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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 俞松良(Sung-Liang Yu) | |
dc.contributor.author | Chia-Ying Hsu | en |
dc.contributor.author | 徐嘉盈 | zh_TW |
dc.date.accessioned | 2021-06-15T13:34:40Z | - |
dc.date.available | 2026-01-29 | |
dc.date.copyright | 2016-02-24 | |
dc.date.issued | 2016 | |
dc.date.submitted | 2016-01-30 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/51450 | - |
dc.description.abstract | 肺癌是世界各地導致死亡人數最多的癌症。我們藉由微陣列生物晶片去比較一群具有不同侵襲能力的肺腺癌細胞株之轉錄本之差異,發現一個新穎的腫瘤抑制基因,FAM198B,它是在人類研究中從未被報導過的基因。我們發現在臨床肺腺癌病人中,具有高度表現FAM198B轉錄本之病人組別,其整體存活期較低表現FAM198B轉錄本之病人組別來的長。在體外細胞實驗中發現,高度表現FAM198B可以抑制細胞侵襲、移動、生長速度、與非接觸性貼附生長;並且體內動物實驗也證實FAM198B能抑制老鼠腫瘤之生長與轉移。此外,我們發現FAM198B是屬於N醣基化蛋白質,其第 98與289號胺基酸為其醣基化位點。藉由去醣基化實驗可證實醣基化能延長FAM198B蛋白質的半衰期並且抑制腫瘤轉移。進一步利用生物晶片及生物途徑分析FAM198B抑制腫瘤轉移的機制,是透過抑制下游细胞外信號调節蛋白激酶(ERK)與基質金屬蛋白酶-1(MMP-1)的表現。總結以上結果,我們可以證實FAM198B具有抑癌基因的能力,並且本研究可以提供在癌症診斷與治療上一個全新的思維。 | zh_TW |
dc.description.abstract | Metastasis is a major cause of cancer-related death. Here, we identify a novel tumor suppressor gene, FAM198B, which has never been characterized in humans previously, by comparing the transcriptional profiles of a high metastatic lung adenocarcinoma cell line and its isogenic low metastatic cell line. The high expression of FAM198B was associated with favorable survival in lung adenocarcinoma patients. Enforced expression of FAM198B suppressed cell invasion, migration, mobility, proliferation and anchorage-independent growth in vitro and reduced tumor growth and metastasis in in vivo mouse models. Additionally, we found that FAM198B is an N-glycosylated protein with two extracellular N-linked glycosylation sites (Asn98 and Asn289). Deglycosylation nearly eliminated the metastasis suppression activity of FAM198B due to a decrease in stability. A microarray analysis was used to examine the underlying mechanism of FAM198B in metastasis suppression and identified MMP1 as a critical downstream target of FAM198B. The FAM198B-mediated MMP-1 downregulation was via inhibition of the phosphorylation of extracellular signal-regulated kinase (ERK). Taken together, these results indicate that FAM198B acts as a tumor suppressor to inhibit cancer cell invasion and metastasis via the ERK/MMP1 signaling pathways and may serve as a potential therapeutic target for lung adenocarcinoma. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T13:34:40Z (GMT). No. of bitstreams: 1 ntu-105-F96424024-1.pdf: 5018054 bytes, checksum: f954bf6619748a117352f44bbbcf45a6 (MD5) Previous issue date: 2016 | en |
dc.description.tableofcontents | Acknowledge.……………………………………………………………….……….…...i
中文摘要…………………………………………………………..……………………iv Abstract…………………………………………………………………………………..v Contents……………………………………………………………………......……….vii List of Figures………………………………………………................................…….xii List of Tables…………………………………………………………………….……..xv Chapter I: FAM198B is associated with prolonged survival and inhibits metastasis in lung adenocarcinoma via blockage of ERK-mediated MMP-1 expression............1 A. Introduction…………………………………………………………………….2 1. Lung cancer………………………………………………………………...2 2. Matrix metalloproteinase (MMPs)…………………………………………2 3. Family with sequence similarity 198, member B (FAM198B)…………….3 4. Protein glycosylation……………………………………………………….3 5. Research motive and strategy………………………………………………4 B. Materials and Methods…………………………………………………………5 1. Human lung cancer patients and tumor specimens………………………...5 2. Plasmids and transfection…………………………………………………..5 3. Viruses and transduction…………………………………………………....6 4. Cell lines and culture conditions…………………………………………...6 5. Immunoblotting and antibodies………………………………………….....7 6. Stability of FAM198B……………………………………………………...8 7. Real-time Quantitative Polymerase Chain Reaction…………………….…8 8. In vitro invasion and migration assays……………………………………..8 9. Single-cell tracking migration assay………………………………………..9 10. Cell proliferation assay and anchorage-independent growth assay………...9 11. Microarray and pathway analysis…………………………………………10 12. Glycosidase assay…………………………………………………………11 13. Immunofluorescence analysis……………………………………………..11 14. In vivo animal models…………………………………………………….12 15. Statistical analysis……………………………………………………...