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研究生:張語琦
研究生(外文):Yu-Chi
論文名稱:金針菇免疫調節蛋白FIP-fve抑制A549肺癌細胞轉移與增生之研究
論文名稱(外文):Inhibition of lung cancer metastasis and proliferation unction by fungal immunomodulatory protein, FIP-fve, from Flammulina velutipes
指導教授:柯俊良柯俊良引用關係
口試委員:柯俊良馬明琪李宜儒
口試日期:2010-06-22
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:醫學分子毒理學研究所
學門:醫藥衛生學門
學類:其他醫藥衛生學類
論文種類:學術論文
論文出版年:2010
畢業學年度:98
語文別:中文
論文頁數:101
中文關鍵詞:免疫調節蛋白肺癌轉移
外文關鍵詞:immunomodulatory proteinxlung cancer metastasismetastasis
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FIP-fve為一個從金針菇 (Flammulina velutipes) 純化出來的免疫
調節蛋白,被歸類在真菌類免疫調節蛋白 (FIPs),此類的蛋白具有調控 IFN-γ 增加,減少過敏發炎,而對抗癌症功效的文獻較少。Rac1是一個小分子訊息傳遞 G 蛋白,參與了許多細胞的訊息調控,例如細胞增生,細胞間的附著與細胞的移行調控等。RACGAP1 (Rac GTP水解酶活化蛋白 1) 可水解 Rac 上的 GTP 從而抑制 Rac 的活性。在MTT assay 中可以發現,FIP-fve能夠抑制肺癌細胞 A549 的細胞存活率。將 A549細胞處理 FIP-fve 48 小時後進行 wound-healing assay,發現 FIP-fve 可以抑制 A549 細胞的移行能力,而以 Texas Red®-X phalloidin 標定同樣經由 FIP-fve 處理過的 A549 細胞,可以看到filopodia fibers 的數量明顯下降,我們以 pull down assay 分析,則呈現出經 FIP-fve 處理後的 A549 細胞,其可抑制由 EGF 刺激的 Rac1活性。經由 RT-PCR 和 western blotting分析,顯示出 RACGAP1 的表現量會被 FIP-fve 所抑制,而 reporter luciferase assay 中也發現到,RACGAP1 promoter 的活性會在處理過 FIP-fve 後有明顯下降的情形。因此,我們以 lentivirus系統 knockdown A549細胞中 RACGAP1的表現,則發現到細胞生長的情況有顯著的降低,以 wound healing closure 則發現細胞移行有促進的現象,但以boyden chamber分析卻沒有顯著影響。綜合以上實驗結果我們推論,FIP-fve 可以透過抑制Rac1的活化,而降低肺癌細胞A549的移行能力,但似乎與RACGAP1無關。然而,FIP-fve可能透過抑制 RACGAP1 的表現來減少 A549 細胞的增殖。
FIP-fve is an immunomodulatory protein isolated from Flammulina velutipes and it is classed as a new family of fungal immunomodulatory proteins (FIPs) that have anti-inflammatory function, but little is known for its effect on anti-cancer. Rac1 is a small signaling G protein that is a pleiotropic regulator of many cellular processes, including the cell cycle, cell-cell adhesion and motility. It inhibited cell survival of A549 lung cancer cell detected by MTT assay after FIP-fve treatment for 48h. Wound-healing assay was used to evaluate the inhibitory effects of FIP-fve on migration ability of A549 cells. F-actin labeling with Texas Red®-X phalloidin reveals that A549 cells exhibit numerous filopodia, whereas the FIP-fve-treated cells exhibit fewer filopodia fibers. To confirm the role of Rac1 in the inhibition of filopodia reduced by FIP-fve in A549 cells, FIP-fve inhibits EGF-induced activation of Rac1. We demonstrated that FIP-fve decrease mRNA and protein level of RACGAP1 using RT-PCR and western blotting. The reporter activity of RACGAP1 was detected by reporter luciferase assay, and exhibited the inhibition after treat FIP-fve. In this study, we knockdown the expression of RACGAP1 through lentivirus system and the cell growth is downregulated that assessed by proliferation assay. In conclusion, FIP-fve downregulate migration through inhibiting the activation of Rac1 but is not assosiated with RACGAP1. The inhibition of proliferation of A549 cells treated by FIP-fve may through negatively regulate RACGAP1.

