Oncogenic DIRAS3 promotes malignant phenotypes of glioma by activating EGFR-AKT signaling
Oncogenic DIRAS3 promotes malignant phenotypes of glioma by activating EGFR-AKT signaling
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致癌 DIRAS3 通过激活 EGFR-AKT 信号传导促进神经胶质瘤的恶性表型
DOI：
10.1016/j.bbrc.2018.09.119
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发表时间：
2018-10-28
影响因子：
3.1
通讯作者：
Li, Yun
中科院分区：
文献类型：
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作者：
Peng, Yong;Jia, Jiaoying;Li, Yun
表皮生长因子受体（EGFR）-Akt信号级联激活在胶质瘤恶性表型中起关键作用，尤其是在经典型和间质型胶质瘤中。然而，调节和维持EGFR-AKT信号转导激活的分子和机制仍不清楚。先前的报道显示DIRAS 3在卵巢癌、乳腺癌、肺癌和前列腺癌中抑制细胞增殖并诱导自噬，其在上述癌症中是杂合性丢失或下调的，并且在功能上作为肿瘤抑制剂，而DIRAS 3在胶质瘤中的作用仍然不清楚。本研究探讨DIRAS 3在胶质瘤中的生物学功能和作用，发现DIRAS 3在胶质瘤中表达上调，与胶质瘤患者预后不良呈正相关，同时过表达DIRAS 3促进胶质瘤细胞增殖和侵袭。进一步的机制研究表明，DIRAS 3在经典型和间充质型GBM中的表达水平较高，DIRAS 3的过表达促进EGFR下游的EGFR-AKT信号激活，增加AKT磷酸化，同时MK-2206对AKT的抑制逆转了DIRAS 3的促肿瘤功能。这些发现揭示了DIRAS 3在胶质瘤的发生和发展中的新的致癌作用，这表明DIRAS 3可以作为胶质瘤的潜在诊断标志物和有希望的治疗靶点。(C)2018爱思唯尔公司All rights reserved.
Epidermal growth factor receptor (EGFR)-Akt signaling cascade activation plays a pivotal role in gliomas malignant phenotype, especially in Classical and Mesenchymal subtype gliomas. However, the molecules and mechanisms underlying regulate and maintain the activation of EGFR-AKT signaling remains unclear. Previously reports showed that DIRAS3 inhibits cell proliferation and induces autophagy in ovarian, breast, lung and prostate cancers, which is heterozygosity loss or down-regulated in aforementioned cancers and functionally as a tumor suppressor, whereas the role of DIRAS3 in glioma is still veiled. Here, in this study, we investigated the biological function and role of DIRAS3 in gliomas, and found that DIRAS3 is up-regulated in gliomas and is positively correlated with poor prognosis of glioma patients, meanwhile, over-expressed DIRAS3 promotes glioma cells proliferation and invasion. Further mechanistic study showed that the expression level of DIRAS3 in Classical and Mesenchymal subtype GBMs is higher, and over-expression of DIRAS3 promotes EGFR-AKT signaling activation at the downstream of EGFR and increases AKT phosphorylation, meanwhile suppression of AKT by MK-2206 reverses the tumor promoting function of DIRAS3. Taken together, these findings reveal a novel oncogenic role of DIRAS3 in the development and progression of glioma, which suggest that DIRAS3 could serve as a potential diagnostic marker and a promising therapeutic target of gliomas. (C) 2018 Elsevier Inc. All rights reserved.