Brain-expressed X-linked 2 Is Pivotal for Hyperactive Mechanistic Target of Rapamycin (mTOR)-mediated Tumorigenesis
Brain-expressed X-linked 2 Is Pivotal for Hyperactive Mechanistic Target of Rapamycin (mTOR)-mediated Tumorigenesis
复制标题
脑表达的 X 连锁 2 对于雷帕霉素 (mTOR) 介导的肿瘤发生的高活性机制靶点至关重要
DOI：
10.1074/jbc.m115.665208
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发表时间：
2015-10-16
影响因子：
4.8
通讯作者：
Zhang, Hongbing
中科院分区：
文献类型：
--
作者：
Hu, Zhongdong;Wang, Ying;Zhang, Hongbing
上游原癌基因和抑癌基因的频繁改变激活了雷帕霉素（mTOR）的机制靶点并导致癌症。然而，mTOR的下游效应在很大程度上仍然难以捉摸。在这里，我们报道脑表达的X-linked 2 （BEX2）是mTOR的一种新的下游效应物。mTOR抑制剂雷帕霉素可消除Tsc2（-/-）小鼠胚胎成纤维细胞、Pten（-/-）小鼠胚胎成纤维细胞、Tsc2缺陷大鼠子宫平滑肌瘤细胞和神经元特异性Tsc1敲除小鼠大脑中升高的BEX2。此外，BEX2在肝脏特异性Pten敲除小鼠的肝脏、Tsc2杂合缺失小鼠的肾脏和结节性硬化症（TSC）患者的肾脏中也有所增加。STAT3和NF-kappa b同时介导mTOR上调BEX2， BEX2参与mTOR上调VEGF生成和血管生成。BEX2的缺失减弱了mTOR活化细胞的肿瘤发生。因此，STAT3/NF-kappa B-BEX2-VEGF信号通路的增强有助于mtor诱导的过度活跃的肿瘤发生。BEX2可能成为治疗mTOR信号通路异常激活的肿瘤的靶点。
Frequent alteration of upstream proto-oncogenes and tumor suppressor genes activates mechanistic target of rapamycin (mTOR) and causes cancer. However, the downstream effectors of mTOR remain largely elusive. Here we report that brain-expressed X-linked 2 (BEX2) is a novel downstream effector of mTOR. Elevated BEX2 in Tsc2(-/-) mouse embryonic fibroblasts, Pten(-/-) mouse embryonic fibroblasts, Tsc2-deficient rat uterine leiomyoma cells, and brains of neuronal specific Tsc1 knockout mice were abolished by mTOR inhibitor rapamycin. Furthermore, BEX2 was also increased in the liver of a hepatic specific Pten knock-out mouse and the kidneys of Tsc2 heterozygous deletion mice, and a patient with tuberous sclerosis complex (TSC). mTOR up-regulation of BEX2 was mediated in parallel by both STAT3 and NF-kappa B. BEX2 was involved in mTOR up-regulation of VEGF production and angiogenesis. Depletion of BEX2 blunted the tumorigenesis of cells with activated mTOR. Therefore, enhanced STAT3/NF-kappa B-BEX2-VEGF signaling pathway contributes to hyperactive mTOR-induced tumorigenesis. BEX2 may be targeted for the treatment of the cancers with aberrantly activated mTOR signaling pathway.