MicroRNA-575 acts as a novel oncogene via targeting multiple signaling pathways in glioblastoma
Experimental and Molecular Pathology(2022)
摘要
Purpose: Glioblastoma (GBM) patients currently face poor survival outcomes with an average survival period of < 15 months, while only 3-5% of patients survive longer than 36 months. Although the mechanisms of tumor-igenesis are still being elucidated, miRNAs are promising candidates to explore as novel and prognostic bio-markers in GBM. In this study, we identified the association between miR-575 expression and overall survival (OS) of primary GBM patients and undertook functional studies to discern the contribution of miR-575 to GBM tumorigenesis. Methods: Total RNAs were isolated from 254 FFPE GBM tumor samples and miR expression was assayed (simultaneously) using NanoString Technologies. To determine the association between miR-575 and patients' prognosis, Kaplan-Meier, univariable and multivariable Cox regression analyses were performed. Cell prolifer-ation, colony formation, migration assays were conducted to investigate the function of miR-575 in vitro and in vivo. In silico target gene network analysis was performed to identify the putative targets of miR-575 in GBM, which were further verified by luciferase reporter assay, as well as qPCR and immunoblotting. Results: Our clinical data (n = 254) show that miR-575 is associated with worse GBM OS by univariable analysis (UVA, HR = 1.27, p-value < 0.001) and multivariable (MVA, HR = 1.23, p = 0.007) analysis incorporating critical clinical variables. Functional studies indicated that overexpression of miR-575 significantly increased cell pro-liferation and migration of GBM cells in vitro, as well as tumor growth in vivo. Subsequent in silico target gene network and mechanistic studies identified CDKN1B/p27 and PTEN, as potential targets of miR-575 in GBM. MicroRNA-575 can also regulate the activity of AKT and ERK pathways in GBM. Conclusion: miR-575 has prognostic value in GBM, with higher expression associating with worse OS of patients, and contributes to GBM tumorigenesis by regulating multiple signaling pathways in GBM.
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关键词
MicroRNA-575,Oncogene,CDKN1B,p27,PTEN,Tumor progression,Glioblastoma
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