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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 阮雪芬 | |
| dc.contributor.author | Yi-Te Chou | en |
| dc.contributor.author | 周宜德 | zh_TW |
| dc.date.accessioned | 2021-06-15T04:46:59Z | - |
| dc.date.available | 2012-08-06 | |
| dc.date.copyright | 2010-08-06 | |
| dc.date.issued | 2010 | |
| dc.date.submitted | 2010-08-05 | |
| dc.identifier.citation | 1. Garcia M, J.A., Ward EM, Center MM, Hao Y, Siegel RL, Thun MJ, Global Cancer Facts & Figures 2007. American Cancer Society, 2007.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/45834 | - |
| dc.description.abstract | Annexin家族廣泛存在於各物種內，是一群於C端具有獨特重複片段 (annexin repeat)的蛋白質，能藉由重複片段與鈣離子結合，並由鈣離子作為橋梁，可與膜上特定帶負電的磷脂質結合；而成員間的差異在於N端序列的變異性高，這使它們各自具有獨特的功能，參與了多樣的生理功能，包括：胞器運送、訊息傳遞、細胞分裂、細胞生長調節、細胞凋亡等。許多已發表的研究結果指出不同的annexin成員會於特定的腫瘤細胞中表現量上升，除了可作為生物標誌的可能性外，也暗示著annexin可能參與了腫瘤生成與發展的過程。根據先前我們實驗室發表的研究報告指出，annexin家族成員之一的annexin A4在受到胃幽門螺旋桿菌 (Helicobacter pylori)感染的胃癌病人組織及胃癌細胞株中皆會有表現量上升的現象，而抑制annexin A4表現則會減少因幽門螺旋桿菌感染而導致的interleukin-8分泌。為了探討annexin A4於胃癌細胞中的功能及其表現量增加後對胃癌細胞產生的影響，我們運用了蛋白質二維膠體電泳合併質譜儀的方法，偵測annexin A4大量表現後胃癌細胞AGS的蛋白質體變化；我們總共鑑定出36個表現量出現明顯差異的蛋白質，經由生物資訊資料庫軟體Ingenuity Pathway Analysis的輔助分析，推測細胞中產生了內質網壓力反應。在已發表的文獻中指出內質網壓力能促進細胞遷移能力，於是我們利用西方墨點法、創傷癒合實驗、胃癌細胞遷移能力測試及微陣列資料分析，證實了在annexin A4表現上升的胃癌細胞中，內質網壓力反應相關的蛋白質表現量有上升的趨勢，其下游的轉錄因子Nuclear factor kappa B (NF-kB)及c-myc的表現量上升，且同時促進Akt的活化，這些變化誘導真核起始因子4E (eukaryotic initiation factor 4E, EIF4E)的表現增加，導致胃癌細胞遷移的能力提高的結果。而給予細胞內質網壓力反應抑制劑8-(N,N-Diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8)則能回復這個現象。我們的結果提供了一個可能的作用機制，以解釋為何annexin A4表現量增加會導致胃癌細胞遷移的能力，這將為胃癌的治療提供有用的資訊。 | zh_TW |
| dc.description.abstract | The annexin family is ubiquitous proteins capable of binding to membrane with their C-terminal annexin repeats in a Ca2+-dependent manner. The variances of N-terminal of each annexin member contribute to their wide variety of functions including vesicle trafficking, signaling, cell division, growth regulation and apoptosis. Their differentially expressions in distinct tumors are considered as biomarkers and may imply the participation in tumorgenesis. Our previous study showed that annexin A4, a member of annexin family, was overexpressed in both gastric tumor tissues and host cancer cells infected by Helicobacter pylori (H. pylori). Meanwhile, the production of IL-8, an indicator of infection, decreased after annexin A4 knockdown. To investigate the role of annexin A4 in gastric cancer cells, proteomics and network analysis were performed. 36 differentially expressed proteins and a network analysis related to protein folding were identified using Ingenuity Pathway Analysis software. Furthermore, we found ER stress pathway which may increase cell migration ability was very important in annexin A4-overexpressed cells. Therefore, we used western blotting, wound healing assay, cell migration ability assay to elucidate the expression levels of proteins involved in the response to ER stress and migration ability in annexin A4-overexpressed gastric cancer cells. Here, we show that annexin A4 overexpression not only increases ER stress related protein expression and migration ability but also activates two transcription factors, Nuclear factor kappa B (NF-kB) and c-myc, and triggers Akt phosphorylation. These changes might lead to a