探討肝細胞生長因子在軟骨肉瘤轉移之機制

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题名:	探討肝細胞生長因子在軟骨肉瘤轉移之機制 Study of hepatocyte growth factor in migration in human chondrosarcoma cells
作者:	洪雅慧;Hung, Ya-Hui
贡献者:	基礎醫學研究所碩士班
关键词:	軟骨肉瘤;肝細胞生長因子;基質金屬蛋白?細胞移行;Chondrosarcoma;Hepatocyte growth factor;Cell migration;Matrix metalloproteinase
日期:	2012-07-04
上传时间:	2012-08-31 16:33:42 (UTC+8)
出版者:	中國醫藥大學
摘要:	人類軟骨肉瘤的特性是高度惡性表現力和轉移能力。在先前研究中，肝細胞生長因子 (Hepatocyte growth factor；HGF) 會誘導癌細胞的增生、移行和促進腫瘤細胞的侵犯力。然而，肝細胞生長因子在人類軟骨肉瘤細胞遷移能力的影響作用卻尚不清楚。在我們的研究中發現，肝細胞生長因子會增加人類軟骨肉瘤細胞 (JJ012及SW1353細胞) 的細胞移行能力和基質金屬蛋白?MMP-2 (Matrix metalloproteinase) 的表現。我們預先在人類軟骨肉瘤?胞中處理PI3K (Phosphatidylinositol 3-kinase)抑制劑 (LY294002和Wortmannin)，發現可抑制HGF所誘導的癌細胞遷移和MMP-2的表現。在軟骨肉瘤細胞中加入肝細胞生長因子，會增加PI3K、AKT (Protein kinase B) 及PKCδ (Protein kinase C) 蛋白?磷酸化表現。此外，使用轉錄因子NF-κB的抑制劑 (PDTC) 或IkB蛋白?抑制劑 (TPCK) 也能抑制肝細胞生長因子所誘導的細胞遷移力和MMP-2的表現。肝細胞生長因子也可誘導IkB激? (IKKa/β)、IkB和p65磷酸化。此外，肝細胞生長因子所增加MMP-2的表現可藉由加入PI3K抑制劑 (LY294002及Wortmannin)、AKT抑制劑及NF-κB的抑制劑 (PDTC和TPCK) 所抑制。這些結果說明，HGF透過活化PI3K和AKT，同時活化下游IKKa/β和NF-κB路徑，導致MMP-2的活化並促使人類軟骨肉瘤細胞移行能力增加。 Chondrosarcoma is characterized by a high malignant and metastatic potential. It has been report that hepatocyte growth factor (HGF) induced proliferation, motility, and promoted invasion of tumor cells. However, the effect of HGF on migration activity in human chondrosarcoma cells is mostly unknown. Here, we found that HGF increased the migration and expression of matrix metalloproteinase (MMP)-2 in human chondrosarcoma cells (JJ012 and SW1353 cells). Pretreatment of chondrosarcoma cells with LY294002 and Wortmannin, which are PI3K inhibitors, inhibited the HGF mediated migration and MMP-2 expression. Stimulation of cells with HGF increased the phosphorylation of PI3K (Phosphatidylinositol 3-kinase), AKT (Protein kinase B) and PKCδ (Protein kinase Cδ). In addition, NF-kB inhibitor (PDTC) or IkB protease inhibitor (TPCK) also inhibited HGF-mediated cell migration and MMP-2 up-regulation. Stimulation of cells with HGF induced IκB kinase (IKKa/β) phosphorylation, IkB phosphorylation, and p65 phosphorylation. Furthermore, the HGF mediated increasing MMP-2 expression was inhibited by LY294002, Wortmannin, Akt inhibitor, Rottlerin, PDTC , and TPCK. Taken together, these results suggest that the HGF acts through activate PI3K, AKT, and PKCδ, which in turn activates IKKa/β, and NF-kB, resulting in the activations of MMP-2 and contributing the migration of human chondrosarcoma cells.
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