NHERF-1: Modulator of Glioblastoma Cell Migration and Invasion
NHERF-1: Modulator of Glioblastoma Cell Migration and Invasion
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DOI：
10.1593/neo.81572
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发表时间：
2009-04-01
期刊：
影响因子：
4.8
通讯作者：
Berens, Michael E.
中科院分区：
文献类型：
--
作者：
Kislin, Kerri L.;McDonough, Wendy S.;Berens, Michael E.
恶性神经胶质瘤的侵袭性是一个临床问题，使得肿瘤无法通过手术、电离辐射和替莫唑胺等常规治疗方式治愈。 Na+/H+ 交换调节因子 1 (NHERF-1) 是一种多功能衔接蛋白，可将细胞质信号蛋白和膜受体/转运蛋白招募到功能复合物中。这项研究表明，多形性胶质母细胞瘤 (GBM) 肿瘤边缘的高度侵袭性细胞中 NHERF-1 表达增加，并且 NHERF-1 维持胶质瘤迁移和侵袭。通过激光捕获显微切割从患者肿瘤核心和相应的侵入白质区域分离的人 GBM 细胞来评估基因表达谱。通过用小干扰 RNA 降低 NHERF-1 的表达，然后进行径向迁移、三维胶原蛋白分散、免疫荧光和存活测定，检查了 NHERF-1 在 GBM 细胞系迁移和分散中的作用。 NHERF-1蛋白的原位表达仅限于神经胶质瘤细胞和血管内皮，在邻近的正常脑组织中检测到很少甚至没有检测到。 NHERF-1 的耗竭阻止了神经胶质瘤细胞系的迁移和分散，并导致细胞间的粘附性增加。 NHERF-1 耗尽的多形性胶质母细胞瘤细胞的应力纤维明显减少，细胞尺寸更大，形状更圆，细胞突起更少。当 NHERF-1 表达减少时，神经胶质瘤细胞对替莫唑胺治疗变得敏感，导致细胞凋亡增加。总而言之，这些结果为 NHERF-1 作为恶性胶质瘤高侵袭性表型的参与者提供了第一个证据，并暗示 NHERF-1 作为 GBM 治疗的可能治疗靶点。
The invasive nature of malignant gliomas is a clinical problem rendering tumors incurable by conventional treatment modalities such as surgery, ionizing radiation, and temozolomide. Na+/H+ exchanger regulatory factor 1 (NHERF-1) is a multifunctional adaptor protein, recruiting cytoplasmic signaling proteins and membrane receptors/transporters into functional complexes. This study revealed that NHERF-1 expression is increased in highly invasive cells that reside in the rim of glioblastoma multiforme (GBM) tumors and that NHERF-1 sustains glioma migration and invasion. Gene expression profiles were evaluated from laser capture-microdissected human GBM cells isolated from patient tumor cores and corresponding invaded white matter regions. The role of NHERF-1 in the migration and dispersion of GBM cell lines was examined by reducing its expression with small-interfering RNA followed by radial migration, three-dimensional collagen dispersion, immunofluorescence, and survival assays. The in situ expression of NHERF-1 protein was restricted to glioma cells and the vascular endothelium, with minimal to no detection in adjacent normal brain tissue. Depletion of NHERF-1 arrested migration and dispersion of glioma cell lines and caused an increase in cell-cell cohesiveness. Glioblastoma multiforme cells with depleted NHERF-1 evidenced a marked decrease in stress fibers, a larger cell size, and a more rounded shape with fewer cellular processes. When NHERF-1 expression was reduced, glioma cells became sensitized to temozolomide treatment resulting in increased apoptosis. Taken together, these results provide the first evidence for NHERF-1 as a participant in the highly invasive phenotype of malignant gliomas and implicate NHERF-1 as a possible therapeutic target for treatment of GBM.