Department of Laboratory Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai, China.
Cell Death Dis. 2017 Oct 12;8(10):e3122. doi: 10.1038/cddis.2017.507.
The downregulation of receptor tyrosine kinase EphA7 is frequent in epithelial cancers and linked to tumor progression. However, the detailed mechanism of EphA7-mediated prostate tumor progression remains elusive. To test the role of EphA7 receptor in prostate cancer (PCa) progression directly, we generated EphA7 receptor variants that were either lacking the cytoplasmic domain or carrying a point mutation that inhibits its phosphorylation by site-directed mutagenesis. Overexpression of wild-type (WT) EphA7 in PCa cells resulted in decreased tumor volume and increased tumor apoptosis in primary tumors. In addition, ectopic expression of WT EphA7 both can delay PCa cell proliferation and could inhibit PCa cell migration and invasion. This protein can also induce PCa cell apoptosis that correlated with increasing the protein expression levels of Bax, elevating the caspase-3 activities, reducing the protein expression levels of Bcl-2 and facilitating the dephosphorylation of Akt, which is further increased by the stimulation of ephrinA5-Fc. However, expression of these EphA7 mutants in PCa cells has no effect in vivo and in vitro. The expression of EphA7 and ephrinA5 was significantly decreased in PCa specimens compared with BPH tissues or paired normal tissues. Moreover, the phosphorylation of EphA7 was positively related with ephrinA5 expression in human prostate tissues. In sum, receptor phosphorylation of EphA7, at least in part, suppress PCa tumor malignancy through targeting PI3K/Akt signaling pathways.
EphA7 受体酪氨酸激酶的下调在上皮性癌中很常见，并且与肿瘤进展有关。然而，EphA7 介导的前列腺肿瘤进展的详细机制仍不清楚。为了直接测试 EphA7 受体在前列腺癌 (PCa) 进展中的作用，我们生成了缺失胞质结构域或通过定点突变使其磷酸化失活的 EphA7 受体变体。PCa 细胞中 EphA7 野生型 (WT) 的过表达导致原发肿瘤中的肿瘤体积减小和肿瘤细胞凋亡增加。此外，WT EphA7 的异位表达既可以延迟 PCa 细胞的增殖，又可以抑制 PCa 细胞的迁移和侵袭。该蛋白还可以诱导 PCa 细胞凋亡，这与 Bax 蛋白表达水平的增加、caspase-3 活性的升高、Bcl-2 蛋白表达水平的降低以及 Akt 的去磷酸化有关，而 ephrinA5-Fc 的刺激进一步增加了 Akt 的去磷酸化。然而，这些 EphA7 突变体在 PCa 细胞中的表达在体内和体外均没有效果。与 BPH 组织或配对的正常组织相比，PCa 标本中 EphA7 和 ephrinA5 的表达明显降低。此外，人前列腺组织中 EphA7 的磷酸化与 ephrinA5 的表达呈正相关。总之，EphA7 受体的磷酸化至少部分通过靶向 PI3K/Akt 信号通路抑制 PCa 肿瘤的恶性程度。
