/ms to identify LECT2-binding proteins and found that MET receptor is strongly interacted with LECT2 protein. Despite the presence of HGF, the LECT2 binding causes an antagonistic effect to MET receptor activation through recruiting protein tyrosine phosphatase 1B (PTP1B). The antagonistic effect of LECT2 on MET activation also mainly contributes to the blockage of vascular invasion and metastasis of HCC. Furthermore, serial deletions and mutations of LECT2 showing that HxGxD motif is primarily responsible for MET receptor binding and the antagonistic effects. We also identified LECT2 as an endogenous anti-angiogenic factor which could inhibit VEGFR2-dependent angiogenesis. This finding revealed another critical role of LECT2 in HCC progression. In this study, we uncover a bi-functional mechanism of MET and VEGFR2 regulation by the LECT2 protein in HCC progression in HCC via the direct binding and inactivation of both MET and VEGFR2, opening a potential avenue for treating for developing LECT2 as an HCC therapeutic agent. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-07T23:50:47Z (GMT). No. of bitstreams: 1 ntu-103-D97447002-1.pdf: 3343768 bytes, checksum: e149cd4f11a1755d17b087573d63b45f (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | 口試委員審定書……………………………………………………………………………… II
誌謝…………………………………………………………………………………………… III 中文摘要……………………………………………………………………………………… V 英文摘要……………………………………………………………………………………… VI Chapter 1 Introduction……………………………………………………………………… 01 1.1 Hepatocellular carcinoma (HCC) 1.2 Leukocyte cell-derived chemotaxin 2 (LECT2 1.3 Hepatocyte growth factor (HGF) and its receptor (HGFR/MET) in HCC 1.4 Motivation and purpose Chapter 2 Materials and methods ………………………………………………………… 09 Chapter 3 Results…………………………………………………………………………… 23 3.1 MET is a direct binding target of LECT2 3.2 LECT2 inhibits MET receptor tyrosine kinase activity without competing with HGF binding 3.3 LECT2 functionally binds on α-chain of MET extracellular domain 3.4 The HxGxD motif is critical for the LECT2’s inhibitory activity 3.5 LECT2 inhibits MET activation by recruiting PTP1B 3.6 LECT2 was negatively correlated with the phospho-MET level in patients with HCC 3.7 LECT2 also suppress tumor growth through inhibit tumor angiogenesis 3.8 rLECT2 protein inhibited VEGF-stimulated VEGFR2 phosphorylation in HUVEC Chapter 4 Discussion………………………………………………………………………… 38 Chapter 5 Figures and figure legends ……………………………………………………… 44 Chapter 6 Tables ……………………………………………………………………………… 97 Chapter 7 References ………………………………………………………………………… 103 Appendix ……………………………………………………………………………………… 113 | |
| dc.language.iso | en | |
| dc.title | 探討白血球趨化因子2抑制肝癌惡性進程之分子機轉 | zh_TW |
| dc.title | Evaluation of the Molecular Mechanism of Leukocyte Cell-Derived Chemotaxin 2 Suppress Hepatocellular Carcinoma Aggressive Progression | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 林明燦(Ming-Tsan Lin),蕭宏昇(Michael Hsiao),洪文俊(Wen-Chun Hung),王朝鐘(Chau-Jong Wang) | |
| dc.subject.keyword | 肝癌,白血球趨化蛋白2,惡性進程,血管侵犯,肝細胞生長因子受體,酪胺酸磷酸水解?1,血管生成因子,血管生成因子受體2, | zh_TW |
| dc.subject.keyword | Hepatocellular carcinoma (HCC),Leukocyte cell-derived chemotoxin 2( LECT2),vascular invasion,metastasis,MET (Hepatocyte growth factor receptor, HGFR/MET),protein tyrosine phosphatase 1B (PTP1B),Angiogenesis,Vascular endothelial growth factor (VEGF),Vascular endothelial growth factor receptor 2 (VEGFR2), | en |
| dc.relation.page | 114 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2014-01-27 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 毒理學研究所 | zh_TW |
| 顯示於系所單位： | 毒理學研究所 | |
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