EphA6 promotes angiogenesis and prostate cancer metastasis and is associated with human prostate cancer progression

// Shibao Li 1, * , Yingyu Ma 2, * , Chongwei Xie 3 , Zhiyuan Wu 1 , Zhihua Kang 1 , Zujun Fang 4 , Bing Su 5, 6 , Ming Guan 1 1 Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China 2 Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA 3 Biomedical Research Institute, Shenzhen-PKU-HKUST Medical Center, Shenzhen, Guangdong 518036, China 4 Department of Urology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China 5 Xinxiang Key Lab of Translational Cancer Research, The Third Affiliated Hospital, Xinxiang Medical University, Xinxiang, Henan 453003, China 6 Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, The State University of New York, Buffalo, NY 14214, USA * These authors have contributed equally to this work Correspondence to: Bing Su, e-mail: bsu2@buffalo.edu Ming Guan, e-mail: guanming88@yahoo.com Keywords: Eph, ephrin, EphA6, metastasis, prostate cancer Received: March 21, 2015      Accepted: May 13, 2015      Published: May 27, 2015 ABSTRACT Metastasis is the primary cause of prostate cancer (CaP)-related death. We investigate the molecular, pathologic and clinical outcome associations of EphA6 expression and CaP metastasis. The expression profiling of Eph receptors (Ephs) and their ephrin ligands was performed in parental and metastatic CaP cell lines. Among Ephs and ephrins, only EphA6 is consistently overexpressed in metastatic CaP cells. Metastatic potential of EphA6 is assessed by RNAi in a CaP spontaneous metastasis mouse model. EphA6 knock-down in human PC-3M cells causes decreased invasion in vitro and reduced lung and lymph node metastasis in vivo . In addition, knock-down of EphA6 decreases tube formation in vitro and angiogenesis in vivo . EphA6 mRNA expression is higher in 112 CaP tumor samples compared with benign tissues from 58 benign prostate hyperplasia patients. Positive correlation was identified between EphA6 expression and vascular invasion, neural invasion, PSA level, and TNM staging in CaP cases. Further, genome-wide gene expression analysis in EphA6 knock-down cells identified a panel of differentially regulated genes including PIK3IPA, AKT1, and EIF5A2, which could contribute to EphA6-regulated cancer progression. These findings identify EphA6 as a potentially novel metastasis gene which positively correlates with CaP progression. EphA6 may be a therapeutic target in metastatic CaP.