Abstract
To identify the miRNA regulators of C-X-C motif chemokine receptor 4 (CXCR4) and the underlying mechanism as well as the therapeutic and prognostic values in human glioblastoma (GBM). miRNA profile analyses and bioinformatics predictions were used to identify the mediators of CXCR4, which were confirmed by luciferase reporter assay, Western blot assay and immunohistochemistry. The effects of miR-663 on CXCR4-mediated GBM malignancy were investigated by gain-of-function experiments. Orthotopic xenografts derived from constitutive or induced miR-663-expressing GBM cells were used to determine the antitumor effects of miR-663 and CXCR4-specific antagonist AMD3100. Bivariate correlation analyses were used to examine the correlation of miR-663 and CXCR4 levels in glioma. The prognostic values of miR-663 and CXCR4 were examined in 281 cases of astrocytic glioma from our hospital and 476 cases of GBM from The Cancer Genome Atlas database using the multivariate Cox regression analysis and Kaplan-Meier analysis. miR-663 negatively regulated CXCR4 expression by targeting its coding sequence in GBM and compromised the proliferative and invasive capacities of GBM cells induced by CXCR4 overexpression. Constitutive or induced miR-663 overexpression combined with CXCR4 antagonist AMD3100 suppressed orthotopic GBM growth and prolonged tumor-bearing mice survival. Clinically, miR-663 and CXCR4 were inversely correlated in GBM and composed a valuable biomarker set in predicting the outcomes of GBM patients. miR-663 negatively regulated CXCR4 to inhibit its oncogenic effect. Combination of miR-663 and CXCR4 can serve as a valuable prognostic biomarker set as well as molecular targets for therapeutic intervention of GBM.
Highlights
Glioma is the most common primary tumor in the central nervous system [1]
Combination of miR-663 and C–X–C motif chemokine receptor 4 (CXCR4) can serve as a valuable prognostic biomarker set as well as molecular targets for therapeutic intervention of GBM
We constructed the wild-type reporter (CXCR4-coding sequences (CDS)-wt) and the corresponding mutant reporters (CXCR4-mut-1, CXCR4mut-2 and CXCR4-mut-1,2) to validate the prediction. miR663 was effective to reduce the luciferase activity of cells expressing CXCR4-CDS-wt or CXCR4-mut-2 but not cells expressing CXCR4-mut-1 or the double mutant (CXCR4-mut-1,2) in primary GBM cells (Fig. 1C) and U87-MG (Supplementary Fig. S1)
Summary
Glioma is the most common primary tumor in the central nervous system [1]. Grade II glioma tends to progress to higher grade malignancies, including grade III anaplastic glioma and grade IV GBM. GBM is the most lethal and highly recurrent glioma. Therapeutic interventions for GBM are insufficient and partially effective due to limited understandings of the genetic and biologic heterogeneities of the tumor. A number of alterations in genome and transcriptome of GBM have been identified [2,3,4], the molecular mechanisms underlying GBM malignancy remain to be elucidated. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/)
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