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完整後設資料紀錄
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 | 廖瑩妤 | zh_TW |
dc.contributor.author | Ying-Yu Liao | en |
dc.date.accessioned | 2023-09-22T16:15:18Z | - |
dc.date.available | 2023-11-09 | - |
dc.date.copyright | 2023-09-22 | - |
dc.date.issued | 2023 | - |
dc.date.submitted | 2023-08-11 | - |
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T., Yeh, C. C., Liu, S. Y., Huang, M. C., & Lai, I. R. (2018). The O-glycosylating enzyme GALNT2 suppresses the malignancy of gastric adenocarcinoma by reducing EGFR activities. Am J Cancer Res, 8(9), 1739-1751. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30323967 Kawada, K., Hasegawa, S., Murakami, T., Itatani, Y., Hosogi, H., Sonoshita, M., Sakai, Y. (2011). Molecular mechanisms of liver metastasis. Int J Clin Oncol, 16(5), 464-472. doi:10.1007/s10147-011-0307-2 Lemke, G. (2013). Biology of the TAM receptors. Cold Spring Harb Perspect Biol, 5(11), a009076. doi:10.1101/cshperspect.a009076 Lin, M. C., Huang, M. J., Liu, C. H., Yang, T. L., & Huang, M. C. (2014). GALNT2 enhances migration and invasion of oral squamous cell carcinoma by regulating EGFR glycosylation and activity. Oral Oncol, 50(5), 478-484. doi:10.1016/j.oraloncology.2014.02.003 Liu, S. Y., Shun, C. T., Hung, K. Y., Juan, H. F., Hsu, C. L., Huang, M. C., & Lai, I. R. (2016). Mucin glycosylating enzyme GALNT2 suppresses malignancy in gastric adenocarcinoma by reducing MET phosphorylation. Oncotarget, 7(10), 11251-11262. doi:10.18632/oncotarget.7081 Lu, Y., Wan, J., Yang, Z., Lei, X., Niu, Q., Jiang, L., Wu, F. (2017). Regulated intramembrane proteolysis of the AXL receptor kinase generates an intracellular domain that localizes in the nucleus of cancer cells. FASEB J, 31(4), 1382-1397. doi:10.1096/fj.201600702R Maxson, J. E., Luty, S. B., MacManiman, J. D., Abel, M. L., Druker, B. J., & Tyner, J. W. (2014). Ligand independence of the T618I mutation in the colony-stimulating factor 3 receptor (CSF3R) protein results from loss of O-linked glycosylation and increased receptor dimerization. J Biol Chem, 289(9), 5820-5827. doi:10.1074/jbc.M113.508440 Park, J. H., Katagiri, T., Chung, S., Kijima, K., & Nakamura, Y. (2011). Polypeptide N-acetylgalactosaminyltransferase 6 disrupts mammary acinar morphogenesis through O-glycosylation of fibronectin. 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Y., Kao, Y. R., Shiah, S. G., Chu, Y. W., Lee, H. S., & Wu, C. W. (2005). Expression of axl in lung adenocarcinoma and correlation with tumor progression. Neoplasia, 7(12), 1058-1064. doi:10.1593/neo.05640 Sun, Z., Xue, H., Wei, Y., Wang, C., Yu, R., Wang, C., Li, G. (2019). Mucin O-glycosylating enzyme GALNT2 facilitates the malignant character of glioma by activating the EGFR/PI3K/Akt/mTOR axis. Clin Sci (Lond), 133(10), 1167-1184. doi:10.1042/CS20190145 Tarp, M. A., & Clausen, H. (2008). Mucin-type O-glycosylation and its potential use in drug and vaccine development. Biochim Biophys Acta, 1780(3), 546-563. doi:S0304-4165(07)00216-4 [pii] 10.1016/j.bbagen.2007.09.010 Ten Hagen, K. G., Fritz, T. A., & Tabak, L. A. (2003). All in the family: the UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferases. Glycobiology, 13(1), 1R-16R. doi:10.1093/glycob/cwg007 cwg007 [pii] Tian, E., & Ten Hagen, K. G. (2009). Recent insights into the biological roles of mucin-type O-glycosylation. 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Mucin glycosylating enzyme GALNT2 regulates the malignant character of hepatocellular carcinoma by modifying the EGF receptor. Cancer Res, 71(23), 7270-7279. doi:10.1158/0008-5472.CAN-11-1161 Zhang, R., Yang, Y., Dong, W., Lin, M., He, J., Zhang, X., Lv, L. (2022). D-mannose facilitates immunotherapy and radiotherapy of triple-negative breast cancer via degradation of PD-L1. Proc Natl Acad Sci U S A, 119(8). doi:10.1073/pnas.2114851119 Zhang, Y., Arner, E. N., Rizvi, A., Toombs, J. E., Huang, H., Warner, S. L., Brekken, R. A. (2022). AXL Inhibitor TP-0903 Reduces Metastasis and Therapy Resistance in Pancreatic Cancer. Mol Cancer Ther, 21(1), 38-47. doi:10.1158/1535-7163.MCT-21-0293 | - |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/89819 | - |
dc.description.abstract | 大腸直腸癌是世界上第三大最常被診斷的惡性腫瘤,也是癌症死亡的第二大原因。它的發展歷時數年,從良性腺瘤性瘜肉開始變成具有高度異型增生的腺瘤,然後發展為侵襲性癌症。轉移性大腸癌的預後很差,5年存活率不到20%,有腹膜轉移的患者的整體存活率比癌細胞轉移到肝臟或肺臟的患者要差。因此,開發更敏感的診斷標誌物和轉移性大腸癌的新治療方法迫在眉睫。
