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研究生:劉振偉
研究生(外文):Chen-Wei Liu
論文名稱:Nanog在Snail造成肺癌細胞上皮-間質轉移中扮演之角色及其與訊號傳遞路徑
論文名稱(外文):Snail Regulate Nanog Status during Epithelial-Mesenchymal Transition via Smad1/Akt/GSK-3beta Signaling Pathway in Non-Small-Cell Lung Cancer
指導教授:顏茂雄顏茂雄引用關係康照洲康照洲引用關係
指導教授(外文):Mao-Hsiung YenJaw-Jou Kang
口試委員:林雅雯鄭幼文陳惠文顏茂雄康照洲
口試委員(外文):Ya-Wen LinYu-Wen ChengHuei-Wen ChenMao-Hsiung YenJaw-Jou Kang
口試日期:20140910
學位類別:博士
校院名稱:國防醫學院
系所名稱:醫學科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2014
畢業學年度:103
語文別:中文
論文頁數:85
中文關鍵詞:上皮-間質轉移間質轉移非小細胞肺癌非腫瘤幹細胞
外文關鍵詞:SnailNanogepithelial-mesenchymal transitioncancer stem cellnon-small-cell lung cancerSmadAktNoggin
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上皮-間質轉移對於腫瘤細胞轉化腫瘤類幹細胞特性具有重要性也是腫瘤細胞轉移的關鍵步驟。在本研究中,我們在非小細胞肺癌細胞株建立Snail蛋白大量表現細胞株並研究對上皮-間質轉移作用機制。另ㄧ方面,我們也想證實Snail蛋白調控Nanog表現以及其下游分子訊號傳遞路徑。實驗結果發現,肺癌病人中Snail蛋白與腫瘤轉移以及Nanog蛋白具有高度相關性,與肺癌進程息息相關。當肺癌細胞株大量表現Snail蛋白後,能誘導上皮-間質轉移的發生,使細胞增加轉移能力、化療藥物抗性、腫瘤球形成以及使細胞具有類幹細胞特性。本研究發現Snail表現與Smad1、Akt以及GSK-3β磷酸化具有顯著相關性。接著,在分子機制方面,當細胞處在上皮-間質轉移時前處理細胞LY294002、SB431542、LDN193189等抑制劑與Noggin後,皆能顯著抑制Snail蛋白所誘導Nanog蛋白之表現以及Smad1和Akt活化並使GSK-3β再次活化。此外,當LY294002處理細胞後能抑制Akt過度活化使GSK-3β再次活化但並不會改變Smad1的活化狀態。綜合以上結果,Snail蛋白在肺癌細胞及上皮-間質轉移過程中扮演重要的角色,我們也發現Snail蛋白調控Nanog表現的訊號傳遞分子機制是透過Smad1/Akt/GSK-3β訊號傳遞路徑,這些研究結果能提供非小細胞肺癌的預後程度判讀與治療標靶藥物的開發。
The epithelial-mesenchymal transition (EMT), a crucial step in cancer metastasis, is important in transformed cancer cells with stem cell-like properties. In this study, we established a Snail-overexpressing cell model in non-small-cell lung cancer (NSCLC) and investigated its underlying mechanism. We also identified the downstream molecular signaling pathway that contributed to the role of Snail to regulated Nanog expression. Our data shown that high level Snail expression correlate with metastasis and high Nanog expression in NSCLC. NSCLC cells expressing Snail are characterized by active EMT characteristics, and exhibit increased ability of migration, chemoresistance, sphere formation and stem cell-like properties. Then, the signals required for Snail-mediated Nanog expression was studied. Our data demonstrated that LY294002, SB431542, LDN193189 and Noggin pretreatment inhibited Snail-induced Nanog expression during EMT. This study shown a significant correlation between the Snail and phosphorylation Smad1, Akt or GSK-3β pretreatment with SB431542, LDN193189 and Noggin prevented Snail-induced Smad1 and Akt hyper-activation and reactivated GSK-3β. In addition, LY294002 pretreatment also prevented Akt hyper-activation and reactivated GSK-3β but without any changes in Smad1 activation. These findings demonstrated that the novel mechanistic insight into an important role of Snail in NSCLC during EMT, and suggest provide an useful therapeutic targets in NSCLC prognosis and treatment.
目錄 (Contents) 頁次
目錄 I
表目錄 V
圖目錄 VI
字母縮寫表 IX
中文摘要 XI
英文摘要 XII
緒論 (Introduction) 1
第一節、肺癌 (Lung cancer) 1
第二節、上皮-間質轉移 (Epithelial-Mesenchymal Transition) 3
第三節、腫瘤幹細胞 (Cancer stem cells) 7
壹、血癌幹細胞 7
貳、實體腫瘤幹細胞 8
第四節、上皮-間質轉移與腫瘤幹細胞 9
第五節、上皮-間質轉移調節因子 Snail 10
第六節、研究動機 14
第二章 材料與方法 (Materials and Methods) 15
第一節、實驗材料 15
壹、細胞株 (Cell lines) 14
貳、藥品與試劑 (Chemicals and Reagents) 15
叁、抗體 (Antibodies) 16
第二節、實驗方法 17
壹、細胞培養 (Cell culture) 17
貳、質體 (Plasmids) 18
叁、細胞毒性測試 (Cell viability test/MTT assay) 19
肆、細胞總蛋白質液收集 (Cell lysate collection) 19
伍、西方墨點法 (Western blot analysis) 19
陸、質體轉染 (Plasmid transfection) 20
柒、細胞RNA萃取(RNA extraction) 21
捌、反轉錄聚合酶鏈鎖反應(Reverse Transcription Polymerase Chain
Reaction, RT-PCR) 21
玖、免疫螢光染色 (Immunofluorescence staining) 22
拾、細胞移行分析 (Transwell Migration assay) 23
拾壹、流式細胞儀分析 (Flow cytometry analysis) 23
拾貳、老鼠肺部移生試驗 (Lung colonization assay) 24
拾叁、腫瘤異種移植 (Tumor Xenograft) 24
拾肆、免疫組織染色法 (Immunohistochemical analysis) 24
拾伍、統計分析 (Statistic analysis) 25
第三章 實驗結果 (Results)
第一節、探討肺癌病人檢體中Snail的表現與臨床病理因子相關性分析 26
第二節、探討肺癌細胞株Snail大量表現能誘導上皮間質轉移產生 26
第三節、探討Snail大量表現能增加A549細胞在老鼠體內轉移能力以及增加腫瘤的生長 27
第四節、探討Snail大量表現能誘導細胞具有幹細胞特性 28
第五節、探討肺癌病人檢體中Snail與Nanog之臨床相關性 29
第六節、探討Snail對於Snail相關的訊號傳遞路徑PI3K/Akt、MAPKs、STAT3和TGF-β/Smad與Nanog蛋白質表現之影響 29
第七節、探討Smad1在Snail誘導PI3K/Akt訊號傳遞路徑與Nanog蛋白質表現生成中所扮演之角色 30
第八節、探討Cisplatin與不同訊號傳遞路徑抑制劑共同處理對於Snail大量表現肺癌細胞株化療藥物敏感性響 32
第九節、探討CL1-5細胞株中內生性Snail對Smad1/Akt/GSK-3β訊號傳遞路徑與Nanog蛋白質表現生成之影響 32
第四章 討論 (Discussion) 35
第五章 結論 (Conclusion) 42
第六章、未來展望 (Future work) 43
圖表集 (Figures and Tables) 46
參考文獻 (References) 75

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