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Updated: May 4, 2026
Characterization of Functionally Associated miRNAs in Glioblastoma and their Engineering into Artificial Clusters for Gene Therapy
Published on: October 4, 2019
miR-218 opposes a critical RTK-HIF pathway in mesenchymal glioblastoma
Lijoy K Mathew1, Nicolas Skuli, Vera Mucaj
1Abramson Family Cancer Research Institute, Howard Hughes Medical Institute, Penn Molecular Profiling Facility - Bioinformatics Group, and Departments of Cell and Developmental Biology, Pathology and Laboratory Medicine, Cancer Biology, and Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104.
Abstract:
Glioblastoma multiforme (GBM) and the mesenchymal GBM subtype in particular are highly malignant tumors that frequently exhibit regions of severe hypoxia and necrosis. Because these features correlate with poor prognosis, we investigated microRNAs whose expression might regulate hypoxic GBM cell survival and growth. We determined that the expression of microRNA-218 (miR-218) is decreased significantly in highly necrotic mesenchymal GBM, and orthotopic tumor studies revealed that reduced miR-218 levels confer GBM resistance to chemotherapy. Importantly, miR-218 targets multiple components of receptor tyrosine kinase (RTK) signaling pathways, and miR-218 repression increases the abundance and activity of multiple RTK effectors. This elevated RTK signaling also promotes the activation of hypoxia-inducible factor (HIF), most notably HIF2α. We further show that RTK-mediated HIF2α regulation is JNK dependent, via jun proto-oncogene. Collectively, our results identify an miR-218-RTK-HIF2α signaling axis that promotes GBM cell survival and tumor angiogenesis, particularly in necrotic mesenchymal tumors.
Insights
MicroRNA-218 (miR-218) is decreased in aggressive brain tumors, promoting resistance to chemotherapy and tumor growth. Restoring miR-218 may offer new glioblastoma treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Glioblastoma multiforme (GBM), especially the mesenchymal subtype, is a highly aggressive brain tumor.
- Tumor hypoxia and necrosis are common in GBM and correlate with poor patient prognosis.
- MicroRNAs (miRNAs) play crucial roles in regulating cancer cell survival and growth.
Purpose of the Study:
- To investigate the role of microRNAs in regulating hypoxic glioblastoma cell survival and growth.
- To identify specific miRNAs whose expression is altered in aggressive GBM subtypes.
- To elucidate the molecular mechanisms by which altered miRNA expression affects GBM progression.
Main Methods:
- Analysis of miRNA expression in GBM tissues, focusing on necrotic and mesenchymal subtypes.
- Orthotopic tumor xenograft models in mice to assess the impact of miRNA levels on tumor growth and chemotherapy response.
- Target validation studies to identify downstream effectors of the identified miRNA.
- Western blotting and functional assays to measure protein levels and signaling pathway activity.
Main Results:
- MicroRNA-218 (miR-218) expression is significantly decreased in highly necrotic mesenchymal GBM.
- Reduced miR-218 levels confer glioblastoma resistance to chemotherapy.
- miR-218 directly targets multiple components of receptor tyrosine kinase (RTK) signaling pathways.
- Repression of miR-218 leads to increased RTK signaling, activating hypoxia-inducible factor 2-alpha (HIF2α) in a JNK-dependent manner.
- The identified miR-218-RTK-HIF2α axis promotes GBM cell survival and tumor angiogenesis.
Conclusions:
- A novel signaling axis involving miR-218, RTK, and HIF2α is identified in glioblastoma.
- This axis plays a critical role in promoting GBM cell survival, chemotherapy resistance, and tumor angiogenesis, particularly in necrotic mesenchymal tumors.
- Targeting this miR-218-RTK-HIF2α pathway represents a potential therapeutic strategy for glioblastoma.
