Glioma-mediated microglial activation promotes glioma proliferation and migration: roles of Na+/H+ exchanger isoform 1.
Microglia play important roles in extracellular matrix remodeling, tumor invasion, angiogenesis, and suppression of adaptive immunity in glioma. Na(+)/H(+) exchanger isoform 1 (NHE1) regulates microglial activation and migration. However, little is known about the roles of NHE1 in intratumoral microglial activation and microglia-glioma interactions. Our study revealed up-regulation of NHE1 protein expression in both glioma cells and tumor-associated Iba1(+) microglia in glioma xenografts and glioblastoma multiforme microarrays. Moreover, we observed positive correlation of NHE1 expression with Iba1 intensity in microglia/macrophages. Glioma cells, via conditioned medium or non-contact glioma-microglia co-cultures, concurrently upregulated microglial expression of NHE1 protein and other microglial activation markers (iNOS, arginase-1, TGF-β, IL-6, IL-10 and the matrix metalloproteinases MT1-MMP and MMP9). Interestingly, glioma-stimulated microglia reciprocally enhanced glioma proliferation and migration. Most importantly, inhibition of microglial NHE1 activity via small interfering RNA (siRNA) knockdown or the potent NHE1-specific inhibitor HOE642 significantly attenuated microglial activation and abolished microglia-stimulated glioma migration and proliferation. Taken together, our findings provide the first evidence that NHE1 function plays an important role in glioma-microglia interactions, enhancing glioma proliferation and invasion by stimulating microglial release of soluble factors. NHE1 upregulation is a novel marker of the glioma-associated microglial activation phenotype. Inhibition of NHE1 represents a novel glioma therapeutic strategy by targeting tumor-induced microglial activation.
Department of Neurology, University of Pittsburgh , Pittsburgh, PA 15213 , USA.
Wen
W
Zhu
Department of Neurology, University of Pittsburgh , Pittsburgh, PA 15213 , USA.
Karen E
KE
Carney
Department of Neurology, University of Pittsburgh , Pittsburgh, PA 15213 , USA.
Victoria M
VM
Pigott
Department of Neurology, University of Pittsburgh , Pittsburgh, PA 15213 , USA.
Lindsay M
LM
Falgoust
Department of Neurological Surgery.|Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA and.
Paul A
PA
Clark
Department of Neurological Surgery.|Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA and.
John S
JS
Kuo
Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA.|Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, PA, USA.
Dandan
D
Sun
D001932:Brain Neoplasms / Q000473:pathology*; D002135:Calcium-Binding Proteins; D027682:Cation Transport Proteins / Q000032:analysis / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D016764:Cell Polarity; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000032:analysis; D005910:Glioma / Q000473:pathology*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008840:Microfilament Proteins; D017628:Microglia / Q000502:physiology*; D009361:Neoplasm Invasiveness; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000032:analysis / Q000502:physiology*
C112986:AIF1 protein, human; D002135:Calcium-Binding Proteins; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D008840:Microfilament Proteins; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9