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Updated: May 18, 2026
Characterization of Functionally Associated miRNAs in Glioblastoma and their Engineering into Artificial Clusters for Gene Therapy
Published on: October 4, 2019
Effect of miR-21 and miR-30b/c on TRAIL-induced apoptosis in glioma cells
C Quintavalle1, E Donnarumma, M Iaboni
1Department of Cellular and Molecular Biology and Pathology, 'Federico II' University of Naples, Naples, Italy.
Abstract:
Glioblastoma is the most frequent brain tumor in adults and is the most lethal form of human cancer. Despite the improvements in treatments, survival of patients remains poor. To define novel pathways that regulate susceptibility to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in glioma, we have performed genome-wide expression profiling of microRNAs (miRs). We show that in TRAIL-resistant glioma cells, levels of different miRs are increased, and in particular, miR-30b/c and -21. We demonstrate that these miRs impair TRAIL-dependent apoptosis by inhibiting the expression of key functional proteins. T98G-sensitive cells treated with miR-21 or -30b/c become resistant to TRAIL. Furthermore, we demonstrate that miR-30b/c and miR-21 target respectively the 3' untranslated region of caspase-3 and TAp63 mRNAs, and that those proteins mediate some of the effects of miR-30 and -21 on TRAIL resistance, even in human glioblastoma primary cells and in lung cancer cells. In conclusion, we show that high expression levels of miR-21 and -30b/c are needed to maintain the TRAIL-resistant phenotype, thus making these miRs as promising therapeutic targets for TRAIL resistance in glioma.
Insights
High levels of miR-21 and miR-30b/c microRNAs (miRs) promote resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in glioblastoma. These miRs are potential therapeutic targets for overcoming TRAIL resistance in brain tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Glioblastoma is a highly lethal adult brain cancer with poor patient survival.
- Current treatments for glioblastoma have limited efficacy.
- Understanding mechanisms of resistance to apoptosis-inducing agents is crucial for improving glioblastoma therapy.
Purpose of the Study:
- To identify novel molecular pathways regulating resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in glioma.
- To investigate the role of microRNAs (miRs) in TRAIL resistance in glioblastoma cells.
Main Methods:
- Genome-wide microRNA expression profiling was performed on glioma cells.
- Functional assays were conducted to assess the impact of specific miRs on TRAIL-induced apoptosis.
- Target validation was performed using luciferase reporter assays and analysis of protein expression.
Main Results:
- TRAIL-resistant glioma cells exhibit increased levels of specific miRs, notably miR-30b/c and miR-21.
- Overexpression of miR-21 or miR-30b/c confers TRAIL resistance in sensitive glioma cells.
- miR-30b/c and miR-21 target the 3' untranslated regions of caspase-3 and TAp63 mRNAs, respectively, influencing TRAIL resistance.
Conclusions:
- Elevated expression of miR-21 and miR-30b/c is essential for maintaining the TRAIL-resistant phenotype in glioblastoma.
- These miRs represent promising therapeutic targets for overcoming TRAIL resistance in glioma and potentially other cancers.
- The findings provide insights into novel mechanisms of therapeutic resistance in glioblastoma.