Overexpression of RASD1 inhibits glioma cell migration/invasion and inactivates the AKT/mTOR signaling pathway.
Overexpression of RASD1 inhibits glioma cell migration/invasion and inactivates the AKT/mTOR signaling pathway.
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RASD1 过表达抑制胶质瘤细胞迁移/侵袭并失活 AKT/mTOR 信号通路
DOI：
10.1038/s41598-017-03612-0
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发表时间：
2017-06-09
影响因子：
4.6
通讯作者：
Yu R
中科院分区：
文献类型：
--
作者：
Gao S;Jin L;Liu G;Wang P;Sun Z;Cao Y;Shi H;Liu X;Shi Q;Zhou X;Yu R
RAS信号通路在恶性胶质瘤中由于过度表达和/或活性增加而过度活跃。先前的一项研究证实，RASD1是RAS小G蛋白超家族的成员，在对化疗有反应的少突胶质细胞肿瘤中是一个显著调节异常的基因。然而，RASD1在人脑胶质瘤发展过程中的作用和机制仍然很大程度上不清楚。在目前的研究中，通过分析公共基因组学数据库，我们发现高水平的RASD1预示着星形细胞瘤患者的良好生存。因此，我们建立了慢病毒介导的RASD_1过表达胶质瘤细胞，发现过表达RASD_1对胶质瘤细胞的增殖没有显著影响。然而，RASD1的过表达抑制了胶质瘤细胞的迁移和侵袭。在颅内胶质瘤异种移植模型中，RASD1的过表达显著减少了肿瘤细胞侵袭周围组织的数量，而不影响肿瘤的大小。细胞内信号阵列显示，随着RASD1的过度表达，AKT和S6核糖体蛋白的磷酸化水平显著降低。有趣的是，在II级和III级星形细胞瘤组织中，RASD1蛋白水平显著高于非肿瘤脑组织。这些发现表明，胶质瘤组织中RASD1的上调可能通过失活AKT/mTOR信号通路而起到抑制肿瘤扩张的作用。
The RAS signaling pathway is hyperactive in malignant glioma due to overexpression and/or increased activity. A previous study identified thatRASD1, a member of the RAS superfamily of small G-proteins, is a significantly dysregulated gene in oligodendroglial tumors that responded to chemotherapy. However, the role and mechanism of RASD1 in the progression of human glioma remain largely unknown. In the present study, by analyzing a public genomics database, we found that high levels of RASD1 predicted good survival of astrocytoma patients. We thus established lentivirus-mediated RASD1-overexpressing glioma cells and found that overexpressing RASD1 had no significant effects on glioma cell proliferation. However, the overexpression of RASD1 inhibited glioma cell migration and invasion. In the intracranial glioma xenograft model, the overexpression of RASD1 significantly reduced the number of tumor cells invading into the surrounding tissues without affecting the tumor size. An intracellular signaling array revealed that the phosphorylation of both AKT and the S6 ribosomal protein significantly decreased with RASD1 overexpression in glioma cells. Interestingly, RASD1 protein levels were significantly higher in grade II and grade III astrocytoma tissues than in nontumorous brain tissues. These findings suggest that the upregulation of RASD1 in glioma tissues may play an inhibitory role in tumor expansion, possibly through inactivating the AKT/mTOR signaling pathway.