Xia Guangbin, Kumar S Ram, Masood Rizwan, Zhu Sutao, Reddy Ramchandra, Krasnoperov Valery, Quinn David I, Henshall Susan M, Sutherland Robert L, Pinski Jacek K, Daneshmand Siamak, Buscarini Maurizio, Stein John P, Zhong Chen, Broek Daniel, Roy-Burman Pradip, Gill Parkash S
Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, USA.
Cancer Res. 2005 Jun 1;65(11):4623-32. doi: 10.1158/0008-5472.CAN-04-2667.
Prostate cancer is the most common cancer in men. Advanced prostate cancer spreading beyond the gland is incurable. Identifying factors that regulate the spread of tumor into the regional nodes and distant sites would guide the development of novel diagnostic, prognostic, and therapeutic targets. The aim of our study was to examine the expression and biological role of EphB4 in prostate cancer. EphB4 mRNA is expressed in 64 of 72 (89%) prostate tumor tissues assessed. EphB4 protein expression is found in the majority (41 of 62, 66%) of tumors, and 3 of 20 (15%) normal prostate tissues. Little or no expression was observed in benign prostate epithelial cell line, but EphB4 was expressed in all prostate cancer cell lines to varying degrees. EphB4 protein levels are high in the PC3 prostate cancer cell line and several folds higher in a metastatic clone of PC3 (PC3M) where overexpression was accompanied by EphB4 gene amplification. EphB4 expression is induced by loss of PTEN, p53, and induced by epidermal growth factor/epidermal growth factor receptor and insulin-like growth factor-I/insulin-like growth factor-IR. Knockdown of the EphB4 protein using EphB4 short interfering RNA or antisense oligodeoxynucleotide significantly inhibits cell growth/viability, migration, and invasion, and induces apoptosis in prostate cancer cell lines. Antisense oligodeoxynucleotide targeting EphB4 in vivo showed antitumor activity in murine human tumor xenograft model. These data show a role for EphB4 in prostate cancer and provide a rationale to study EphB4 for diagnostic, prognostic, and therapeutic applications.
前列腺癌是男性中最常见的癌症。晚期前列腺癌扩散至前列腺腺体以外则无法治愈。确定调控肿瘤扩散至区域淋巴结和远处部位的因素将为新型诊断、预后和治疗靶点的开发提供指导。我们研究的目的是检测EphB4在前列腺癌中的表达及其生物学作用。在所评估的72个前列腺肿瘤组织中，有64个（89%）表达EphB4 mRNA。在大多数肿瘤（62个中的41个，66%）以及20个正常前列腺组织中的3个（15%）中发现有EphB4蛋白表达。在良性前列腺上皮细胞系中几乎未观察到表达或无表达，但EphB4在所有前列腺癌细胞系中均有不同程度的表达。EphB4蛋白水平在PC3前列腺癌细胞系中较高，而在PC3的一个转移克隆（PC3M）中则高出数倍，在该克隆中过表达伴有EphB4基因扩增。EphB4的表达由PTEN、p53缺失诱导，并由表皮生长因子/表皮生长因子受体以及胰岛素样生长因子-I/胰岛素样生长因子-IR诱导。使用EphB4小干扰RNA或反义寡脱氧核苷酸敲低EphB4蛋白可显著抑制前列腺癌细胞系中的细胞生长/活力、迁移和侵袭，并诱导细胞凋亡。在体内，靶向EphB4的反义寡脱氧核苷酸在小鼠人肿瘤异种移植模型中显示出抗肿瘤活性。这些数据表明EphB4在前列腺癌中发挥作用，并为研究EphB4在诊断、预后和治疗方面的应用提供了理论依据。
