Expression of the Receptor Tyrosine Kinase EphA2 Is Increased in Smokers and Predicts Poor Survival in Non-Small Cell Lung Cancer
Expression of the Receptor Tyrosine Kinase EphA2 Is Increased in Smokers and Predicts Poor Survival in Non-Small Cell Lung Cancer
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DOI：
10.1158/1078-0432.ccr-09-0473
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发表时间：
2009-07-01
影响因子：
11.5
通讯作者：
Johnson, Faye M.
中科院分区：
文献类型：
--
作者：
Brannan, Jennifer M.;Dong, Wenli;Johnson, Faye M.
目的：酪氨酸激酶受体EphA2在多种上皮癌中表达上调。据报道，表皮生长因子受体（EGFR）和K-Ras在几种体外模型中调节EphA2，但从未在患者肿瘤中检测过这种调节。由于EGFR和K-Ras突变在非小细胞肺癌（NSCLC）中的重要性，我们研究了这些突变与EphA2在这种癌症类型中的关系。通过检测EphA2表达与其他临床参数的相关性，进一步检验EphA2表达的意义。实验设计：采用组织微阵列免疫组化方法分析手术切除的NSCLC标本（n = 279） EphA2的表达。大多数标本检测EGFR和K-Ras突变状态。研究EphA2表达与EGFR或K-Ras突变状态的相关性，以及肿瘤的几个临床病理变量。在两种细胞系中检测了增加EGFR和K-Ras活性对EphA2表达和活性的影响。结果：EphA2在b> 90%的肿瘤中均有表达。EphA2的表达与活化的EGFR呈正相关，但与EGFR突变无关。EphA2在K-Ras突变患者中表达升高。EphA2表达与吸烟史呈正相关，高EphA2评分预示较差的无进展和总生存率。结论：EphA2在NSCLC中的表达与K-Ras突变、EGFR激活、吸烟史和不良预后相关。EphA2的表达在EGFR或K-Ras激活的情况下上调。EphA2作为非小细胞肺癌治疗靶点的潜力有待进一步研究。
Purpose: Up-regulation of the receptor tyrosine kinase EphA2 has been shown in several epithelial cancers. Epidermal growth factor receptor (EGFR) and K-Ras have been reported to regulate EphA2 in several in vitro models, but this regulation has never been examined in tumors from patients. Because of the established importance of EGFR and K-Ras mutations in non - small cell lung cancer (NSCLC), we investigated the relationship between these mutations and EphA2 in this cancer type. The significance of EphA2 expression was further examined by testing for correlation with other clinical parameters.Experimental Design: EphA2 expression was analyzed by immunohistochemistry in tissue microarray format using surgically resected NSCLC specimens (n = 279). EGFR and K-Ras mutation status was determined for most specimens. The correlation between EphA2 expression and EGFR or K-Ras mutation status was examined, along with several clinicopathologic variables of the tumors. The effects of increasing EGFR and K-Ras activity on EphA2 expression and activity were examined in two cell lines.Results: EphA2 expression was detected in >90% of tumor samples. Expression of EphA2 was positively correlated with activated EGFR but not with EGFR mutations. EphA2 expression was increased in patients harboring K-Ras mutations. EphA2 expression was positively correlated with a history of smoking, and high EphA2 scores predicted poorer progression-free and overall survivals.Conclusions: EphA2 expression in NSCLC is associated with K-Ras mutations, EGFR activation, smoking history, and poor prognosis. EphA2 expression is up-regulated in the context of EGFR or K-Ras activation. The potential of EphA2 as a therapeutic target for NSCLC should be further investigated.