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首页> 外文期刊>Glia >H-Ras increases urokinase expression and cell invasion in genetically modified human astrocytes through Ras/Raf/MEK signaling pathway
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H-Ras increases urokinase expression and cell invasion in genetically modified human astrocytes through Ras/Raf/MEK signaling pathway

机译：H-Ras通过Ras / Raf / MEK信号通路增加转基因人类星形胶质细胞中尿激酶表达和细胞侵袭

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Previous study reported that the activation of Ras pathway cooperated with E6/E7-mediated inactivation of p53/pRb to transform immortalized normal human astrocytes (NHA/hTERT) into intracranial tumors strongly resembling human astrocytomas. The mechanism of how H-Ras contributes to astrocytoma formation is unclear. Using genetically modified NHA cells (E6/E7/hTERT and E6/E7/hTERT/Ras cells) as models, we investigated the mechanism of Ras-induced tumorigenesis. The overexpression of constitutively active H-RasV12 in E6/E7/hTERT cells robustly increased the levels of urokinase plasminogen activator (uPA) mRNA, protein, activity and invasive capacity of the E6/E7/hTERT/Ras cells. However, the expressions of MMP-9 and MMP-2 did not significantly change in the E6/E7/hTERT and E6/E7/hTERT/Ras cells. Furthermore, E6/E7/hTERT/Ras cells also displayed higher level of uPA activity and were more invasive than E6/E7/hTERT cells in 3D culture, and formed an intracranial tumor mass in a NOD-SCID mouse model. uPA specific inhibitor (13428) and uPA neutralizing antibody decreased uPA activity and invasion in E6/E7/hTERT/Ras cells. uPA-deficient U-1242 glioblastoma cells were less invasive in vitro and exhibited reduced tumor growth and infiltration into normal brain in xenograft mouse model. Inhibitors of Ras (FTA), Raf (Bay 54-9085) and MEK (UO126), but not of phosphatidylinositol 3-kinase (PI3K) (LY294002) and of protein kinase C (BIM) pathways, inhibited uPA activity and cell invasion. Our results suggest that H-Ras increased uPA expression and activity via the Ras/Raf/MEK signaling pathway leading to enhanced cell invasion and this may contribute to increased invasive growth properties of astrocytomas. (C) 2008 Wiley-Liss, Inc.
机译：先前的研究报道，Ras途径的激活与E6 / E7介导的p53 / pRb失活协同作用，将永生化的正常人星形胶质细胞（NHA / hTERT）转化为与人星形细胞瘤非常相似的颅内肿瘤。 H-Ras如何促成星形细胞瘤形成的机制尚不清楚。使用转基因的NHA细胞（E6 / E7 / hTERT和E6 / E7 / hTERT / Ras细胞）作为模型，我们研究了Ras诱导的肿瘤发生的机制。组成性活性H-RasV12在E6 / E7 / hTERT细胞中的过表达强烈增强了E6 / E7 / hTERT / Ras细胞的尿激酶纤溶酶原激活剂（uPA）mRNA，蛋白质，活性和侵袭能力。然而，在E6 / E7 / hTERT和E6 / E7 / hTERT / Ras细胞中，MMP-9和MMP-2的表达没有明显变化。此外，在3D培养中，E6 / E7 / hTERT / Ras细胞还显示出更高水平的uPA活性，并且比E6 / E7 / hTERT细胞更具侵袭性，并且在NOD-SCID小鼠模型中形成了颅内肿瘤块。 uPA特异性抑制剂（13428）和uPA中和抗体可降低uPA活性并侵袭E6 / E7 / hTERT / Ras细胞。在异种移植小鼠模型中，uPA缺陷型U-1242胶质母细胞瘤细胞在体外的侵袭性较小，并表现出降低的肿瘤生长和向正常脑的浸润。 Ras（FTA），Raf（Bay 54-9085）和MEK（UO126）的抑制剂抑制了uPA活性和细胞侵袭，但不抑制磷脂酰肌醇3-激酶（PI3K）（LY294002）和蛋白激酶C（BIM）通路。我们的结果表明，H-Ras通过Ras / Raf / MEK信号通路增加uPA表达和活性，导致细胞侵袭增加，这可能有助于星形细胞瘤的侵袭性生长特性增加。 （C）2008 Wiley-Liss，Inc.

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