目錄

壹、 中文摘要-------------------------------------------------------1
貳、 英文摘要(Abstract)---------------------------------------3
參、 縮寫表----------------------------------------------------------4
肆、 緒論-------------------------------------------------------------6
一、真菌類免疫調節功能----------------------------------------------6
二、金針菇免疫調節蛋白----------------------------------------------8
三、真菌類蛋白的穩定及吸收---------------------------------------10
四、真菌類的抗癌研究------------------------------------------------12
五、Rac1與細胞移行的關係-----------------------------------------14
六、RACGAP1 (Rac GTPase activating protein 1)----------------15
伍、 研究動機------------------------------------------------------16
陸、 實驗材料------------------------------------------------------18
一、儀器------------------------------------------------------------------18
二、藥品------------------------------------------------------------------19
三、材料------------------------------------------------------------------20
四、細胞株來源---------------------------------------------------------21
柒、 實驗方法------------------------------------------------------22
一、FIP-fve的分離與純化--------------------------------------------22
二、Hollow fiber 純化金針菇蛋白----------------------------------23
三、SDS-聚丙烯醯銨板膠電泳法 (SDS-polyacrylamide slab gelelectrophoresis)------------------------------------------------------------------------------23
(1)SDS-聚丙烯醯銨板膠電泳法之製備-------------------------23
(2)SDS-PAGE之電泳操作-----------------------------------------24
(3)染色與褪色--------------------------------------------------------24
(4)染色液與退色液的製備-----------------------------------------25
四、ELISA IFN-γ活性測定-------------------------------------------25
(1)人類週邊淋巴球 (HPBMCs) 之取得-------------------------25
(2)ELISA plate製備與實驗流程-----------------------------------26
五、細胞培養 (cell culture)--------------------------------------------28
(1)細胞培養 (cell culture)-------------------------------------------28
(2)繼代培養 (passage)-----------------------------------------------29
(3)冷凍細胞 (frozen cell)--------------------------------------------29
(4)解凍細胞 (defrozen cell)-----------------------------------------30
六、MTT assay------------------------------------------------------------30
七、細胞週期分析-流式細胞儀---------------------------------------31
(1)細胞之固定與染色------------------------------------------------31
(2)儀器操作與軟體分析---------------------------------------------32
八、細胞傷口癒合試驗(Wound Healing)-------------------------33
九、細胞轉移試驗(Modified Boyden Chamber)-----------------33
(1)Migration試驗------------------------------------------------------33
(2)Invasion試驗--------------------------------------------------------34
十、免疫螢光染色(Immunofluorescence)-------------------------35
十一、GST-Pull down assay----------------------------------------------36
(1)收取細胞蛋白-------------------------------------------------------36
(2)利用親合性的Glutathione Resin去沉澱活化態的Rac1,並以西方點墨法偵測-----------------------------------------------------------------------------36
十二、反轉錄酶鏈聚合酶連鎖反應 (RT-PCR)----------------------37
(1)RNA純化------------------------------------------------------------37
(2)cDNA的合成 ( RT-PCR )----------------------------------------38
(3)PCR (鏈聚合酶鏈鎖反應)-----------------------------------------38
十三、西方點墨法(Western Blot)---------------------------------------39
(1)樣品製備 (Sample Preparation)----------------------------------39
(2)蛋白濃度定量分析 (Protein Quantification)-------------------40
(3)SDS-聚丙烯醯胺板膠電泳之轉漬 (SDS-PAGE)-------------41
(4)抗體作用及偵測方法 (Antibody Detection)-------------------42
十四、Transient Transfection和Reporter Luciferase Assay---------43
(1)質體DNA的轉染 (Transient Transfection)--------------------43
(2)Reporter Luciferase Assay------------------------------------------44
十五、RNA干擾法(RNA interference)-----------------------------45
(1)VSV-G pseudotypred Lentivirus shRNA system----------------45
(2)Lentivirus shRNA infection of cell--------------------------------46
十六、細胞增生試驗(Proliferation)---------------------------------46
捌、 結果---------------------------------------------------------------48
一、FIP-fve的純化--------------------------------------------------------48
二、FIP-fve的免疫調節功能活性分析--------------------------------48
三、分析FIP-fve對肺癌細胞A549之細胞存活率之影響---------49
四、FIP-fve蛋白對造成肺癌細胞A549細胞週期G1之影響-----50
五、以西方墨點法分析在處理FIP-fve對A549細胞中p21、p27、p53與E2F-1蛋白表現量的影響----------------------------------------------------------50
六、探討FIP-fve對肺癌細胞A549轉移能力的影響---------------51
(1)以wound healing assay評估FIP-fve對於肺癌細胞A549移動性的影響----------------------------------------------------------------------------------52
(2)以Boyden Chamber觀察處理FIP-fve的A549細胞運動性移行(Migration)----------------------------------------------------------------------------------52
(3)以Boyden Chamber觀察處理FIP-fve的A549細胞侵襲性移行(Invasion)----------------------------------------------------------------------------------52
七、FIP-fve蛋白抑制細胞骨架絲狀蛋白(filopodia)的形成-----53
八、FIP-fve蛋白抑制由EGF刺激所產生的活化態Rac1----------54
九、FIP-fve蛋白對於肺癌細胞A549中與細胞移行相關的基因之影響----------------------------------------------------------------------------------54
十、FIP-fve蛋白抑制肺癌細胞A549中RACGAP1 基因表現----55
十一、FIP-fve蛋白抑制肺癌細胞A549中RACGAP1蛋白表現--55
十三、藉由boyden chamber分析經Lentivirus shRNA基因轉
殖降低A549細胞之RACGAP1基因表現後之細胞移行能---------57
十四、藉由wound healing assay分析經Lentivirus shRNA基因轉殖降低A549細胞之RACGAP1基因表現後之細胞移行能力--------------------------58
十五、經Lentivirus shRNA基因轉殖降低A549細胞 RACGAP1表現導致細胞生長能力下降--------------------------------------------------------------------58
十六、以流式細胞儀分析knockdown RACGAP1的A549細胞株之細胞週期-----------------------------------------------------------------------------------59
玖、 討論-----------------------------------------------------------------61
壹拾、 圖表說明-----------------------------------------------------------68
壹拾壹、 附圖-----------------------------------------------------------93
壹拾貳、 參考文獻-----------------------------------------------------94


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