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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-133a Promotes TRAIL Resistance in Glioblastoma via Suppressing Death Receptor 5 and Activating NF-κB Signaling
Shan-Shan Wang1, Lu Feng2, Bao-Guang Hu3
1School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, P.R. China; Guangdong University of Technology, Guangzhou 510515, P.R. China.
Abstract:
Recombinant tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), as a novel cancer therapeutic, is being tested in phase II and III clinical trials; however, TRAIL resistance remains a big obstacle preventing its clinical application. Considering that TRAIL-induced apoptosis through death receptors DR4 and DR5, their activation may be an alternative pathway to suppress TRAIL resistance. In this study, a negative correlation between DR5 expression and TRAIL resistance was observed, and miR-133a was predicted to be the most promising candidate to suppress DR5 expression. Further investigation demonstrated that miR-133a knockdown dramatically suppressed TRAIL resistance in glioblastoma in vitro and in vivo. An NF-κB family member, phosphorylated IκBα (P-IκBα), was shown to be stimulated by miR-133a, leading to the activation of this signaling. Finally, miR-133a was found to be inversely correlated with DR5 expression in human clinical specimens. In conclusion, our data demonstrate that miR-133a promotes TRAIL resistance in glioblastoma by suppressing DR5 expression and activating NF-κB signaling.
Insights
MicroRNA-133a promotes glioblastoma resistance to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) therapy by reducing DR5 expression and activating NF-κB signaling. Targeting miR-133a may overcome TRAIL resistance in cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Recombinant tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic.
- TRAIL resistance is a significant clinical challenge, limiting its application.
- Activating death receptors DR4 and DR5 may overcome TRAIL resistance.
Purpose of the Study:
- To investigate the role of miR-133a in TRAIL resistance in glioblastoma.
- To explore the relationship between miR-133a, DR5 expression, and NF-κB signaling.
- To identify potential therapeutic strategies to overcome TRAIL resistance.
Main Methods:
- Correlation analysis between DR5 expression and TRAIL resistance.
- In vitro and in vivo experiments involving miR-133a knockdown in glioblastoma models.
- Investigation of NF-κB signaling pathway activation by miR-133a.
- Analysis of miR-133a and DR5 expression in human glioblastoma specimens.
Main Results:
- A negative correlation was observed between DR5 expression and TRAIL resistance.
- miR-133a knockdown significantly reduced TRAIL resistance in glioblastoma.
- miR-133a was found to activate NF-κB signaling by stimulating phosphorylated IκBα (P-IκBα).
- miR-133a expression was inversely correlated with DR5 expression in clinical samples.
Conclusions:
- miR-133a promotes TRAIL resistance in glioblastoma by suppressing DR5 expression.
- miR-133a activates NF-κB signaling, contributing to TRAIL resistance.
- Targeting miR-133a presents a potential strategy to enhance TRAIL therapy efficacy in glioblastoma.
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