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研究生:劉漢勳
研究生(外文):Han-Hsun Liu
論文名稱:薑黃素對於溶血磷脂酸刺激卵巢癌細胞表達介白素-8之調節作用探討
論文名稱(外文):Regulation of Interleukin-8 Expression in LPA-stimulated Ovarian Cancer Cells by Curcumin
指導教授:吳鈺琳
指導教授(外文):Yuh-Lin Wu
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生理學研究所
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:2009
畢業學年度:97
語文別:中文
論文頁數:77
中文關鍵詞:卵巢癌介白素-8溶血磷脂酸薑黃素
外文關鍵詞:ovarian cancerInterleukin-8LPACurcumin
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溶血磷脂酸 (lysophosphatidic acid, LPA) 是一種小分子的水解磷脂質,已知在許多癌細胞中對於細胞的增生、遷移及侵入反應是很強的誘發因子。之前的研究指出在卵巢癌患者的腹水中存在著大量的LPA,LPA在卵巢癌細胞發展過程中也會促進一種前發炎性細胞介素 (proinflammatory chemokines) 及血管生成前趨因子 (pro-angiogenic factor) 介白素-8 (IL-8) 的表現。為了探討LPA在卵巢癌細胞中如何調節生成IL-8的表現,以及從薑黃根部萃取出的天然抗癌藥物薑黃素是否會抑制LPA刺激卵巢癌細胞生成IL-8,我們使用SKOV-3和OVCAR-3卵巢癌細胞株進行了一系列的實驗。首先,我們證實了LPA會誘導IL-8的分泌,而薑黃素會抑制這樣的誘導反應,而LPA刺激IL-8上升的反應也出現在DNA轉錄的時期,當IL-8 mRNA的濃度及IL-8促進子活性經由LPA誘導而增加時,薑黃素同樣的會減弱其效用。我們也利用類傷口癒合細胞遷移試驗 (wound-healing assay) 方法來研究溶血磷脂酸、介白素-8和薑黃素對細胞遷移的影響。實驗的結果顯示IL-8會促進SKOV-3卵巢癌細胞的遷移,而藉由LPA刺激產生的細胞遷移效果會被薑黃素以及磷脂酰醇-3-激酶 (PI3K) 的抑制劑LY294002所抑制。此外,我們使用MAPKs、NF�羠及PI3K的抑制劑探討LPA調節IL-8表現所參與的訊息傳遞路徑。實驗結果顯示除了PI3K 以外的MAPKs (p38、 JNK、 ERK) 以及NF�羠對於LPA增加IL-8的釋放扮演重要角色。另外,利用西方墨點法分析的結果也顯示LPA確實會增加MAPKs及PI3K下游訊息分子Akt的磷酸化表現,然而薑黃素在此只抑制JNK的磷酸化,對於p38、ERK及Akt的磷酸化則沒有效果。整體而言,LPA可以藉由MAPK和NF�羠這二條訊息傳導路徑調控IL-8的表現進一步促進卵巢癌細胞的遷移,以及另外一條不需經由IL-8的PI3K傳導路徑;另一方面,薑黃素可以抑制LPA所引起的JNK磷酸化,並因此降低了LPA誘發IL-8生成所產生的卵巢癌細胞遷移。
Lysophosphatidic acid (LPA), one of small lysophospholipids, is a well-recognized potent inducer of cell proliferation, migration and invasion in multiple cancers. Previous studies reported that high level of LPA is present in ascites of ovarian cancer patients and LPA was also shown to increase expression of interleukin-8 (IL-8), a pro-inflammatory and pro-angiogenic factor potentially involved in ovarian cancer progression. To define the molecular regulation mechanism of LPA on IL-8, and to address whether curcumin, an anti-tumor drug, would affect such regulation in ovarian cancer cells, a series of experiments were conducted in SKOV-3&OVCAR-3 ovarian cancer cells. First, we demonstrated that LPA could stimulate IL-8 secretion and such induction was inhibited by curcumin. LPA-induced IL-8 expression appeared to be transcriptional level, as IL-8 mRNA concentration and IL-8 promoter activity were elevated by LPA, and curcumin again was able to blunt such up-regulation. A wound-healing assay was adopted to investigate the functional significance of LPA, IL-8, and curcumin in cell migration, a critical step in cancer progression. Results implied that IL-8 could promote SKOV-3 migration, and LPA-mediated migration was diminished by curcumin and LY294002, a potent inhibitor of phosphoinositide 3-kinase (PI3K). In addition, inhibitors of MAPKs, NF�羠, and PI3K were used to identify the potential signaling players involved in LPA-mediated IL-8 expression. Results indicated that all MAPKs (p38, JNK and ERK) and NF�羠, but not PI3K were important mediating LPA-induced IL-8 production. Biochemical analysis by immunoblotting further revealed that LPA indeed resulted in phosphorylation of all MAPKs and Akt; however curcumin was only capable of attenuating the phosphorylation of JNK, but not p38, ERK or Akt. Taken together, LPA could elicit ovarian cancer cell migration at least in part via IL-8 up-regulation via MAPK and NF�羠 pathways, in parallel with another PI3K-dependent pathway; curcumin could blunt LPA-mediated JNK activation, and possibly therefore reduce LPA-induced IL-8 production to retard LPA-mediated ovarian cancer cell migration.
