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Published on: January 9, 2019
A Profound Basic Characterization of eIFs in Gliomas: Identifying eIF3I and 4H as Potential Novel Target Candidates
Stefanie Krassnig1, Christina Wohlrab1, Nicole Golob-Schwarzl1,2
1Diagnostic & Research Center for Molecular BioMedicine, Department of Neuropathology, Diagnostic and Research Institute of Pathology, Medical University Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Austria.
Abstract:
Glioblastoma (GBM) is an utterly devastating cerebral neoplasm and current therapies only marginally improve patients' overall survival (OS). The PI3K/AKT/mTOR pathway participates in gliomagenesis through regulation of cell growth and proliferation. Since it is an upstream regulator of the rate-limiting translation initiation step of protein synthesis, controlled by eukaryotic initiation factors (eIFs), we aimed for a profound basic characterization of 17 eIFs to identify potential novel therapeutic targets for gliomas. Therefore, we retrospectively analyzed expressions of mTOR-related proteins and eIFs in human astrocytoma samples (WHO grades I-IV) and compared them to non-neoplastic cortical control brain tissue (CCBT) using immunoblot analyses and immunohistochemistry. We examined mRNA expression using qRT-PCR and additionally performed in silico analyses to observe the influence of eIFs on patients' survival. Protein and mRNA expressions of eIF3B, eIF3I, eIF4A1, eIF4H, eIF5 and eIF6 were significantly increased in high grade gliomas compared to CCBT and partially in low grade gliomas. However, short OS was only associated with high eIF3I gene expression in low grade gliomas, but not in GBM. In GBM, high eIF4H gene expression significantly correlated with shorter patient survival. In conclusion, we identified eIF3I and eIF4H as the most promising targets for future therapy for glioma patients.
Insights
This study investigated eukaryotic initiation factors (eIFs) as potential glioblastoma (GBM) therapeutic targets. High expression of eIF3I and eIF4H correlated with shorter survival, identifying them as promising targets for glioma treatment.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Research
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with limited therapeutic options.
- The PI3K/AKT/mTOR pathway regulates cell growth and proliferation in gliomagenesis.
- Eukaryotic initiation factors (eIFs) control protein synthesis and are potential therapeutic targets.
Purpose of the Study:
- To characterize the expression of 17 eIFs in human astrocytoma samples.
- To identify novel therapeutic targets for glioma by analyzing eIFs.
- To correlate eIF expression with patient survival in gliomas.
Main Methods:
- Retrospective analysis of astrocytoma samples (WHO grades I-IV) and control brain tissue.
- Immunoblot and immunohistochemistry for protein expression analysis.
- Quantitative real-time PCR (qRT-PCR) for mRNA expression and in silico analysis for survival correlation.
Main Results:
- Increased protein and mRNA expression of eIF3B, eIF3I, eIF4A1, eIF4H, eIF5, and eIF6 in high-grade gliomas.
- High eIF3I gene expression associated with shorter overall survival (OS) in low-grade gliomas.
- High eIF4H gene expression significantly correlated with shorter OS in GBM patients.
Conclusions:
- eIF3I and eIF4H are significantly dysregulated in gliomas.
- eIF3I and eIF4H represent promising therapeutic targets for glioma treatment.
- Targeting specific eIFs may improve outcomes for glioma patients.
