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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 吳漢忠(Han-Chung Wu) | |
| dc.contributor.author | Kai-Wen Cheng | en |
| dc.contributor.author | 鄭凱文 | zh_TW |
| dc.date.accessioned | 2021-06-08T04:46:37Z | - |
| dc.date.copyright | 2009-09-15 | |
| dc.date.issued | 2009 | |
| dc.date.submitted | 2009-07-30 | |
| dc.identifier.citation | References
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/23191 | - |
| dc.description.abstract | Drug resistance in cancer poses a profound challenge for the effective treatment of cancer, especially for advanced and metastatic cancers. Therefore, the discovery of a predictive factor for chemoresistance is critical for both screening and improving adjuvant therapies for cancer patients. The glucose-regulated protein GRP78, a major endoplasmic reticulum (ER) chaperone, is inducible under stress conditions that often characterize tumor microenvironments, may protect cancer cells and confer resistance to a variety of chemotherapeutic drugs. Notably, GRP78 can only be found on the cell surface of cancer cells but not normal cells opens up an exciting opportunity of targeting cell surface GRP78 function as well as using it as a cancer-targeted marker. In this study, we have generated twenty monoclonal antibodies (mAbs) specifically against GRP78. Among these mAbs, four mAbs, GRP78-Ab 17-1, GRP78-Ab 18-1, GRP78-Ab 19-5, and GRP78-Ab 20-7 exhibited higher specificity against surface GRP78 of a nasopharyngeal carcinoma (NPC) cell line, NPC-TW04 cells. Using these anti-GRP78 mAbs, we found that GRP78 is also overexpressed in other cancer cell lines, including CL1-5, MDA-MB 231 and HCT116. Interestingly, a small fraction of GRP78 was detected on several cancer cells surface, which includes NPC-TW04, A549, HepG2, H1299 and PAN-1. In addition, results from immunohistochemical staining of human surgical specimens reveled that GRP78 is up-regulated in both liver and oral cancers. To investigate the potential functions of GRP78, lentiviral vector expressing short hairpin RNA (shRNA) was used to suppress GRP78 expression in NPC-TW04. We found that knockdown of GRP78 significantly reduced cell growth, migration, and inhibited xenograft tumor growth. Taken together, our data suggest that GRP78 may serve as a new molecular target of cancer therapy, and the anti-GRP78 mAbs are useful for detection the surface GRP78 of cancer cells and development of ligand-targeted therapeutics for cancer. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T04:46:37Z (GMT). No. of bitstreams: 1 ntu-98-R96450001-1.pdf: 6376762 bytes, checksum: 2ea92a76dfed5326f8cd7ab2d02cd011 (MD5) Previous issue date: 2009 | en |
| dc.description.tableofcontents | 誌謝 i
中文摘要 ii Abstract iii Contents v Content of figures vii Introduction 1 1.1 Epidemiology of cancer 1 1.2 Cancer treatments 2 1.3 Drug resistance 3 1.4 GRP78 protein 4 1.5 Unfolded protein response (UPR) 5 1.6 Roles of GRP78 in cancer progression 7 1.7 Mechanisms of GRP78 in promoting cancer progression 9 1.8 Roles of GRP78 in drug resistance 10 1.9 Cell surface GRP78 as a therapeutic target 11 1.10 Monoclonal antibody therapy 13 Materials and Methods 16 2.1 Cell lines and culture conditions 16 2.2 Construction of plasmid cDNA clones expressing rGRP78 16 2.3 Expression and purification of recombinant GRP78 protein 17 2.4 SDS-PAGE 18 2.5 Immunization of rGRP78 18 2.6 Generation of mAbs against GRP78 19 2.7 Screening of the anti-GRP78 mAbs against GRP78 by ELISA 20 2.8 Screening of the anti-GRP78 mAbs against GRP78 by Western blotting 21 2.9 Identification of the anti-GRP78 mAbs against surface GRP78 by flow cytometric analysis 22 2.10 Determination of monoclonal antibody class and subclass 22 2.11 Apoptosis assay 23 2.12 Immunofluorescent localization of GRP78 in NPC-TW04 24 2.13 Immunohistochemical localization of cancer patient surgical specimens 24 2.14 Transduction with lentiviral vectors expressing shRNA 25 2.15 Cell growth MTT assay 26 2.16 Cell migration assay 27 2.17 Xenograft tumors 27 Results 29 3.1 Generation of monoclonal antibodies against GRP78 29 3.2 Identification of the anti-GRP78 mAbs against NPC-TW04 by ELISA 29 3.3 Identification of the anti-GRP78 mAbs against surface GRP78 of NPC-TW04 by flow cytometric analysis 30 3.4 Determination of the isotype and subclass of the anti-GRP78 mAbs 30 3.5 Apoptotic effects of the anti-GRP78 mAbs on NPC-TW04 31 3.6 Immunolocalization of mAbs targeted GRP78 on NPC-TW04 32 3.7 GRP78 is overexpressed on surface in different cancer cell line 32 3.8 GRP78 is up-regulated in human cancer specimens by immunohistochemical staining 33 3.9 GRP78 knockdown inhibits cell growth in vitro 34 3.10 GRP78 knockdown suppresses cell migration in vitro 35 3.11 GRP78 knockdown inhibits tumor growth in vivo 35 Discussion 37 Figures 43 References 65 | |
| dc.language.iso | en | |
| dc.title | 製備GRP78之單株抗體與探討GRP78在腫瘤生成中之功能 | zh_TW |
| dc.title | Generation of Monoclonal Antibodies against GRP78 and Study the Functional Roles of GRP78 in Tumorigenesis | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 97-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 林國儀,呂仁 | |
| dc.subject.keyword | GRP78,抗藥性,單株抗體,治療性抗體,標靶治療, | zh_TW |
| dc.subject.keyword | GRP78,drug resistance,ligand-targeted therapy,monoclonal antibody,short hairpin RNA,therapeutic antibody., | en |
| dc.relation.page | 72 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2009-07-30 | |
| 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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