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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 | 吳漢忠(Han-Chung Wu) | |
dc.contributor.author | Hsien-Cheng Tso | en |
dc.contributor.author | 左先正 | zh_TW |
dc.date.accessioned | 2021-06-08T00:50:29Z | - |
dc.date.copyright | 2015-09-24 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-07-06 | |
dc.identifier.citation | Allan, A.L., and Keeney, M. (2010). Circulating tumor cell analysis: technical and statistical considerations for application to the clinic. Journal of oncology 2010, 426218.
Baeuerle, P.A., and Gires, O. (2007). EpCAM (CD326) finding its role in cancer. British journal of cancer 96, 417-423. Bahnassy, A.A., Zekri, A.R.N., El-Houssini, S., El-Shehaby, A.M.R., Mahmoud, M.R., Abdallah, S., and El-Serafi, M. (2004). Cyclin A and cyclin D1 as significant prognostic markers in colorectal cancer patients. Bmc Gastroenterol 4. Balic, M., Williams, A., Lin, H., Datar, R., and Cote, R.J. (2013). Circulating tumor cells: from bench to bedside. Annual review of medicine 64, 31-44. Bardelli, A., Corso, S., Bertotti, A., Hobor, S., Valtorta, E., Siravegna, G., Sartore-Bianchi, A., Scala, E., Cassingena, A., Zecchin, D., et al. (2013). Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer discovery 3, 658-673. Benvenuti, S., and Comoglio, P.M. (2007). The MET receptor tyrosine kinase in invasion and metastasis. Journal of cellular physiology 213, 316-325. Bottomly, D., Kyler, S.L., McWeeney, S.K., and Yochum, G.S. (2010). Identification of {beta}-catenin binding regions in colon cancer cells using ChIP-Seq. Nucleic acids research 38, 5735-5745. Breindel, J.L., Haskins, J.W., Cowell, E.P., Zhao, M., Nguyen, D.X., and Stern, D.F. (2013). EGF receptor activates MET through MAPK to enhance non-small cell lung carcinoma invasion and brain metastasis. Cancer research 73, 5053-5065. Carpenter, G., and Red Brewer, M. (2009). EpCAM: another surface-to-nucleus missile. Cancer cell 15, 165-166. Chan, G., Hassanain, M., Chaudhury, P., Vrochides, D., Neville, A., Cesari, M., Kavan, P., Marcus, V., and Metrakos, P. (2010). Pathological response grade of colorectal liver metastases treated with neoadjuvant chemotherapy. HPB : the official journal of the International Hepato Pancreato Biliary Association 12, 277-284. Denzel, S., Maetzel, D., Mack, B., Eggert, C., Barr, G., and Gires, O. (2009). Initial activation of EpCAM cleavage via cell-to-cell contact. BMC cancer 9, 402. Dietvorst, M.H., and Eskens, F.A. (2013). Current and Novel Treatment Options for Metastatic Colorectal Cancer: Emphasis on Aflibercept. Biologics in therapy 3, 25-33. Fakih, M.G. (2011). Making sense of anti-EGFR plus oxaliplatin-based therapy in the first-line treatment of metastatic colorectal cancer. Future oncology 7, 223-226. Giannopoulou, E., Antonacopoulou, A., Matsouka, P., and Kalofonos, H.P. (2009). Autophagy: novel action of panitumumab in colon cancer. Anticancer research 29, 5077-5082. Giuliani, F., and Colucci, G. (2007). Cetuximab in colon cancer. The International journal of biological markers 22, S62-70. Gotoh, A., Hidaka, M., Hirose, K., and Uchida, T. (2013). Gas7b (growth arrest specific protein 7b) regulates neuronal cell morphology by enhancing microtubule and actin filament assembly. The Journal of biological chemistry 288, 34699-34706. Higa, R. (2011). [Colorectal cancer: epidemiology and primary profilaxis]. Acta gastroenterologica Latinoamericana 41, 70-73. Jasperson, K.W., Tuohy, T.M., Neklason, D.W., and Burt, R.W. (2010). Hereditary and familial colon cancer. Gastroenterology 138, 2044-2058. Liao, M.Y., Kuo, M.Y., Lu, T.Y., Wang, Y.P., and Wu, H.C. (2015). Generation of an anti-EpCAM antibody and epigenetic regulation of EpCAM in