NHERF-1: Modulator of Glioblastoma Cell Migration and Invasion

Abstract

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.

Gene expression profiling of luminal B breast cancers reveals NHERF1 as a new marker of endocrine resistance

“…Kaplan-Meier analyses were performed separately in the low NHERF1 (a) and high NHERF1 (b) subgroups of tumors. A difference in EFS between endocrine treated patients and patients without systemic treatment (P = 0.009) was observed only in the subgroup with low NHERF1 expression that reside in the rim of tumors and depletion of NHERF1 arrested migration of glioblastoma cells [58]. In contrast, earlier studies suggested that NHERF1 is a tumor suppressor gene in breast cancer [59].…”

The Src Homology 3 Domain-containing Guanine Nucleotide Exchange Factor Is Overexpressed in High-grade Gliomas and Promotes Tumor Necrosis Factor-like Weak Inducer of Apoptosis-Fibroblast Growth Factor-inducible 14-induced Cell Migration and Invasion via Tumor Necrosis Factor Receptor-associated Factor 2

“…Moreover, specific depletion of TRAF2 in GB has been shown to inhibit growth and confer radiosensitization to tumor cells (48). Similarly, signaling through Fn14 by TWEAK in glioma results in increased resistance to cytotoxic therapy-induced apoptosis and enhanced survival via TRAF recruitment and Rac1-dependent NF-B activation (13,14,24,36). Furthermore, RhoG has been shown to promote the activation of NF-B (49).…”

Ezrin-Radixin-Moesin-binding Phosphoprotein 50 (EBP50) and Nuclear Factor-κB (NF-κB)

“…The up-regulation of EBP50 has been reported in multiple disease states including hepatocellular carcinomas, cholangiopathies, glioblastoma, breast cancer, psoriasis, and vascular injury (21,(32)(33)(34)(35)(36)(37). However, little is known about the transcriptional regulation of EBP50 expression in normal and disease states.…”