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    請使用永久網址來引用或連結此文件: http://libir.tmu.edu.tw/handle/987654321/6719


    題名: MMP-9與COX-2在TPA誘導之人類神經膠質瘤轉移之角色探討
    Roles of MMP-9 and COX-2 in TPA-induced metastasisi of human glioblastoma cells
    作者: 夏琳婷
    Lin-Ting Hsia
    貢獻者: 生藥學研究所
    關鍵詞: 神經細胞瘤
    轉移
    glioblastoma
    U87
    TPA
    COX-2
    PKC
    ROS
    flavone
    日期: 2006
    上傳時間: 2009-09-11 17:19:10 (UTC+8)
    摘要: 神經膠質瘤(Glioblastoma)為腦癌中最惡性且轉移和侵犯能力最強的一種原發性腦癌。為了要瞭解神經膠質瘤細胞如何侵犯和轉移的機制，本實驗利用人類神經膠質瘤細胞株(U87MG)探討12-ο-tetradecanoylphorbol 13-acetate(TPA)所誘導產生的基質金屬蛋白酶(Matrix metalloproteinases-9, MMP-9)表現和環氧酶(Cyclooxygenase, COX)活化在癌細胞轉移和侵犯的機制中所扮演的角色。利用Spheroid assay和wound migration assay和In vitro invasion assay三種體外實驗，探討TPA所誘導的神經膠質瘤細胞的轉移和侵犯的生理活性現象。TPA本身是很強的細胞癌化促進劑，在動物皮膚試驗及細胞實驗中均被證實。TPA之所以能夠促進細胞癌化是經由活化細胞內的訊息傳導路徑。在U87MG細胞中，TPA所誘導之MMP-9酵素活性和COX-2蛋白的表現是相呼應的。若使用COX-2抑制劑(NS398)則可抑制MMP-9的酵素活性並且顯著地降低TPA所誘導之癌細胞轉移和侵犯的現象。在加入TPA的U87MG細胞中可以偵測到ERKs透過蛋白質的磷酸化而活化，並且如果將細胞培養在加入ERKs抑制劑PD98059中，可以明顯地降低TPA所誘導的MMP-9和COX-2蛋白表現進而抑制細胞的轉移和侵犯。除此之外，TPA也可刺激U87MG細胞中protein kinase C-?? (PKC??)活性的增加。加入了PKC的抑制劑(GF109203X, GF和Go6976, Go)可以明顯的抑制由TPA所誘導的ERKs磷酸化和COX-2蛋白及MMP-9酵素的活性表現。同時，我們也發現活性氧物質Reactive oxygen species(ROS)的活化也包含在此訊息傳導的路徑中。在加入了ROS抑制劑Superoxide dismutase(SOD),Tempol(TEM)和Diphenylene iodonium(DPI)後，可抑制由TPA所誘導產生的ROS和細胞中的訊息傳遞。本篇實驗證實了MMP-9酵素活性和COX-2蛋白的活化在TPA所誘導的神經膠質瘤細胞轉移和侵犯中扮演了相當重要的角色，而細胞內的激酶與ROS的活化、COX-2基因的表現也參與其中。
    Astrocytic glioma is a type of malignant brain tumor and the mortality of patients with astrocytic glioma remains high in the world. Therefore, investigating transformation mechanism of glioma, and developing effective agents to block its transformation are important issues for glioma treatment. In the present study, tumor promoter 12-ο-tetradecanoylphorbol 13-acetate (TPA) addition induces migration, invasion, and transformation in U87MG glioblastoma cells by spheroid formation and wound healing assay and transwell invasion assay accompanied by stimulating MMP-9 enzyme activity. A significant increase in COX-2 protein and mRNA level was observed in TPA-treated U87MG glioma cells, and adding chemical COX inhibitor NS398 reduces the TPA-induced MMP-9 activation and transformation in U87MG cells. Suppression of ERKs, but not JNKs, by chemical inhibitors TPA-induced transformation reduced MMP-9 enzyme activity, and COX-2 protein in U87MG cells. Addition of PKC inhibitors GF109203X(GF) and Go6976(Go) significantly attenuates TPA-induced transformation in according with suppressing ERKs protein phosphorylation, and membrane translocation of PKC?? protein. Suppression of TPA-induced transformation events by reactive oxygen species scavengers Superoxide dismutase(SOD),Tempol(TEM) and Diphenylene iodonium(DPI) were identified in the present model. These data indicate that activation of PKC-ERKs via ROS production is involved in the transformation and MMP-9 activation of glioma in response to TPA, and COX-2-dependency are identified.
    資料類型: thesis
    顯示於類別:[生藥學研究所] 博碩士論文

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