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系統識別號 U0026-0812200914153287
論文名稱(中文) 表皮生長因子調控胃腺癌AGS細胞中胃泌素基因表現之分子機轉
論文名稱(英文) The molecular mechanisms regulating gastrin gene expression under EGF treatment in AGS cells
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 96
學期 2
出版年 97
研究生(中文) 李秉澤
研究生(英文) Pin-Tse Lee
電子信箱 s5892105@mail.ncku.edu.tw
學號 s5892105
學位類別 博士
語文別 中文
論文頁數 120頁
口試委員 口試委員-賴明德
口試委員-林茂榮
口試委員-譚婉玉
指導教授-張文昌
召集委員-呂增宏
口試委員-劉校生
中文關鍵字 胃泌素基因表現  表皮生長因子 
英文關鍵字 AGS cells  EGF  gastrin 
學科別分類
中文摘要 胃泌素(gastrin)屬於胃腸之賀爾蒙,主要功能為調控胃酸的分泌。先前有研究報導證實胃泌素可扮演生長因子的角色並與胃腸系統的惡化(gastrointestinal tract malignancy)有關。此外,胃泌素亦會藉由其下游所調控之相關基因而參與包含細胞生長、細胞凋亡、血管新生、細胞轉移(migration)與invasion等調控,於細胞的癌化過程中扮演重要角色。另一方面,亦有證據顯示於肺癌、胰臟癌與結腸直腸癌中皆發現具有胃泌素mRNA高度表現的現象,但是其為何大量表現於上述各不同癌症中的原因與詳細之相關調控機轉至今仍尚未明瞭。根據先前之研究報告指出,表皮生長因子(epidermal growth factor)刺激下會促進胃泌素之轉錄活性(transcriptional activity),並進而增加mRNA的表現量。在本研究中發現在表皮生長因子(EGF)刺激下除了增加的轉錄活性(transcriptional activity)外,經由mRNA穩定度之分析結果顯示亦會提昇胃泌素mRNA的穩定度,此結果證實EGF參與胃泌素mRNA turnover之調控並與已知之轉錄作用(transcriptional regulation)共同控制胃泌素mRNA的表現量。利用生物素標定之RNA探針(biotin-labeled RNA probe)/ pull-down 實驗並配合質譜儀分析(mass spectrometry analysis),發現異質核醣核蛋白k (heterogeneous nuclear ribonucleoprotein K)與 poly(C)結合蛋白1 (poly(C) binding protein 1)皆會結合於胃泌素mRNA之3’非轉錄區域(3’untranslated region)。此外亦發現核仁蛋白nucleolin除了會藉由AGCCCU序列而專一性結合於胃泌素mRNA,也會與異質核醣核蛋白k進行蛋白質間之交互作用。當細胞受到表皮生長因子EGF刺激後,則會提昇核仁蛋白與異質核醣核蛋白k之交互作用。利用siRNA針對此三個RNA結合蛋白進行功能性分析後發現,分別抑制三個RNA結合蛋白的表現量後,在正常狀態下對於胃泌素mRNA的穩定度皆分別會有不同程度的影響。然而在EGF刺激下,核仁蛋白為扮演最主要提昇胃泌素mRNA穩定度的角色。因此我們提出一個全新的mRNA穩定度之調控模式,亦即結合於C-rich區域上之異質核醣核蛋白k與poly(C)結合蛋白1所形成之複合體會促進核仁蛋白結合於胃泌素mRNA之3’非轉錄區域的能力,進而提昇胃泌素mRNA的穩定度。
英文摘要 Gastrin, a gastrointestinal hormone responsible for gastric acid secretion, has been confirmed as a growth factor for gastrointestinal tract malignancies. Besides, it has been shown that gastrin regulates many genes involved in cell proliferation, apoptosis, angiogenesis, cell migration and invasion. High expression of gastrin mRNA was observed in lung, pancreatic and colorectal cancer, however, the detail regulatory mechanism is unclear. Previous studies indicated that EGF stimulates gastrin mRNA expression. In this study, EGF was also found to increase gastrin mRNA stability. And this result indicates mRNA turnover regulation mechanism is involved in the control of gastrin mRNA expression. Using biotin-labeled RNA probe pull-down assay combined with mass spectrometry analysis, we identified the heterogeneous nuclear ribonucleoprotein K (hnRNP K) and poly(C) binding protein 1 (PCBP1) bound with the C-rich region in gastrin mRNA 3’UTR. Nucleolin bound with the AGCCCU motif and interacted with hnRNP K were also demonstrated. Under EGF treatment, we observed the amount of nucleolin interacting with hnRNP K and gastrin mRNA was increased. Using siRNA technology to define their functional roles, we found hnRNP K, PCBP1 and nucleolin were all responsible for stabilizing gastrin mRNA. Moreover, nucleolin plays a crucial role in mediating the increased gastrin mRNA stability induced by EGF signaling. Besides, we also observed hnRNP K/PCBP1 complex bound with the C-rich region in the gastrin mRNA increased nucleolin binding with gastrin mRNA. Therefore, we provide a novel binding model.