蛋白質轉譯後修飾最常見的是醣化,異常醣化經常在許多癌症中觀察到,但其在腫瘤發生所扮演之角色尚須進一步釐清。醣化有兩種主要的類型分別是氮型和氧型,在氧型醣化中,N-乙醯基半乳糖胺通過GalNAc轉移酶 (GALNT) 連接到位於高基氏體中的絲氨酸或蘇氨酸上。 在20種GALNT同功酶中,根據資料庫顯示GALNT2與大腸癌患者的不良存活率相關。我們的研究指出,與鄰近的非腫瘤組織相比,GALNT2在大腸癌組織中是過度表現且與患者的低存活率相關。GALNT2的過度表現促進大腸癌細胞的遷移和侵襲,相反,抑制GALNT2的表現則會顯著降低癌細胞侵襲性;在腹腔注射模擬癌細胞轉移的活體小鼠 (NOD/SCID mice) 模型實驗中也是跟癌細胞有相同實驗結果。有趣的是,我們發現GALNT2會修飾受體酪氨酸激酶AXL上的氧型聚醣,並通過蛋白酶體途徑調控AXL表現量。此外,AXL抑製劑和小分子核醣核酸顯著逆轉GALNT2促進的侵襲性。這些發現證明GALNT2會部分影響AXL上氧型聚醣進而促進大腸癌侵襲。 | zh_TW |
dc.description.abstract | Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer death in the world. Colorectal neoplasms take years to develop, initially as benign adenomatous polyps, as advanced adenomas with high-grade dysplasia, and then as invasive tumors. The prognosis of metastatic CRC is poor, with a 5-year survival rate of less than 20%. CRC patients with peritoneal metastasis have poorer overall survival than those with liver or lung metastasis. Therefore, it is urgent to develop more sensitive diagnostic markers and new treatment of metastatic colorectal cancer. The most common and complex post-translational modification of proteins is glycosylation. Abnormal glycosylation is frequently observed in many types of cancer, but it is unclear if it contributes intrinsically to tumorigenesis. There are two major types of glycosylation: N-linked and O-linked. In O-glycosylation, an N-Acetylgalactosamine (GalNAc) is attached to Ser (S) or Thr (T) residues in the Golgi by GalNAc-transferases (GALNTs). Among 20 GALNT isoenzymes, GALNT2 is consistently associated with poor survival of patients with colorectal cancer in public databases. In our study, immunohistochemistry revealed that GALNT2 was overexpressed in colorectal cancer tissues compared with adjacent non-tumor tissues. GALNT2 overexpression was significantly associated with poor survival of patients with colorectal cancer. In vitro and animal experiments showed that reducing the expression of GALNT2 inhibited the migration, invasion and peritoneal metastasis of colon cancer cells. Interestingly, we found that O-glycans on AXL were modified by GALNT2 and determined AXL levels through a proteasome-dependent pathway. Additionally, both the AXL inhibitor and siRNA significantly reversed the GALNT2-mediated invasiveness. In conclusion, we demonstrate that GALNT2 promotes colorectal cancer invasion at least in part through AXL. | en |
dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2023-09-22T16:15:18Z No. of bitstreams: 0 | en |
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dc.description.tableofcontents | Contents
口試委員會審定書 I 誌謝 II 中文摘要 III Abstract IV List of Figures VIII List of Tables X Chapter 1 Introduction 1 1.1 Colorectal cancer 1 1.2 TAM family 2 1.3 O-Glycosylation 3 Chapter 2 Materials and Methods 6 2.1 Patient samples 6 2.2 Immunohistochemistry 6 2.3 Cell lines and cell culture 7 2.4 cDNA synthesis and real-time RT-PCR 7 2.5 Plasmid construction and cell transfection 8 2.6 Western blot analysis 9 2.7 MTT assay 9 2.8 Transwell migration and Matrigel invasion assays 10 2.9 Lectin pull-down assay 10 2.10 Generation of GALNT2 knockout cells 11 2.11 Confocal microscopy 12 2.12 Protein degradation analysis 12 2.13 In vivo metastasis model 13 2.14 Statistical analysis 13 Chapter 3 Results 14 3.1 Colorectal tumors exhibit elevated expression of GALNT2, which correlates with poorer survival outcomes. 14 3.2 GALNT2 overexpression enhances the migratory and invasive abilities of colon cancer cells. 15 3.3 Colorectal cancer cell invasiveness is suppressed by GALNT2 knockdown. 16 3.4 Effects of GALNT2 on peritoneal tumor metastasis in NOD/SCID mice. 16 3.5 The knockout of GALNT2 has minor impact on EGFR and MET signaling. 17 3.6 AXL protein levels are regulated by GALNT2, which adds O-glycans onto AXL. 18 Chapter 4 Discussion 22 References 27 | - |
dc.language.iso | en | - |
dc.title | GALNT2調控大腸直腸癌細胞轉移之角色 | zh_TW |
dc.title | The role of GALNT2 in regulating metastasis of colorectal cancer cells | en |
dc.type | Thesis | - |
dc.date.schoolyear | 111-2 | - |
dc.description.degree | 博士 | - |
dc.contributor.oralexamcommittee | 陳啟豪;劉炯輝;王淑慧;龔秀妮 | zh_TW |
dc.contributor.oralexamcommittee | Chi-Hau Chen;Chiung-Hui Liu;Shu-Huei Wang;Hsiu-Ni Kung | en |
dc.subject.keyword | 大腸直腸癌,氧型醣化,GALNT2,侵襲性,AXL, | zh_TW |
dc.subject.keyword | Colorectal cancer (CRC),O-glycosylation,GALNT2,invasion,AXL, | en |
dc.relation.page | 49 | - |
dc.identifier.doi | 10.6342/NTU202304055 | - |
dc.rights.note | 同意授權(限校園內公開) | - |
dc.date.accepted | 2023-08-11 | - |
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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