Ligand-dependent EphA7 signaling inhibits prostate tumor growth and progression.
Ligand-dependent EphA7 signaling inhibits prostate tumor growth and progression.
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配体依赖性 EphA7 信号传导抑制前列腺肿瘤的生长和进展
DOI：
10.1038/cddis.2017.507
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发表时间：
2017-10-12
影响因子：
9
通讯作者：
Guan M
中科院分区：
文献类型：
--
作者：
Li S;Wu Z;Ma P;Xu Y;Chen Y;Wang H;He P;Kang Z;Yin L;Zhao Y;Zhang X;Xu X;Ma X;Guan M
受体酪氨酸激酶EphA7的下调在上皮性癌症中很常见，并与肿瘤的进展有关。然而，EphA7介导的前列腺癌进展的详细机制仍然不清楚。为了直接测试EphA7受体在前列腺癌(PCa)进展中的作用，我们产生了EphA7受体变异体，这些变异体要么缺乏细胞质结构域，要么携带一个点突变，通过定点突变抑制其磷酸化。野生型(WT)EphA7在PCa细胞中的过表达导致原发肿瘤的肿瘤体积缩小和肿瘤细胞凋亡增加。此外，WT EphA7的异位表达既可以延缓PCa细胞的增殖，又可以抑制PCa细胞的迁移和侵袭。该蛋白还可诱导PCa细胞发生凋亡，其机制与上调Bax蛋白表达水平、上调caspase-3活性、降低Bcl2蛋白表达水平、促进Akt蛋白去磷酸化有关，而这一作用可通过ewitinA5-Fc的刺激而进一步增强。然而，这些EphA7突变体在PCa细胞中的表达在体内和体外都没有影响。在PCa组织中，EphA7和ewitinA5的表达明显低于BPH组织或配对的正常组织。此外，人前列腺组织中EphA7的磷酸化水平与其表达呈正相关。总之，EphA7的受体磷酸化至少部分地通过靶向PI3K/Akt信号通路来抑制PCa肿瘤的恶性。
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.
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影响因子：
7.2
作者：
Lisabeth EM;Falivelli G;Pasquale EB
通讯作者：
Pasquale EB
影响因子：
3.8
作者：
Lee H;Park S;Kang YS;Park S
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Park S
影响因子：
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作者：
Guan, Ming;Xu, Chong;Yes, Chuanzhong
通讯作者：
Yes, Chuanzhong
影响因子：
2.7
作者：
Taneja, R;Thisse, B;Chambon, P
通讯作者：
Chambon, P
影响因子：
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作者：
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通讯作者：
Theocharis S