EphA2 Mutation in Lung Squamous Cell Carcinoma Promotes Increased Cell Survival, Cell Invasion, Focal Adhesions, and Mammalian Target of Rapamycin Activation
EphA2 Mutation in Lung Squamous Cell Carcinoma Promotes Increased Cell Survival, Cell Invasion, Focal Adhesions, and Mammalian Target of Rapamycin Activation
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DOI：
10.1074/jbc.m109.075085
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发表时间：
2010-06-11
影响因子：
4.8
通讯作者：
Salgia, Ravi
中科院分区：
文献类型：
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作者：
Faoro, Leonardo;Singleton, Patrick A.;Salgia, Ravi
非小细胞肺癌（NSCLC）预后差，需要改进治疗。EphA 2的表达在NSCLC转移中增加。在这项研究中，我们研究了EphA 2在NSCLC中的突变，并检查了参与NSCLC的分子途径。对肿瘤和细胞系DNA进行测序。通过在BEAS 2B细胞中表达来模拟一种EphA 2突变，并进行功能和生物化学研究。在H2170和2/28个鳞状细胞癌患者样品中检测到G391 R突变。EphA 2 G391 R引起EphA 2的组成性激活，同时增加Src、corpine和p130 Cas的磷酸化。野生型（WT）和G391 R细胞的侵袭性增加了20%和40%，这是减弱与敲低Src，corneum，或p130 Cas。WT和G391 R细胞表现出粘着斑面积增加70%。哺乳动物雷帕霉素靶蛋白（mTOR）磷酸化在G391 R细胞中增加，与WT（30%）相比，存活率增加（55%），对雷帕霉素的敏感性增加。复发性EphA 2突变存在于肺鳞状细胞癌中，并通过激活粘着斑和肌动蛋白细胞骨架调节蛋白以及mTOR来增加肿瘤侵袭和存活。EphA 2作为治疗靶点的进一步研究是必要的。
Non-small cell lung cancer (NSCLC) has a poor prognosis and improved therapies are needed. Expression of EphA2 is increased in NSCLC metastases. In this study, we investigated EphA2 mutations in NSCLC and examined molecular pathways involved in NSCLC. Tumor and cell line DNA was sequenced. One EphA2 mutation was modeled by expression in BEAS2B cells, and functional and biochemical studies were conducted. A G391R mutation was detected in H2170 and 2/28 squamous cell carcinoma patient samples. EphA2 G391R caused constitutive activation of EphA2 with increased phosphorylation of Src, cortactin, and p130Cas. Wild-type (WT) and G391R cells had 20 and 40% increased invasiveness; this was attenuated with knockdown of Src, cortactin, or p130Cas. WT and G391R cells demonstrated a 70% increase in focal adhesion area. Mammalian target of rapamycin (mTOR) phosphorylation was increased in G391R cells with increased survival (55%) compared with WT (30%) and had increased sensitivity to rapamycin. A recurrent EphA2 mutation is present in lung squamous cell carcinoma and increases tumor invasion and survival through activation of focal adhesions and actin cytoskeletal regulatory proteins as well as mTOR. Further study of EphA2 as a therapeutic target is warranted.