colorectal cancer. International journal of oncology 46, 1788-1800. Lin, C.W., Liao, M.Y., Lin, W.W., Wang, Y.P., Lu, T.Y., and Wu, H.C. (2012). Epithelial cell adhesion molecule regulates tumor initiation and tumorigenesis via activating reprogramming factors and epithelial-mesenchymal transition gene expression in colon cancer. The Journal of biological chemistry 287, 39449-39459. Litvinov, S.V., Velders, M.P., Bakker, H.A., Fleuren, G.J., and Warnaar, S.O. (1994). Ep-CAM: a human epithelial antigen is a homophilic cell-cell adhesion molecule. The Journal of cell biology 125, 437-446. Liu, Y., Li, Y., Liu, Z., Zhang, L., Anniko, M., and Duan, M. (2011). Prognostic significance of matrix metalloproteinase-20 overexpression in laryngeal squamous cell carcinoma. Acta oto-laryngologica 131, 769-773. Luraghi, P., Reato, G., Cipriano, E., Sassi, F., Orzan, F., Bigatto, V., De Bacco, F., Menietti, E., Han, M., Rideout, W.M., 3rd, et al. (2014). MET signaling in colon cancer stem-like cells blunts the therapeutic response to EGFR inhibitors. Cancer research 74, 1857-1869. Maetzel, D., Denzel, S., Mack, B., Canis, M., Went, P., Benk, M., Kieu, C., Papior, P., Baeuerle, P.A., Munz, M., et al. (2009). Nuclear signalling by tumour-associated antigen EpCAM. Nature cell biology 11, 162-171. Marshall, J. (2005). The role of bevacizumab as first-line therapy for colon cancer. Seminars in oncology 32, S43-47. Matsukawa, S., Shiratori, T., Kugimiya, M., Matsuo, S., Kaji, S., and Aoyama, Y. (2010). [A recurrence after surgery for colon cancer with metastases of the liver and periaortic lymph nodes, with CR achieved by using bevacizumab+mFOLFOX6]. Gan to kagaku ryoho Cancer & chemotherapy 37, 1389-1391. Mbah, N. (2009). Hospital frequency of large bowel cancer: factors thought to influence outcome. Nigerian journal of clinical practice 12, 37-41. Munz, M., Kieu, C., Mack, B., Schmitt, B., Zeidler, R., and Gires, O. (2004). The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation. Oncogene 23, 5748-5758. Nagrath, S., Sequist, L.V., Maheswaran, S., Bell, D.W., Irimia, D., Ulkus, L., Smith, M.R., Kwak, E.L., Digumarthy, S., Muzikansky, A., et al. (2007). Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450, 1235-1239. Ozkumur, E., Shah, A.M., Ciciliano, J.C., Emmink, B.L., Miyamoto, D.T., Brachtel, E., Yu, M., Chen, P.I., Morgan, B., Trautwein, J., et al. (2013). Inertial focusing for tumor antigen-dependent and -independent sorting of rare circulating tumor cells. Science translational medicine 5, 179ra147. Peppone, L.J., Mahoney, M.C., Cummings, K.M., Michalek, A.M., Reid, M.E., Moysich, K.B., and Hyland, A. (2008). Colorectal cancer occurs earlier in those exposed to tobacco smoke: implications for screening. Journal of cancer research and clinical oncology 134, 743-751. Perrigue, M.M., Kantor, E.D., Hastert, T.A., Patterson, R., Potter, J.D., Neuhouser, M.L., and White, E. (2013). Eating frequency and risk of colorectal cancer. Cancer causes & control : CCC 24, 2107-2115. Riethdorf, S., Fritsche, H., Muller, V., Rau, T., Schindlbeck, C., Rack, B., Janni, W., Coith, C., Beck, K., Janicke, F., et al. (2007). Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the CellSearch system. Clinical cancer research : an official journal of the American Association for Cancer Research 13, 920-928. Scheller, J., Chalaris, A., Garbers, C., and Rose-John, S. (2011). ADAM17: a molecular switch to control inflammation and tissue regeneration. Trends in immunology 32, 380-387. Siegel, R., Desantis, C., and Jemal, A. (2014a). Colorectal cancer statistics, 2014. CA: a cancer journal for clinicians 64, 104-117. Siegel, R., Ma, J., Zou, Z., and Jemal, A. (2014b). Cancer statistics, 2014. CA: a cancer journal for clinicians 