Department of Urology, Shengjing Hospital of China Medical University, China.
Department of Nuclear Medicine, Shenzhen Hospital, Southern Medical University, China.
Biomed Res Int. 2019 Jun 16;2019:3808432. doi: 10.1155/2019/3808432. eCollection 2019.
The aberrant expression of Eya2 has been observed in a wide range of cancer types. However, the clinical significance and biological effects of EYA2 in human prostate cancer remain unknown. In this study, we showed that increased levels of Eya2 protein correlated with advanced TNM stage, T stage, and a higher Gleason score. Data from the Cancer Genome Atlas (TCGA) prostate cohort consistently revealed that Eya2 mRNA was positively correlated with a higher Gleason score, higher T stage, and positive nodal metastasis in prostate cancer. Furthermore, data from the Oncomine database showed increased levels of EYA2 mRNA expression in prostate cancer tissues compared with normal tissues. Eya2 protein expression was also higher in prostate cancer cell lines compared with a normal RWPE-1 cell line. We selected LNCaP and PC-3 cell lines for plasmid overexpression and shRNA knockdown. CCK-8, colony formation, and Matrigel invasion assays demonstrated that the overexpression of Eya2 promoted proliferation, colony number, and invasion while Eya2 shRNA inhibited proliferation rate, colony formation, and invasion ability. CCK-8 and Annexin V assays showed that Eya2 reduced sensitivity to docetaxel and docetaxel-induced apoptosis while Eya2 shRNA showed the opposite effects. The overexpression of Eya2 also downregulated the cleavage of caspase3 and PARP while Eya2 depletion upregulated caspase3 and PARP cleavage. Notably, JC-1 staining demonstrated that Eya2 upregulated mitochondrial membrane potential. We further revealed that the overexpression of Eya2 upregulated Bcl-2, matrix metalloproteinase 7 (MMP7), and AKT phosphorylation. Accordingly, data from the TCGA prostate cohort indicated that EYA2 mRNA was positively correlated with the expression of Bcl-2 and MMP7. The inhibition of AKT attenuated EYA2-induced Bcl-2 upregulation. In conclusion, our data demonstrated that Eya2 was upregulated in prostate cancers. EYA2 promotes cell proliferation and invasion as well as cancer progression by regulating docetaxel sensitivity and mitochondrial membrane potential, possibly via the AKT/Bcl-2 axis.
Eya2 的异常表达已在多种癌症类型中观察到。然而，EYA2 在人类前列腺癌中的临床意义和生物学作用尚不清楚。在这项研究中，我们发现 Eya2 蛋白水平的升高与 TNM 分期较晚、T 分期较高和 Gleason 评分较高相关。来自癌症基因组图谱（TCGA）前列腺队列的数据一致表明，Eya2 mRNA 与前列腺癌中较高的 Gleason 评分、较高的 T 分期和阳性淋巴结转移呈正相关。此外，来自 Oncomine 数据库的数据显示，前列腺癌组织中 EYA2 mRNA 的表达水平高于正常组织。Eya2 蛋白表达在前列腺癌细胞系中也高于正常 RWPE-1 细胞系。我们选择 LNCaP 和 PC-3 细胞系进行质粒过表达和 shRNA 敲低。CCK-8、集落形成和 Matrigel 侵袭实验表明，Eya2 的过表达促进了增殖、集落数和侵袭，而 Eya2 shRNA 则抑制了增殖率、集落形成和侵袭能力。CCK-8 和 Annexin V 实验表明，Eya2 降低了对多西紫杉醇的敏感性和多西紫杉醇诱导的细胞凋亡，而 Eya2 shRNA 则表现出相反的效果。Eya2 的过表达还下调了 caspase3 和 PARP 的裂解，而 Eya2 耗竭则上调了 caspase3 和 PARP 的裂解。值得注意的是，JC-1 染色表明 Eya2 上调了线粒体膜电位。我们进一步发现，Eya2 的过表达上调了 Bcl-2、基质金属蛋白酶 7（MMP7）和 AKT 磷酸化。相应地，来自 TCGA 前列腺队列的数据表明，EYA2 mRNA 与 Bcl-2 和 MMP7 的表达呈正相关。AKT 的抑制减弱了 EYA2 诱导的 Bcl-2 上调。总之，我们的数据表明 Eya2 在前列腺癌中上调。EYA2 通过调节多西紫杉醇敏感性和线粒体膜电位促进细胞增殖和侵袭以及癌症进展，可能通过 AKT/Bcl-2 轴。
