Department of Neurosurgery, Henan Provincial People's Hospital, P.R. China.
Department of Neurosurgery, People's Hospital of Zhengzhou University, P.R. China.
Mol Cells. 2017 Oct;40(10):761-772. doi: 10.14348/molcells.2017.0104. Epub 2017 Oct 17.
Glioblastoma is the most frequent and most aggressive brain tumor in adults. Solute carrier family 8 member 2 (SLC8A2) is only expressed in normal brain, but not present in other human normal tissues or in gliomas. Therefore, we hypothesized that SLC8A2 might be a glioma tumor suppressor gene and detected the role of SLC8A2 in glioblastoma and explored the underlying molecular mechanism. The glioblastoma U87MG cells stably transfected with the lentivirus plasmid containg SLC8A2 (U87MG-SLC8A2) and negative control (U87MG-NC) were constructed. In the present study, we found that the tumorigenicity of U87MG in nude mice was totally inhibited by SLC8A2. Overexpression of SLC8A2 had no effect on cell proliferation or cell cycle, but impaired the invasion and migration of U87MG cells, most likely through inactivating the extracellular signal-related kinases (ERK)1/2 signaling pathway, inhibiting the nuclear translocation and DNA binding activity of nuclear factor kappa B (NF-κB), reducing the level of matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator (uPA)-its receptor (uPAR) system (ERK1/2-NF-κB-MMPs/uPA-uPAR), and altering the protein levels of epithelial to mesenchymal transitions (EMT)-associated proteins E-cardherin, vimentin and Snail. In addition, SLC8A2 inhibited the angiogenesis of U87MG cells, probably through combined inhibition of endothelium-dependent and endothelium-nondependent angiogenesis (vascular mimicry pattern). Totally, SLC8A2 serves as a tumor suppressor gene and inhibits invasion, angiogenesis and growth of glioblastoma.
胶质母细胞瘤是成人中最常见和最具侵袭性的脑肿瘤。溶质载体家族 8 成员 2（SLC8A2）仅在正常脑组织中表达，而不在其他人类正常组织或神经胶质瘤中表达。因此，我们假设 SLC8A2 可能是一种神经胶质瘤肿瘤抑制基因，并检测了 SLC8A2 在胶质母细胞瘤中的作用，探讨了其潜在的分子机制。构建了稳定转染 SLC8A2 慢病毒质粒的胶质母细胞瘤 U87MG 细胞（U87MG-SLC8A2）和阴性对照（U87MG-NC）。本研究发现，SLC8A2 完全抑制了 U87MG 裸鼠的致瘤性。SLC8A2 的过表达对细胞增殖或细胞周期没有影响，但损害了 U87MG 细胞的侵袭和迁移，很可能是通过使细胞外信号相关激酶（ERK）1/2 信号通路失活，抑制核因子κB（NF-κB）的核转位和 DNA 结合活性，降低基质金属蛋白酶（MMPs）和尿激酶型纤溶酶原激活物（uPA）-其受体（uPAR）系统（ERK1/2-NF-κB-MMPs/uPA-uPAR）的水平，改变上皮间质转化（EMT）相关蛋白 E-钙粘蛋白、波形蛋白和 Snail 的蛋白水平。此外，SLC8A2 抑制了 U87MG 细胞的血管生成，可能是通过联合抑制内皮依赖性和非内皮依赖性血管生成（血管模拟模式）。总之，SLC8A2 作为一种肿瘤抑制基因，抑制了胶质母细胞瘤的侵袭、血管生成和生长。