英文摘要 4
中文摘要 6
前言 (Introduction) 8
1. 卵巢癌 (Ovarian cancer) 8
2. 溶血磷脂酸 (Lysophosphatidic acid) 10
3. 介白素-8 (Interleukin-8) 14
4. 薑黃素 (Curcumin) 16
5. 研究動機 (Objective) 17
實驗材料與方法 (Materials and Methods) 19
1. 藥劑和試劑 (Chemicals and reagents) 19
2. 細胞培養 (Cell culture) 20
3. 介白素-8酶聯免疫吸附試驗法 (Interleukin-8 enzyme linked immunosorbent assay; IL-8 ELISA) 21
4. 半定量反轉錄聚合酶連鎖反應 (Semiquantitative reverse transcription-polymerase chain reaction;Semiquantitative RT-PCR) 22
5. Real-time PCR………...…………………………………………...…… 25
6. 四甲基偶氮唑鹽微量酶反應比色法 (MTT assay) 26
7. 轉染作用 (Transfection)……………………………………………...….26
8. 冷光酵素活性分析 (Luciferase reporter assay)………….……………..27
9. b-galactosidas (b-gal) reporter geneassay……….………………………27
10. 類傷口癒合細胞遷移試驗 (Wound-healing assay)..………………...….28
11. 西方墨點法 (Western blot)……………………………………………….29
12. 統計 (Statistics) 32
結果 (Results) 33
1. 溶血磷脂酸可誘導卵巢癌細胞釋放介白素-8,薑黃素具有抑制效果…33
2. 四甲基偶氮唑鹽微量酶反應比色法 (MTT assay) 試驗薑黃素對於卵巢癌細胞存活率的影響 33
3. 溶血磷脂酸可調節生成介白素-8 mRNA的表現 34
4. 薑黃素可抑制溶血磷脂酸調節生成介白素-8 mRNA的表現 34
5. 薑黃素減弱溶血磷脂酸所刺激的介白素-8促進子活性….……….…...35
6. 薑黃素抑制卵巢癌細胞遷移作用 36
7. 介白素-8增加卵巢癌細胞遷移作用…………………………………….36
8. PI3K抑制劑抑制溶血磷脂酸刺激卵巢癌細胞產生之遷移作用……...37
9. 溶血磷脂酸可藉由MAPK及NF�羠訊息路徑來促進介白素-8的釋放……………………………………………………………………………......37
10. 薑黃素抑制溶血磷脂酸引發之JNK磷酸化 (phosphorylation)……...38
11. 薑黃素抑制溶血磷脂酸引發之NFkB磷酸化 (phosphorylation)…….39
12. 薑黃素對溶血磷脂酸增加卵巢癌細胞Akt磷酸化
(phosphorylation) 無抑制效果……………………………………………….40
討論 (Discussion)…………………………………………………………………...41
參考文獻 (References) 45
圖與圖誌 (Figures and Figure Legends) 54
圖一、在SKOV-3細胞株中,薑黃素會抑制經由溶血磷脂酸所引發之介白素-8釋放………………………………………………………………………..55
圖二、在SKOV-3細胞株中,薑黃素對細胞毒性之影響…………………..56
圖三、在SKOV-3細胞株中,溶血磷脂酸能促使介白素-8 mRNA表現量增加………………………………………………………………………………..57
圖四、在SKOV-3細胞株中,薑黃素抑制溶血磷脂酸所刺激的介白素-8 mRNA表現…………………………………………………………………….58
圖五、在SKOV3細胞株中,real-time PCR結果顯示溶血磷脂酸能促使介白素-8 mRNA表現量增加…………………………………………………….59
圖六、在SKOV-3細胞株中,real-time PCR結果顯示薑黃素會抑制溶血磷脂酸所刺激的介白素-8 mRNA表現………………………………………….60
圖七、在SKOV-3細胞株中,薑黃素減弱溶血磷脂酸所刺激的介白素-8 促進子活性………………………………………………………………………..61
圖八、利用類傷口癒合細胞遷移試驗 (Wound-healing assay) 發現薑黃素可抑制溶血磷脂酸引起的細胞遷移……………………………………………..62
圖九、利用類傷口癒合細胞遷移試驗 (Wound-healing assay) 發現外加介白素-8可增加細胞遷移…………………………………………………………..63
圖十、利用類傷口癒合細胞遷移試驗 (Wound-healing assay) 發現PI3K抑制劑可抑制溶血磷脂酸引起的細胞遷移……………………………………..64
圖十一、溶血磷脂酸能刺激SKOV-3細胞株經由MAPK及NF�羠路徑產生介白素-8………………………………………………………………………...65
圖十二、在SKOV-3細胞株中,溶血磷脂酸會使p38磷酸化………...……66
圖十三、薑黃素對溶血磷脂酸刺激p38磷酸化之影響………..…………….67
圖十四、在SKOV-3細胞株中,溶血磷脂酸會使JNK磷酸化.……………68
圖十五、薑黃素對溶血磷脂酸刺激JNK磷酸化之影響……..……………...69
圖十六、在SKOV-3細胞株中,溶血磷脂酸會使ERK磷酸化………...….70
圖十七、薑黃素對溶血磷脂酸刺激ERK磷酸化之影響……………………71
圖十八、薑黃素對溶血磷脂酸刺激NFkB磷酸化之影響…………………..72
圖十九、在SKOV-3細胞株中,溶血磷脂酸會使Akt磷酸化………....…..73
圖二十、在SKOV-3細胞株中,薑黃素不影響溶血磷酸所刺激的Akt磷酸化……….…...………………………………………………………………..…74
圖二十一、薑黃素透過抑制JNK的活化來抑制溶血磷脂酸促進SKOV-3細胞株的遷移……………………………………………………………….…….75
致謝 (Acknowledgements)…………..…………………………………………......76
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