64, 9-29. Sieuwerts, A.M., Kraan, J., Bolt, J., van der Spoel, P., Elstrodt, F., Schutte, M., Martens, J.W., Gratama, J.W., Sleijfer, S., and Foekens, J.A. (2009). Anti-epithelial cell adhesion molecule antibodies and the detection of circulating normal-like breast tumor cells. Journal of the National Cancer Institute 101, 61-66. Steinke, V., Engel, C., Buttner, R., Schackert, H.K., Schmiegel, W.H., and Propping, P. (2013). Hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome. Deutsches Arzteblatt international 110, 32-38. Stordal, B., and Davey, R. (2009). ERCC1 expression and RAD51B activity correlate with cell cycle response to platinum drug treatment not DNA repair. Cancer chemotherapy and pharmacology 63, 661-672. Sweetser, S., Smyrk, T.C., and Sinicrope, F.A. (2013). Serrated colon polyps as precursors to colorectal cancer. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 11, 760-767; quiz e754-765. Ulrich, A., Z'Graggen, K., Weitz, J., and Buchler, M.W. (2005). Functional results of the colon J-pouch versus transverse coloplasty pouch in Heidelberg. Recent results in cancer research Fortschritte der Krebsforschung Progres dans les recherches sur le cancer 165, 205-211. Visvader, J.E., and Lindeman, G.J. (2008). Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nature reviews Cancer 8, 755-768. Went, P., Vasei, M., Bubendorf, L., Terracciano, L., Tornillo, L., Riede, U., Kononen, J., Simon, R., Sauter, G., and Baeuerle, P.A. (2006). Frequent high-level expression of the immunotherapeutic target Ep-CAM in colon, stomach, prostate and lung cancers. British journal of cancer 94, 128-135. Went, P.T., Lugli, A., Meier, S., Bundi, M., Mirlacher, M., Sauter, G., and Dirnhofer, S. (2004). Frequent EpCam protein expression in human carcinomas. Human pathology 35, 122-128. Wilson, A.J., Byun, D.S., Nasser, S., Murray, L.B., Ayyanar, K., Arango, D., Figueroa, M., Melnick, A., Kao, G.D., Augenlicht, L.H., et al. (2008). HDAC4 promotes growth of colon cancer cells via repression of p21. Molecular biology of the cell 19, 4062-4075. Zhang, C., Gao, C., Xu, Y., and Zhang, Z. (2014). CtBP2 could promote prostate cancer cell proliferation through c-Myc signaling. Gene 546, 73-79. Zlot, A.I., Silvey, K., Newell, N., Coates, R.J., and Leman, R. (2012). Family history of colorectal cancer: clinicians' preventive recommendations and patient behavior. Preventing chronic disease 9, E21. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/18078 | - |
dc.description.abstract | 上皮細胞黏附因子 (EpCAM),屬第一型穿膜醣蛋白,於所有的腺狀細胞癌及鱗狀上皮細胞癌都有很高的表現量。過去的研究顯示,此蛋白也出現在癌幹細胞中,並有助於惡性腫瘤的生長。其中又以大腸直腸癌的上皮細胞黏附因子表現量,在所有癌症中為最高。由我們先前的研究得知,上皮細胞黏附因子在大腸癌幹細胞中具有調節腫瘤細胞起始的能力,又與癌症的惡性程度有密切的相關性。因此在本研究中,我們透過磷酸化受體酪氨酸激酶陣列 (phosphor-receptor tyrosine kinase array) 來探討EpCAM的訊息傳遞並且發現上皮細胞黏附因子之細胞外域 (EpEX) 可以活化肝細胞生長因子受體 (Hepatocyte growth factor receptor, HGFR, c-Met)。更進一步發現EpEX可以透過活化 c-Met來促進細胞增生能力、細胞移動能力、細胞轉移能力以及細胞集落形成能力。其次,我們發現EpEX可以透過c-Met與 Erk 訊息傳遞來增加腫瘤壞死因子α轉化酶 (TACE) 以及γ-分泌酶 (γ-secretase) 的活性。為了進一步探討受到EpICD所調控的基因,我們透過融合瘤的技術成功建立了三株對抗EpICD的單株抗體。此外,EpEX會透過增加 γ-secretase 的活性來促進上皮細胞黏附因子之細胞外域 (EpICD) 以及 c-Myc 的表現量。EpICD 可以透過調節 β-catenin-FHL2 的核轉移來調控此複合體的基因調節能力。 | zh_TW |
dc.description.abstract | Epithelial cell adhesion molecule (EpCAM) is a type Ⅰ transmembrane glycoprotein overexpressed in almost all adenocarcinomas and squamous cell carcinomas. It’s also a well-known cancer stem cell marker and contributes to tumor growth. EpCAM is highly expressed in colon cancer. Our previous study pointed out that EpCAM plays an important role in regulating tumorigenesis in colon cancer stem cells and in regulating tumor malignancy. In this study, we identified the signaling of EpCAM through receptor tyrosine kinase array and found that EpCAM extracellular