Abstract 1195: EphA4 is a novel tumor suppressor in lung adenocarcinoma

Abstract Lung cancer is the leading cause of death from cancer, but the mechanisms behind its initiation and progression are not completely understood. Receptor tyrosine kinases (RTKs) are important in normal cellular physiology as well as in the pathogenesis of a variety of tumors. In this study, we explored the roles of the human Eph kinase family in lung adenocarcinoma. The Eph fmaily is the largest RTK superfamily with 14 receptors and 8 ligands (ephrins). Eph receptors have been implicated both as tumor suppressors and oncogenes. To explore the effect of Eph receptors and ephrins on lung cancer, we analyzed gene expression and survival data from 432 lung adenocarcinomas from Director's Challenge Consortium by univariate Cox proportional hazards model. Of the 11 Eph receptors and 8 ephrins analyzed, only the expression of EphA4, EphA5, EphB2, ephrinA1, and ephrinB3 correlated with overall survival. Analysis of an independent dataset confirmed that EphA4 and ephrinA1 expression negatively correlated with survival in lung adenocarcinoma. After adjusting for age, gender and stage, low EphA4 expression remained significantly associated with a poor outcome for both overall and relapse-free survival with a hazard ratio of 1.57. To validate the gene expression profile data, we measured EphA4 expression in 9 NSCLC cell lines and found that the expression levels of EphA4 by microarray were well correlated with expression levels measure by qPCR and Western blotting (R2=0.89, R2=0.79 respectively), which indicate that the tissue microarray probesets are of high quality. To investigate the role of EphA4 as a putative tumor suppressor, we overexpressed EphA4 in NSCLC cell lines with low basal expression and found that the cell migration was inhibited by 38% and E-cadherin expression was increased. Likewise, E-cadherin expression was decreased with EphA4 knockdown in NSCLC cell lines with high basal EphA4 expression. These data are consistent with a role for EphA4 as a tumor suppressor via increased expression of the cell surface adhesion protein E-cadherin and concomitant decreased cell migration. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1195. doi:10.1158/1538-7445.AM2011-1195