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Characterization of Functionally Associated miRNAs in Glioblastoma and their Engineering into Artificial Clusters for Gene Therapy
Published on: October 4, 2019
miR-663 Suppresses Oncogenic Function of CXCR4 in Glioblastoma
Yu Shi1, Cong Chen1, Shi-Zhu Yu2
1Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China.
Purpose:
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).
Experimental Design:
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.
Results:
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.
Conclusions:
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.
Insights
MicroRNA-663 (miR-663) inhibits glioblastoma (GBM) growth by targeting C-X-C motif chemokine receptor 4 (CXCR4). This miR-663/CXCR4 axis offers a promising therapeutic target and prognostic biomarker for GBM patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis.
- C-X-C motif chemokine receptor 4 (CXCR4) is implicated in GBM progression and malignancy.
- Identifying molecular regulators of CXCR4 is crucial for developing novel GBM therapies.
Purpose of the Study:
- To identify microRNA (miRNA) regulators of CXCR4 in GBM.
- To elucidate the underlying mechanism of miRNA regulation on CXCR4.
- To evaluate the therapeutic and prognostic potential of identified miRNA-CXCR4 interactions in GBM.
Main Methods:
- miRNA profiling and bioinformatics analyses to identify CXCR4 regulators.
- Luciferase reporter assays, Western blot, and immunohistochemistry to confirm interactions.
- Gain-of-function experiments and orthotopic xenograft models to assess therapeutic effects.
- Correlation and survival analyses in clinical GBM and astrocytic glioma cohorts.
Main Results:
- miR-663 was identified as a negative regulator of CXCR4 in GBM, targeting its coding sequence.
- miR-663 overexpression suppressed GBM cell proliferation and invasion induced by CXCR4.
- Combined miR-663 overexpression and CXCR4 antagonism (AMD3100) inhibited tumor growth and improved survival in vivo.
- Inverse correlation between miR-663 and CXCR4 levels in GBM, serving as a predictive biomarker set.
Conclusions:
- miR-663 inhibits the oncogenic effects of CXCR4 in glioblastoma.
- The miR-663/CXCR4 axis represents a potential therapeutic target for GBM.
- Combined assessment of miR-663 and CXCR4 levels can serve as a valuable prognostic biomarker for GBM patients.
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