domain (EpEX) might activate c-Met signaling, which promotes cell proliferation, migration, invasion and colony formation. Subsequent study of EpEX signaling pathway found that EpEX activated the c-Met-ERK signaling pathway and increased the activity of TACE and γ-secretase. Moreover, to investigate the genes regulated by EpICD using ChIP Assay, we successfully generated three monoclonal antibodies against EpICD by hybridoma technology. EpEX was found to upregulate EpICD and c-Myc by increasing γ-secretase activity. EpICD could regulate the nuclear translocation of β-catenin-FHL2 complex then decrease the down-stream gene expression. In conclusion, our results indicate that EpCAM can regulate tumorigenesis through production of EpEX and EpICD. EpEX can activate the c-Met-ERK signaling pathway, while EpICD can turn on gene expression after being translocated into the nucleus. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T00:50:29Z (GMT). No. of bitstreams: 1 ntu-104-R02450018-1.pdf: 2486267 bytes, checksum: 989d56deaf513a19ca097d820c4f2ab2 (MD5) Previous issue date: 2015 | en |
dc.description.tableofcontents | 致謝 1
中文摘要 2 Abstract 3 Contents 5 List of abbreviations 7 Introduction 10 1.1 Epithelial cell adhesion molecule (EpCAM) 10 1.2 Molecular mechanism of EpCAM signaling 10 1.3 Expression of EpCAM in tumor tissue 11 1.4 EpCAM expression on cancer stem cell 12 1.5 EpCAM as a biomarker of circulating tumor cells 13 1.6 Epidemiology of colorectal cancer 14 1.7 Pathogenesis of colorectal cancer 15 1.8 Treatment of colorectal cancer 16 Materials and Methods 19 2.1 Cell lines and cell culture 19 2.2 Receptor protein tyrosine phosphatase-receptor protein tyrosine kinase array 19 2.3 Western blotting 20 2.4 Transfection with lentiviral vectors expressing shRNA 21 2.5 Cell proliferation assay (MTT assay) 22 2.6 Cell migration using the ibidi culture insert 22 2.7 Cell invasion assay 23 2.8 Colony formation assay 23 2.9 Reverse transcription/real time PCR 24 2.10 TACE activity assay 24 2.11 γ-secretase activity assay 25 2.13 Nuclear and cytoplasm lysate extraction 25 2.14 Immunofluorescence assay 25 2.15 Chromation immnoprecipitation (ChIP) 26 2.16 Flow cytometry 27 2.17 Immunoprecipitation and immunoblotting 27 2.18 Cellular ELISA 28 2.19 Immunogold labeling and transmission electron microscopy 28 2.20 Statistical analysis 29 Results 30 3.1 EpEX-Fc activates c-Met and ErbB family in colon cancer cells. 30 3.2 EpEX-Fc promotes cell proliferation, migration, invasion and colony formation through c-Met signaling in HCT116 cells. 31 3.3 Knocksown of c-Met inhibits the EpEX-induced celluar functions. 32 3.4 EpEX increases the TACE activity through c-MET/ ERK pathway. 32 3.5 EpEX increases nuclear translocation of β-catenin-FHL2-EpICD complex 34 3.6 Inhibition of EpICD cleavage attenuates the binding of β-catenin to promoters of target genes 34 3.7 Generation of EpICD monoclonal antibodies by hybridoma technology 36 Discussion 38 References 62 | |
dc.language.iso | en | |
dc.title | 上皮細胞黏附因子在腫瘤生成中活化與訊息傳遞的分子機制 | zh_TW |
dc.title | The Molecular Mechanisms of EpCAM Activation and Signaling in Tumorigenesis | en |
dc.type | Thesis | |
dc.date.schoolyear | 103-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 呂仁(Jean Lu),沈家寧(Chia-Ning Shen) | |
dc.subject.keyword | 大腸直腸癌,上皮細胞黏附因子,上皮細胞黏附因子之細胞外域,上皮細胞黏附因子之細胞內域,肝細胞生長因子受體,β-catenin,FHL2, | zh_TW |
dc.subject.keyword | colorectal cancer,EpCAM,EpEX,EpICD,c-Met,β-catenin,FHL2, | en |
dc.relation.page | 66 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2015-07-06 | |
dc.contributor.author-college | 牙醫專業學院 | zh_TW |
dc.contributor.author-dept | 口腔生物科學研究所 | zh_TW |
顯示於系所單位: | 口腔生物科學研究所 |
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