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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
Gene expression profiling of glioblastoma cell lines depending on TP53 status after tumor-treating fields (TTFields)
Yeon-Joo Lee1, Hyun Wook Seo1, Jeong-Hwa Baek2
1Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul, South Korea.
Abstract:
Glioblastoma is frequently associated with TP53 mutation, which is linked to a worse prognosis and response to conventional treatments (chemoradiotherapy). Therefore, targeting TP53 is a promising strategy to overcome this poor therapeutic response. Tumor-treating fields (TTFields) are a recently approved treatment for newly diagnosed glioblastoma, which involves direct application of low-intensity, intermediate-frequency alternating electric fields to the tumor, thereby offering a local tumor-killing effect. However, the influence of TP53 mutation status on the effectiveness of TTFields is controversial. Here, we identified the key gene signatures and pathways associated with TTFields in four glioblastoma cell lines varying in TP53 mutation status using gene profiling and functional annotation. Overall, genes associated with the cell cycle, cell death, and immune response were significantly altered by TTFields regardless of TP53 status. TTFields appeared to exert enhanced anti-cancer effects by altering the immune system in the inflammatory environment and regulating cell cycle- and cell death-related genes, but the precise genes influenced vary according to TP53 status. These results should facilitate detailed mechanistic studies on the molecular basis of TTFields to further develop this modality as combination therapy, which can improve the therapeutic effect and minimize side effects of chemoradiotherapy.
Insights
Tumor-treating fields (TTFields) show promise for glioblastoma treatment, regardless of TP53 mutation status. TTFields alter immune response and cell cycle genes, with specific effects varying by TP53 status, suggesting potential for combination therapy.
Area of Science:
- Oncology
- Biotechnology
- Genetics
Background:
- Glioblastoma (GBM) often harbors TP53 mutations, correlating with poor prognosis and resistance to chemoradiotherapy.
- Tumor-treating fields (TTFields) represent a novel treatment modality for newly diagnosed GBM, delivering electric fields to induce tumor cell death.
Purpose of the Study:
- To investigate the impact of TP53 mutation status on the molecular mechanisms of TTFields efficacy in glioblastoma.
- To identify key gene signatures and pathways modulated by TTFields across glioblastoma cell lines with differing TP53 mutation profiles.
Main Methods:
- Gene profiling and functional annotation were employed on four glioblastoma cell lines with varying TP53 mutation statuses.
- Analysis focused on identifying differentially expressed genes and enriched pathways in response to TTFields treatment.
Main Results:
- TTFields significantly altered genes involved in cell cycle, cell death, and immune response, irrespective of TP53 mutation status.
- Enhanced anti-cancer effects were observed through immune system modulation and regulation of cell cycle/death genes.
- Specific gene targets influenced by TTFields differed based on the TP53 mutation status of the glioblastoma cells.
Conclusions:
- TTFields demonstrate a broad impact on glioblastoma biology, affecting fundamental cellular processes.
- The efficacy of TTFields may be influenced by TP53 mutation status, necessitating further investigation into specific molecular targets.
- These findings support the development of TTFields as a combination therapy to improve glioblastoma treatment outcomes and reduce side effects.
