Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
Department of Neurosurgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010050, Inner Mongolian Autonomous Region, China.
Front Biosci (Landmark Ed). 2019 Mar 1;24(6):1060-1070. doi: 10.2741/4768.
Glioblastoma multiforme (GBM) is a brain tumor that deeply infiltrates adjacent tissues and causes significant mortality. Thus, understanding the mechanisms that derive the invasion of brain tissue by GBM might help the treatment of this cancer. To this end, we examined the impact of BMP4 on invasion of GBM. In this study, Human GBM samples, GBM cells and human orthotopic GBM-xenografted animal model, quantitative PCR, immunostaining, immunoblotting, Scratch wound and transwell assays were used to detect the effect and the mechanism of BMP4 in GBM cells. BMP4 expression was found to positively correlate with E-cadherin and claudin expression in human GBM samples. Elevation or suppression of BMP4 expression resulted in a respective increase or decrease in E-cadherin and claudin levels, both and . Suppression of BMP4 expression was associated with enhanced GBM cell migration and invasion, while BMP4 overexpression inhibited these processes. Smad1/5/8 protein phosphorylation positively correlated with BMP4 expression. Pharmacological blockade of Smad1/5/8 phosphorylation impaired BMP4-dependent inhibition of cell migration and invasion. Together, these findings suggest that BMP4 increases E-cadherin and claudin expression in GBM through activation of SMAD signaling, thereby suppressing tumor cell invasion.
多形性胶质母细胞瘤（GBM）是一种浸润性很强的脑肿瘤，会导致很高的死亡率。因此，深入了解导致 GBM 浸润脑组织的机制可能有助于治疗这种癌症。为此，我们研究了 BMP4 对 GBM 浸润的影响。在这项研究中，我们使用了人 GBM 样本、GBM 细胞和人原位 GBM 异种移植动物模型，进行了定量 PCR、免疫染色、免疫印迹、划痕实验和 Transwell 实验，以检测 BMP4 在 GBM 细胞中的作用及其机制。结果发现，BMP4 的表达与人 GBM 样本中 E-钙黏蛋白和闭合蛋白的表达呈正相关。BMP4 表达的升高或降低分别导致 E-钙黏蛋白和闭合蛋白水平的增加或减少，分别为 和 。BMP4 表达的抑制与 GBM 细胞迁移和侵袭的增强相关，而 BMP4 的过表达则抑制了这些过程。Smad1/5/8 蛋白磷酸化与 BMP4 表达呈正相关。Smad1/5/8 磷酸化的药理学阻断损害了 BMP4 依赖的细胞迁移和侵袭抑制作用。综上所述，这些发现表明，BMP4 通过激活 SMAD 信号通路增加 GBM 中的 E-钙黏蛋白和闭合蛋白表达，从而抑制肿瘤细胞侵袭。