substantial rise in the expression of the eukaryotic initiation factor 4E (eIF4E) gene, ultimately promoting the migratory ability of gastric cancer cells. The phenomenon was reversed by treating cells with ER stress signaling inhibitor, 8-(N,N-Diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8). Our results demonstrated a plausible mechanism to explain the phenomena that migratory ability increased in annexin A4-overexpressed gastric cancer cells. Eventually, these findings provide useful information in gastric cancer therapy. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T04:46:59Z (GMT). No. of bitstreams: 1 ntu-99-R97b43005-1.pdf: 7917958 bytes, checksum: 8bc9bbeab966d266bdffe93b6e22822e (MD5) Previous issue date: 2010 | en |
| dc.description.tableofcontents | 誌謝 I
中文摘要 III Abstract V 第1章 簡介 1 1.1. 胃癌 1 1.1.1. 胃癌的危險因子 1 1.2. Annexin蛋白質 2 1.2.1. Annexin A4蛋白質 3 1.3. 內質網 (Endoplasmic reticulum, ER) 4 1.3.1. 內質網壓力 (ER stress)來源 4 1.3.2. 內質網壓力訊息傳遞 (ER stress signaling) 4 1.4. 研究動機 5 第2章 實驗材料與方法 7 2.1. 細胞培養 7 2.1.1. AGS細胞株簡介 7 2.1.2. RPMI-1640培養基配製 7 2.1.3. 細胞解凍 7 2.1.4. 細胞繼代培養 8 2.1.5. 細胞冷凍保存 8 2.1.6. 細胞計數 8 2.2. 建構pcDNA3.1(+)-Annexin A4表現載體 8 2.2.1. 細胞總RNA萃取 8 2.2.2. 反轉錄聚合酶鏈鎖反應 (Reverse Transcription PCR) 9 2.2.3. 聚合酶鏈鎖反應放大目標基因 (PCR amplification) 10 2.2.4. 聚合酶鏈鎖反應產物純化 (PCR clean up) 10 2.2.5. 質體抽取與保存 11 2.2.6. 雙重限制酶切反應 (Double digestion) 11 2.2.7. 1 %洋菜膠體製備及核酸電泳 12 2.2.8. 膠體萃取 (Gel extraction) 12 2.2.9. 接合反應 (Ligation) 12 2.2.10. 質體轉形作用 (Plasmid transformation) 12 2.2.11. 菌落聚合酶鏈鎖反應 (Colony PCR) 13 2.3. 細胞轉染 (Cell transfection) 13 2.4. 細胞蛋白質溶解液製備 13 2.5. 蛋白質濃度測定 13 2.6. 二維膠體電泳 (Two-dimensional electrophoresis) 14 2.6.1. 一維等電點電泳 (isoelectronic focusing, IEF) 14 2.6.2. SDS二維膠片鑄膠 15 2.6.3. 二維電泳 15 2.6.4. 膠片染色 16 2.6.5. 蛋白質圖譜比對 16 2.6.6. 膠體內酶切萃取 (In-gel digestion) 16 2.6.7. MALDI-TOF-TOF質譜 16 2.6.8. MASCOT蛋白質身份鑑定 17 2.7. 西方墨點法 (Western blot) 17 2.8. 創傷癒合實驗 (Wound healing assay) 18 2.9. 細胞遷移能力實驗 (Cell migration ability assay) 18 2.10. 微陣列資料分析 18 第3章 結果 20 3.1. 於AGS中大量表現annexin A4 20 3.2. 二維膠體電泳分離大量表現annexin A4的AGS細胞總蛋白質 20 3.3. 鑑定出36種表現量產生差異的蛋白質點 21 3.4. 使用Ingenuity Pathway Analysis (IPA)分析表現量有差異的蛋白質，發現可能與內質網壓力有關 21 3.5. 以西方墨點法驗證內質網壓力的產生 22 3.6. 大量表現annexin A4的細胞中轉錄因子NF-κB增加 22 3.7. 創傷癒合實驗顯示annexin A4增加後細胞遷移能力上升 22 3.8. 細胞遷移能力實驗測試細胞遷移能力的變化程度 23 3.9. 藥物抑制內質網壓力的產生將降低annexin A4表現量上升細胞的遷移能力 23 3.10. 微陣列資料中指出annexin A4增加後，與細胞遷移有關的EIF4E於mRNA層級的表現量大幅上升 24 3.11. eIF4E在蛋白質層級的表現量亦有上升 24 3.12. 內質網壓力可能透過TNF、c-myc及caspase分子而使EIF4E增加 24 3.13. Annexin A4表現量上升的細胞中，c-myc表現量提高 24 3.14. Annexin A4增加導致了Akt磷酸化程度上升 25 第4章 結論與討論 26 第5章 參考文獻 32 第6章 圖 37 第7章 表 53 附錄 58 | |
| dc.language.iso | zh-TW | |
| dc.title | Annexin A4經由引發內質網壓力而促進細胞遷移能力 | zh_TW |
| dc.title | Annexin A4 Enhances Cell Migration Ability through Triggering Endoplasmic Reticulum Stress Signaling | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 98-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 黃宣誠,陳水田,陳炯年,徐駿森 | |
| dc.subject.keyword | 蛋白質體學,Annexin A4,胃癌,內質網壓力,細胞遷移, | zh_TW |
| dc.subject.keyword | Proteomics,annexin A4,gastric cancer,ER stress,cell migration, | en |
| dc.relation.page | 59 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2010-08-05 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 分子與細胞生物學研究所 | zh_TW |
| 顯示於系所單位： | 分子與細胞生物學研究所 | |
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