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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
MicroRNA-203 Modulates the Radiation Sensitivity of Human Malignant Glioma Cells
Ji Hyun Chang1, Yeo Hyun Hwang2, David J Lee2
1Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea.
Purpose:
We investigated whether miR-203 could modulate the radiation sensitivity of glioblastoma (GBM) cells and which target gene(s) could be involved.
Methods And Materials:
Three human malignant glioma (MG) cell lines and normal human astrocytes were transfected with control microRNA, pre-miR-203, or antisense miR-203. Real-time PCR (RT-PCR), clonogenic assays, immunofluorescence, and invasion/migration assays were performed. To predict the target(s), bioinformatics analyses using microRNA target databases were performed.
Results:
Overexpression of miR-203 increased the radiation sensitivity of all 3 human MG cell lines and prolonged radiation-induced γ-H2AX foci formation. Bioinformatics analyses suggested that miR-203 could be involved in post-transcriptional control of DNA repair, PI3K/AKT, SRC, and JAK/STAT3 and the vascular signaling pathway. Western blot analysis validated the fact that miR-203 downregulated ATM, RAD51, SRC, PLD2, PI3K-AKT, JAK-STAT3, VEGF, HIF-1α, and MMP2. Overexpression of miR-203 inhibited invasion and migration potentials, downregulated SLUG and Vimentin, and upregulated Claudin-1 and ZO1.
Conclusions:
These data demonstrate that miR-203 potentially controls DNA damage repair via the PI3K/AKT and JAK/STAT3 pathways and may collectively contribute to the modulation of radiation sensitivity in MG cells by inhibiting DNA damage repair, prosurvival signaling, and epithelium-mesenchyme transition. Taken together, these findings demonstrate that miR-203 could be a target for overcoming the radiation resistance of GBM.
Insights
MicroRNA-203 enhances glioblastoma radiation sensitivity by inhibiting DNA repair and promoting cell death. This microRNA (miRNA) could be a therapeutic target for overcoming radiation resistance in glioblastoma (GBM).
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- Glioblastoma (GBM) exhibits significant radioresistance, limiting treatment efficacy.
- MicroRNAs (miRNAs) play crucial roles in cancer progression and treatment response.
- Identifying novel targets to enhance radiotherapy is critical for GBM treatment.
Purpose of the Study:
- To investigate the role of miR-203 in modulating glioblastoma radiation sensitivity.
- To identify potential target genes regulated by miR-203 in glioblastoma cells.
Main Methods:
- Transfection of human malignant glioma (MG) cell lines with miR-203 mimics or inhibitors.
- Assessment of radiation sensitivity using clonogenic assays and DNA damage markers (γ-H2AX).
- Bioinformatics analysis and Western blot to identify and validate miR-203 targets involved in DNA repair, signaling pathways, and epithelial-mesenchyme transition (EMT).
Main Results:
- Overexpression of miR-203 significantly increased radiation sensitivity in MG cell lines.
- miR-203 downregulated key proteins involved in DNA repair (ATM, RAD51), PI3K/AKT, JAK/STAT3, and EMT (SLUG, Vimentin).
- miR-203 inhibited cell invasion and migration, suggesting a role in suppressing EMT.
Conclusions:
- miR-203 enhances glioblastoma radiation sensitivity by targeting DNA repair and prosurvival pathways.
- The PI3K/AKT and JAK/STAT3 pathways are implicated in miR-203-mediated radiosensitization.
- miR-203 represents a potential therapeutic strategy to overcome radiation resistance in glioblastoma.
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