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.
Highlights
Sodium/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 and Warburg effects in glioma
High expression of SLC9A1 mRNA was associated with malignancy in gliomas Analysis of the RNAseq data revealed that SLC9A1 mRNA expression was higher in glioblastoma than WHO grade II and III gliomas in Chinese Glioma Genome Atlas (CGGA) cohort (Fig. 1a) as well as in The Cancer Genome Atlas (TCGA) cohort (Fig. 1b)
Among the different molecular subtypes defined by TCGA network [21], the high level of SLC9A1 mRNA expression was significantly enriched in mesenchymal (ME) subtype in both CGGA and TCGA datasets (Fig. 1e, f )
Summary
Sodium/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. Sodium/hydrogen exchanger 1 (NHE1), encoded by the SLC9A1 gene (SoLute Carrier family 9A1) in humans [6], is the main H+ efflux mechanism in maintaining alkaline pHi in cancer cells [7]. Several new studies illustrate that NHE1 promotes tumor cell proliferation in gastric cancer [8], hepatocellular carcinoma [9], ovarian cancer [10], non-small cell lung cancer [11] and breast cancer invasiveness and progression [12, 13]. To date, there are no clinical studies exploring pharmacological inhibition of NHE1 protein in cancer treatment [4, 14]
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