….13 C. Results…………………………………………………………………...........14 1. Discovery of FAM198B in an isogenic lung cancer metastasis cell model……………………………………………………………………...14 2. Down-regulation of FAM198B is associated with poor overall survival in lung adenocarcinoma patients…………………………………………….14 3. FAM198B inhibits lung tumor invasion in vitro and metastasis in vivo….15 4. FAM198B inhibits lung tumor growth in vitro and tumorigenesis in vivo………………………………………………………………………..17 5. FAM198B is an N-linked glycosylated protein…………………………...19 6. N-glycosylation is critical for FAM198B function via stabilization of FAM198B…………………………………………………………………21 7. FAM198B suppresses cancer cell invasion and metastasis through ERK-mediated MMP-1 inhibition……………………………………………....22 D. Discussion……………………………………………………………………..25 Chapter II: Detection and molecular characterization of circulating tumor cells in non-small cell lung cancer patients with advanced metastasis…………….............31 A. Introduction…………………………………………………………………...32 1. Lung cancer…………………………………………………………….....32 2. EGFR tyrosine kinase inhibitors………………………………………….32 3. Circulating tumor cells……………………………………….………..….33 4. CTCs capturing platforms………………………………………………...34 5. Research motive and strategy……………………………………………..35 B. Materials and Methods……………….……………………………………….36 1. Cell lines…………………………………………………………………..36 2. Blood spiking experiment and sample processing………………………..36 3. Clinical blood samples…………………………………………………….37 4. Flow cytometry……………………………………………………………38 5. CTC recovery by DEPArray™ system……………………………………38 6. Whole genome amplification……………………………………………...39 7. EGFR mutations analysis by MALDI-TOF MS…………………………..39 8. Statistical analysis………………………………………………..………..39 C. Results………………………………………………………………………...40 1. EpCAM expression of lung cancer cell lines……………………………..40 2. Evaluation of EpCAM-based CTC capture efficiency by using different anti-EpCAM antibodies…………………………………………………...40 3. Clinical lung cancer CTCs enrichment and enumeration by IsoFlux and sorting by DEPArray……………………………………………………....42 4. Evaluation of whole genome amplification efficiency by H1975#8 cells…42 Chapter III: DUSP13B, DDR2 genes may confer acquired resistance to EGFR-TKI, gefitinib in Lung Adenocarcinomas with EGFR-Activating Mutations.......44 A. Introduction…………………………………………………………………...45 1. Lung cancer……………………………………………………………….45 2. EGFR (epithermal growth factor receptor)……………………………….45 3. RNAi……………………………………………………………………...46 4. DUSP13 (dual specific phosphatase 13)…………………………..……...47 5. DDR2 (discoidin domain receptor 2)……………………………………..48 6. Research motive and strategy……………………………………………..49 B. Materials and Methods……………….……………………………………….51 1. Cell lines……………………………………………………………..……51 2. Immunoblotting and antibodies……………………..…………………….51 3. Drug treatment…………………………………………………………….52 4. Cell proliferation assay……………………………………………………53 5. Anchorage-independent growth assay……………………………...……..53 6. Colony formation assay……………………………………………..…….53 7. In vivo animal experiment…………………………………………….…..54 8. Drug synergism……………………………………………………………54 9. Flow cytometry……………………………………………………………55 10. Caspase activity…………………………………………………………...55 11. Statistical analysis………………………………………………….……...56 C. Results………………………………………………………………………...57 1. Acquired gefitinib resistance in pc9/gef cells is not due to EGFR-T790M mutation…………………………………………………………………...57 2. Identification of genfitinib-sensitizing genes by pooled shRNA library screening…………………………………………………………………..57 3. Secondary screen for gefitinib-sensitizing genes in PC9/gef cells…………59 4. DUSP13 was overexpressed in PC9/gef cells and may confer acquired-resistance to gefitnib in PC9/gef cells……………………………………...59 5. Knockdown of DUSP13B reverse geifinig resistance in PC9/gef cells through apoptosis………………………………………………………….61 Figures………………………………………………………………………………....63 Tables…………………………………………………………………………………105 References………………………………………………………………………….…115 Appendix………………………………………………………………………….......131 | |
dc.language.iso | en | |
dc.title | 利用系統性體外研究方法鑑定腫瘤抑制基因與
EGFR-TKI抗藥性基因 | zh_TW |
dc.title | Identification of tumor suppressors and EGFR-TKI resistance genes by systemic approaches | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 何肇基(Chao-Chi Ho),蘇剛毅(Kang-Yi Su),張正琪(Cheng-Chi Chang),華國泰(Kuo-Tai Hua) | |
dc.subject.keyword | 肺癌,腫瘤抑制,侵襲,醣基化,轉譯後修飾, | zh_TW |
dc.subject.keyword | lung cancer,tumor suppressor,invasion,glycosylation,post-tranlational modification, | en |
dc.relation.page | 132 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2016-02-01 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
顯示於系所單位: | 醫學檢驗暨生物技術學系 |
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