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

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机构： [1]Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No. 6 Tiantan Xili, Dongcheng District, Beijing 100050, China. [2]Chinese National Clinical Research Center for Neurological Diseases, Beijing, China. [3]Beijing Neurosurgical Institute, Beijing, China. [4]Chinese Glioma Genome Atlas Network, Beijing 100050, China. [5]Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA. [6]Department of Science and Technology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China. [7]School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China. [8]Pólo Dois Portos, Instituto National de Investiga??o Agrária e Veterinária, I.P., Quinta da Almoinha, Dois Portos, Portugal. [9]Department of Neurology, University of Pittsburgh, 7016 Biomedical Science Tower 3 3501 Fifth Ave., Pittsburgh, PA 15260, USA. [10]Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, PA, USA

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关键词： Angiogenesis Anti-PD1 therapy Immunosuppression NHE1 inhibitor HOE642 Tumor-associated microglia macrophage

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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 (pH(i)) 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/6J 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.

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出版当年[2017]版：

大类 | 2 区医学

小类 | 2 区肿瘤学

最新[2023]版：

大类 | 1 区

医学

小类 | 2 区肿瘤学

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出版当年[2016]版：

Q1 ONCOLOGY

最新[2023]版：

Q1 ONCOLOGY

影响因子： 11.4 最新[2023版] 11.4 最新五年平均 5.189 出版当年[2016版] 4.59 出版当年五年平均 4.357 出版前一年[2015版] 6.217 出版后一年[2017版]

第一作者：

第一作者机构： [1]Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No. 6 Tiantan Xili, Dongcheng District, Beijing 100050, China. [2]Chinese National Clinical Research Center for Neurological Diseases, Beijing, China. [3]Beijing Neurosurgical Institute, Beijing, China. [4]Chinese Glioma Genome Atlas Network, Beijing 100050, China. [9]Department of Neurology, University of Pittsburgh, 7016 Biomedical Science Tower 3 3501 Fifth Ave., Pittsburgh, PA 15260, USA.

通讯作者：

通讯机构： [1]Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No. 6 Tiantan Xili, Dongcheng District, Beijing 100050, China. [2]Chinese National Clinical Research Center for Neurological Diseases, Beijing, China. [3]Beijing Neurosurgical Institute, Beijing, China. [4]Chinese Glioma Genome Atlas Network, Beijing 100050, China. [9]Department of Neurology, University of Pittsburgh, 7016 Biomedical Science Tower 3 3501 Fifth Ave., Pittsburgh, PA 15260, USA. [10]Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, PA, USA

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

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