論文目次 口試合格證明.............................................Ⅰ
中文摘要.................................................Ⅱ
英文摘要.................................................Ⅳ
致謝.....................................................Ⅵ
目錄.....................................................Ⅶ
圖目錄.................................................ⅩⅠ
縮寫檢索表...........................................ⅩⅠⅡ
第一章 緒論...............................................1
第一節 引言...............................................1
第二節 研究目標..........................................20
第三節 研究之重要性......................................21
第二章 實驗材料與方法....................................22
第一節 實驗材料..........................................22
第二節 實驗方法..........................................29
一、細胞培養.............................................29
二、細胞株保存...........................................29
三、分離萃取細胞質與細胞核(subcellular fractionation of AGS cells)...............................................30
四、mRNA穩定度分析(mRNA turnover analysis)...............30
五、細胞之基因轉殖(transfection).........................31
六、RT–PCR定量分析(quantitative RT–PCR)................31
七、蛋白質濃度測定(protein concentration determination)...........................................32
八、西方點墨法(Western-blotting).........................33
九、RNA electrophoretic mobility shift assay (RNA-EMSA)....................................................34
十、Biotin pull-down assay與質譜分析(mass spectrometry analysis) ................................................34
十一、蛋白質免疫沉澱分析(protein immunoprecipitation assay)...................................................36
十二、RNA免疫沉澱分析(RNA immunoprecipitation assay).....36
十三、Short interfering RNA (siRNA)......................36
十四、Tet-off mRNA turnover assay........................37
十五、增強細胞通透(permeabilization)與細胞核染色.........38
十六、免疫螢光染色(immunofluorescence staining)..........38
十七、質體DNA之建構(plasmid construction)................39
十八、瓊酯膠電泳(agarose gel electrophoresis)............40
十九、大腸桿菌之勝任細胞製備(competent cell preparation).............................................41
二十、質體DNA萃取(plasmid DNA purification)..............42
第三章 實驗結果..........................................43
第一節 EGF誘導人類胃腺癌細胞(AGS cells)中gastrin mRNA表現量增加.....................................................43
第二節 EGF促進gastrin mRNA穩定度增加.....................43
第三節 Gastrin mRNA之3’ untranslated region (3’UTR) 於AGS細胞中具有與RNA結合蛋白質(RNA binding proteins)形成複合物(RNA-protein complex)的現象..............................44
第四節 hnRNP K與PCBP1會結合於gastrin mRNA之3’UTR........47
第五節 EGF 訊息傳遞路徑調控nucleolin對於gastrin mRNA之結合能力並促進與hnRNP K進行蛋白質與蛋白質間的交互作用........48
第六節 hnRNPK/PCBP1複合物促進nucleolin經由AGCCCU序列結合於gastrin mRNA的能力.......................................51
第七節 減少hnRNP K、PCBP1、與 nucleolin 之蛋白質表現會導致gastrin mRNA表現量降低...................................53
第八節 nucleolin 調控gastrin mRNA穩定度..................54
第九節 EGF促進nucleolin由細胞核傳送至細胞質..............56
第四章 討論..............................................58
第五章 結論..............................................66
參考文獻.................................................67
已發表文獻著作...........................................91
自述.....................................................92
附錄....................................................111
附錄一、Structure of human preprogastrin and its derived peptides................................................111
附錄二、Gastrin-mediated carcinogenic pathways..........112
附錄三、The main site of gastrin synthesis is the gastrin-containing G cell within the antro-pyloric mucosa.......113
附錄四、Current view of mRNA stabilization and degradation.............................................114
附錄五、Examples of post-transcriptionally regulated neuronal mRNAs and the RNA binding proteins (RNA-BP) interacting with them...................................115
附錄六、Schematic view of regulatory levels and factors determining the balance between decay and stabilization of ARE-containing mRNA.....................................116
附錄七、The multiple-functions of nucleolin.............117
附錄八、Schematic representation of the organization of three nucleolin and ‘nucleolin-like proteins’.........118
附錄九、K protein (hnRNPK) modular structure............119
附錄十、A model of K protein acting as a docking platform to integrate signals from kinase cascades at a site of RNA-directed process........................................120

圖目錄
Figure 1. EGF induces the gastrin mRNA expression in AGS cells....................................................94
Figure 2. EGF increases gastrin mRNA stability in AGS cells....................................................95
Figure 3. The RNA secondary structure prediction of human gastrin 3’UTR...........................................96
Figure 4. Gastrin 3’UTR associates with protein complex..................................................97
Figure 5. Probe B and probe C interact with the same RNA-binding proteins in AGS cells............................98
Figure 6. Identification of the RNA binding proteins interacted with the gastrin mRNA.........................99
hnRNP K and PCBP1 interacted with gastrin mRNA..........100
Figure 8. Nucleolin binds with gastrin mRNA 3’UTR and hnRNP K.................................................101
Figure 9. EGF signaling regulates nucleolin interacted with gastrin mRNA and hnRNP K...........................102
Figure 10. Identified the nucleolin binding sequence in the gastrin mRNA........................................103
Figure 11. Silencing of hnRNP K, PCBP1, and nucleolin by SiRNA...................................................104
Figure 12. Silencing of hnRNP K, PCBP1, and nucleolin reduces gastrin mRNA expression level...................105
Figure 13. Mutation of nucleolin binding element decreases gastrin mRNA stability..................................106
Figure 14. Reduction of nucleolin protein expression decreases gastrin mRNA stability........................107
Figure 15. Cytoplasmic accumulation of nucleolin upon EGF treatment in AGS cells..................................108
Figure 16. EGF altered the cytoplasmic distribution of GFP-nucleolin in AGS cells..................................109
Figure 17. The binding model of nucleolin interacted with gastrin mRNA............................................110
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