Shi Hengliang, Zheng Bao, Wu Yuxuan, Tang Yuan, Wang Lei, Gao Yong, Gong Hui, Du Jin, Yu Rutong
Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, P.R. China.
The Graduate School, Xuzhou Medical College, Xuzhou, Jiangsu, P.R. China.
Oncol Rep. 2015 Mar;33(3):1185-90. doi: 10.3892/or.2014.3695. Epub 2014 Dec 23.
It has been reported that by regulating PHD3 stability, Siah1 contributes to the abundance of hypoxia-inducible factor (HIF)-1α, thereby playing an important role in the cellular response to hypoxia. However, the expression level and functional significance of Siah1 in human malignant glioma, which is characterized by high migration and invasion potential, have never been investigated. We report here, that Siah1 was expressed highly in human glioma tissues compared with its expression in normal brain tissues and was correlated with advanced tumor status and stage. The knockdown of Siah1 by short-hairpin RNA severely suppressed the migration and invasion of human glioma U251 cells under hypoxia, while overexpression of Siah1 promoted it. Furthermore, we demonstrated that the glioma cell migration and invasion under hypoxia mediated by Siah1 was achieved by reducing the stability of PHD3, which protected the HIF-1α from degradation. These findings suggest that Siah1 plays important roles in the migration and invasion of human glioma cells under hypoxia, which may provide some guidance for the targeted therapy of human glioma based on the interference of the Siah1-PHD3-HIF-1α signaling pathway.
据报道，通过调节PHD3的稳定性，Siah1有助于缺氧诱导因子（HIF）-1α的丰度，从而在细胞对缺氧的反应中发挥重要作用。然而，Siah1在具有高迁移和侵袭潜能的人类恶性胶质瘤中的表达水平和功能意义从未被研究过。我们在此报告，与正常脑组织中的表达相比，Siah1在人类胶质瘤组织中高表达，并且与肿瘤进展状态和分期相关。通过短发夹RNA敲低Siah1可严重抑制缺氧条件下人胶质瘤U251细胞的迁移和侵袭，而Siah1的过表达则促进其迁移和侵袭。此外，我们证明Siah1介导的缺氧条件下胶质瘤细胞的迁移和侵袭是通过降低PHD3的稳定性来实现的，PHD3的降低保护了HIF-1α不被降解。这些发现表明，Siah1在缺氧条件下人胶质瘤细胞的迁移和侵袭中起重要作用，这可能为基于干扰Siah1-PHD3-HIF-1α信号通路的人类胶质瘤靶向治疗提供一些指导。
