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首页> 外文期刊>Journal of Cellular Physiology >MEK/ERK-dependent uPAR expression is required for motility via phosphorylation of P70S6K in human hepatocarcinoma cells.
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MEK/ERK-dependent uPAR expression is required for motility via phosphorylation of P70S6K in human hepatocarcinoma cells.

机译：MEK / ERK-dependent uPAR表达需要通过磷酸化的P70S6K人类能动性肝癌细胞。

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摘要

Motility and invasiveness events require specific intracellular signaling cascade activations. In cancer liver cells, one of these mechanisms could involve the MAPK MEK/ERK cascade activation which has been shown over expressed and activated in hepatocellular carcinoma. To study whether the MEK/ERK cascade is involved in the motility of HCC, we examined the effect of MEK inhibitor and ERK2 silencing using monolayer wound-healing assays and fluoroblock invasion systems. Evidence was provided that the MAPK cascade is a key transduction pathway which controls HCC cells motility and invasiveness. We could disconnect proliferation to motility using mitomycin C and we established that RNAi-mediated inhibition of ERK2 led to strongly reduced cell motility. To improve our understanding, we analysed the regulation and the role of urokinase receptor (uPAR) in this process. We provided evidence that uPAR was under a MEK/ERK dependent mechanism and blocking uPAR activity using specific antagonist or inhibiting itsexpression by RNA interference which resulted in complete inhibition of motility. Moreover, we found in MAPK inhibited cultures and in uPAR silencing cells that p70S6K phosphorylation on residue Thr-389 was significantly reduced, whereas Ser-421/Thr-424 phosphorylation did not change. We highlighted that the FRAP/mTOR pathway did not affect motility and Thr-389 phosphorylation. Furthermore, we demonstrated that p70S6K inhibition by RNA interference completely inhibited hepatocarcinoma cell motility. Therefore, targeting uPAR and/or MEK/ERK/S6K by RNA interference could be a major therapeutic strategy for the future treatment of invasive hepatocarcinoma cells.
机译：能动性和侵袭性需要特定的事件细胞内的信号级联激活。癌症肝细胞,这些机制之一涉及MAPK MEK / ERK级联激活已被证明在表达和激活吗肝细胞癌。MEK / ERK级联的能动性肝细胞癌,我们检查了MEK抑制剂的影响使用单层愈合ERK2沉默化验和fluoroblock入侵系统。提供MAPK级联是钥匙吗转导通路控制肝癌细胞能动性和侵袭性。扩散使用丝裂霉素C和能动性我们建立了RNAi-mediated抑制ERK2导致强烈降低细胞的能动性。改善我们的理解,我们分析了监管和尿激酶受体的作用在这一过程中(uPAR)。uPAR受到MEK / ERK和依赖机制阻塞uPAR活动使用特定的对手通过RNA干扰或抑制itsexpression导致完全抑制的能动性。文化和p70S6K uPAR沉默细胞磷酸化残留刺- 389显著降低,而ser - 421 /刺- 424磷酸化并没有改变。收紧/ mTOR通路没有影响能动性和刺- 389磷酸化。此外,我们表明,p70S6K完全由RNA干扰抑制抑制肝癌细胞的能动性。因此,针对uPAR和/或MEK / ERK / S6KRNA干扰可能是一个主要的治疗未来治疗侵袭性的策略肝癌细胞。

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