NHERF-1: modulator of glioblastoma cell migration and invasion

Neoplasia. 2009 Apr;11(4):377-87. doi: 10.1593/neo.81572.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Cell Adhesion / genetics
  • Cell Movement / genetics
  • Fluorescent Antibody Technique
  • Gene Expression Profiling
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Humans
  • Image Processing, Computer-Assisted
  • Immunohistochemistry
  • Lasers
  • Microdissection
  • Neoplasm Invasiveness / genetics*
  • Oligonucleotide Array Sequence Analysis
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • RNA, Small Interfering
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sodium-Hydrogen Exchangers / genetics
  • Sodium-Hydrogen Exchangers / metabolism*
  • Tissue Array Analysis
  • Transfection

Substances

  • Phosphoproteins
  • RNA, Small Interfering
  • Sodium-Hydrogen Exchangers
  • sodium-hydrogen exchanger regulatory factor