Department of 1Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center;5The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
Mol Cancer Ther. 2012 Sep;11(9):2021-32. doi: 10.1158/1535-7163.MCT-12-0030. Epub 2012 Jul 17.
The Eph family of receptors is the largest family of receptor tyrosine kinases, but it remains poorly studied in lung cancer. We aimed to systematically explore the human Eph receptors and their ligands, the ephrins, in lung adenocarcinoma. The prognostic impact of Eph receptor and ephrin gene expression was analyzed using 2 independent cohorts of lung adenocarcinoma. Gene expression profiles in lung adenocarcinoma compared with normal adjacent lung were studied in 3 independent cohorts and in cell lines. Gene expression profiles were validated with quantitative polymerase chain reaction (qPCR) and Western blotting in cell lines. Functional studies to assess the role of Eph receptor A4 (EphA4) were carried out in vitro. The biological effects of EphA4 in lung cancer cell lines were assayed following overexpression and knockdown. Of the 11 Eph receptors and 8 ephrins analyzed, only EphA4 and ephrin A1 gene expression were consistently associated with an improved outcome in patients with lung adenocarcinoma. Expression levels of EphA4 by microarray correlated well with expression levels measured by qPCR and Western blotting. EphA4 overexpression reduced cell migration and invasion but did not affect cell cycle, apoptosis, or drug sensitivity. Surprisingly, EphA4 was expressed at higher levels in cancer compared with non-cancer tissues and cell lines. EphA4 gene expression is associated with an improved outcome in patients with resected lung adenocarcinoma, possibly by affecting cancer cell migration and invasion.
Eph 受体家族是受体酪氨酸激酶家族中最大的家族，但在肺癌中的研究仍不完善。我们旨在系统地研究肺腺癌中的人类 Eph 受体及其配体 Ephrins。使用 2 个独立的肺腺癌队列分析 Eph 受体和 Ephrin 基因表达的预后影响。在 3 个独立的队列和细胞系中研究肺腺癌与正常相邻肺的基因表达谱。在细胞系中通过定量聚合酶链反应（qPCR）和 Western blot 验证基因表达谱。进行体外 Eph 受体 A4（EphA4）功能研究以评估其作用。在肺癌细胞系中过表达和敲低 EphA4 后，检测 EphA4 的生物学效应。在分析的 11 种 Eph 受体和 8 种 Ephrins 中，只有 EphA4 和 Ephrin A1 的基因表达与肺腺癌患者的预后改善始终相关。微阵列检测到的 EphA4 表达水平与 qPCR 和 Western blot 测量的表达水平很好地相关。EphA4 的过表达降低了细胞迁移和侵袭，但不影响细胞周期、凋亡或药物敏感性。令人惊讶的是，EphA4 在癌症组织和细胞系中的表达水平高于非癌症组织和细胞系。EphA4 基因表达与切除的肺腺癌患者的预后改善相关，可能通过影响癌细胞的迁移和侵袭。
