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SARI, a Novel Regulator of Glioma Microenvironment by Inhibiting CXCR4+ Myeloid-Derived Suppressor Cells Recruitment
37 Pages Posted: 21 May 2019
More...Abstract
Background: Glioblastoma multiforme (GBM) is one of the most common and lethal types of human primary brain tumours. SARI (Suppressor of AP-1 regulated by interferon) functions as a tumour suppressor in various cancers. However, the role of SARI in regulating the tumour microenvironment remains unknown.
Methods: An intracranial glioma model in nude mice, which we monitored by magnetic resonance imaging (MRI) and 3D micro-CT, were eastablished to exaim the function of SARI in glioma growth and metastasis. The underlying mechanisms of SARI function were determined by flow cytometry, immunofluerence staining, and in vitro assay. Glioma tissue microarray was employed to investigate the expression and predictive role of SARI.
Findings: SARI inhibits glioma tumour growth and metastasis by inhibiting the recruitment of MDSCs in intracranial and subcutaneous glioma. Ectopic expression of SARI efficiently inhibited intracranial and subcutaneous glioma growth as evidenced by MRI and 3D micro-CT. Mechanistically, SARI inhibits the recruitment of CXCR4+ MDSCs into the glioma microenvironment by inhibiting HIF1-α expression and SDF-1α transcription. Notably, the attenuation of SDF-1α/CXCR4 signalling could revert the effect of SARI on the inhibition of glioma progression. Furthermore, tissue microarray staining indicated that SARI expression inversely correlates with poor clinical outcomes in glioma patients.
Interprepation: SARI is a novel regulator of tumour microenvironment and a potential therapeutic and predictive target protein in glioma patients.
Funding: This study was supported by the National Natural Science Foundation of China Program grant (no. 81772939) and the National Key R&D Program of China grant (no. 2017YFA0105702).
Declaration of Interest: All authors declare that there are no conflicts of interest
Ethical Approval: All the animal experiments were approved approved in accordance with institution guidelines by the Ethics Committee of West China Hospital, Sichuan University. The tissue samples obtained from 50 glioma patients (age: from 55 to 75 years old; grade: WHO I-IV) were recruited to perform biopsy at West China hospital (Chengdu, China) and the study was approved by the Ethics Committee of West China Hospital.
Keywords: Glioma; SARI; MDSCs; SDF-1α; CXCR4
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