Elevated Na/H exchanger 1 (SLC9A1) emerges as a marker for tumorigenesis and prognosis in gliomas

Abstract

BackgroundSodium/hydrogen exchanger 1 (NHE1), encoded by the SLC9A1 gene (SoLute Carrier family 9A1) in humans, is the main H+ efflux mechanism in maintaining alkaline intracellular pH (pHi) and Warburg effects in glioma. However, to date, there are no clinical studies exploring pharmacological inhibition of NHE1 protein in cancer treatment. In this study, we investigated NHE1 expression in gliomas and its relationship with glioma clinical outcome.MethodsThe Chinese Glioma Genome Atlas (CGGA) dataset containing transcriptome sequencing data of 325 glioma samples and the Cancer Genome Atlas (TCGA) with 698 glioma mRNAseq data were analyzed in this study. Mouse SB28 and GL26 intracranial syngeneic glioma models in C57BL/6 J mice were established to investigate NHE1 expression and impact of NHE1 protein inhibition with its inhibitor HOE642 on tumorigenesis and anti-PD1 therapy. Tumor angiogenesis, immunogenicity, and progression were assessed by immunofluorescence staining and flow cytometric profiling.ResultsAnalysis of SLC9A1 mRNA expression in two data sets, CGGA and TCGA, reveals significantly higher SLC9A1 mRNA levels in higher grade gliomas. The SLC9A1 mRNA expression was especially enriched in isocitrate dehydrogenase (IDH)1/2 wild-type glioblastoma (GBM) and in mesenchymal glioma subtypes. Worsened survival probabilities were correlated with the elevated SLC9A1 mRNA levels in gliomas. The underlying mechanisms include promoting angiogenesis, and extracellular matrix remodeling. Increased SLC9A1 mRNA expression was also associated with tumor-associated macrophage accumulation. NHE1 inhibitor HOE642 reduced glioma volume, invasion, and prolonged overall survival in mouse glioma models. Blockade of NHE1 protein also stimulated immunogenic tumor microenvironment via activating CD8 T-cell accumulation, increasing expression of interferon-gamma (Ifng), and sensitized animals to anti-PD-1 therapy.ConclusionOur findings strongly suggest that NHE1 protein emerges as a marker for tumorigenesis and prognosis in glioma. Blocking NHE1 protein is a novel strategy for adjuvant anti-cancer therapies.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0923-z) contains supplementary material, which is available to authorized users.

<p>Adipose Mesenchymal Stem Cell-Derived Exosomal microRNA-1236 Reduces Resistance of Breast Cancer Cells to Cisplatin by Suppressing SLC9A1 and the Wnt/β-Catenin Signaling</p>

“…SCL9A1 has been reported as an oncogene in several cancers. 30 Similar roles of SCL9A1 have been reported in BC. For instance, silencing of SCL9A1 by CIAPIN1 was responsible for the inhibition in cell migration, inhibition, and matrix metalloproteinase production in MDA-MB-231 cells.…”

Hydrogen Ion Dynamics of Cancer and a New Molecular, Biochemical and Metabolic Approach to the Etiopathogenesis and Treatment of Brain Malignancies

“…Thus, NHE1 has become a specific and major factor in the etiopathogenesis of MG regarding its etiology, migration, survival in hostile microenvironmental conditions and relentless progression [33,34,35]. NHE 1 un-regulation maintains an intracellular alkaline pHi, which also prevents an intracellular acidification (IAc) as the main mediator of a selective apoptosis of MG cells.…”

Physiological, Structural, and Functional Analysis of the Paralogous Cation–Proton Antiporters of NhaP Type from Vibrio cholerae

“…The NhaP type antiporters belong to the phylogenetically diverse cation/proton antiporter superfamily (CPA1) that includes the pharmacologically important NHEs, NHXs from plants, NhaP1 from archaea, and others [4,6,7,8,9,10,11,12,13]. The structural and functional analysis of prokaryotic antiporters has contributed to the overall understanding of human homologs important in health and disease [14].…”

“…It has been shown that chemical inhibition of NHE1 along with paclitaxel therapy resulted in a significant decrease in the invasive and migratory behaviour of breast cancer cells, indicating the potential of using NHE1 as a novel co-adjuvant target in combination with paclitaxel therapy to enhance the efficacy of breast cancer treatment [15]. Enhanced expression of NHE1 is also an indication of malignant gliomas [12]. Inhibitors against NHE1 significantly decreased the metastasis and enhanced the survival rate in mouse glioma models [12].…”

“…Enhanced expression of NHE1 is also an indication of malignant gliomas [12]. Inhibitors against NHE1 significantly decreased the metastasis and enhanced the survival rate in mouse glioma models [12]. A structural model of clinically important human NHE1 was generated using the E. coli NhaA (Ec-NhaA) structure as a template to predict the binding site of NHE1 inhibitors [16].…”