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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
Microarray analysis in a cell death resistant glioma cell line to identify signaling pathways and novel genes
Janina Seznec1, Ulrike Naumann
1Laboratory of Molecular Neuro-Oncology, Department of General Neurology, Hertie-Institute for Clinical Brain Research and Center Neurology, University of Tuebingen, Otfried-Mueller-Str. 27, Tuebingen 72076, Germany. ulrike.naumann@uni-tuebingen.de.
Abstract:
Glioblastoma multiforme (GBM) is a lethal type of cancer mainly resistant to radio- and chemotherapy. Since the tumor suppressor p53 functions as a transcription factor regulating the expression of genes involved in growth inhibition, DNA repair and apoptosis, we previously assessed whether specific differences in the modulation of gene expression are responsible for the anti-tumor properties of a dominant positive p53, chimeric tumor suppressor (CTS)-1. CTS-1 is based on the sequence of p53 and designed to resist various mechanisms of inactivation which limit the activity of p53. To identify CTS-1-regulated cell death-inducing genes, we generated a CTS-1-resistant glioma cell line (229R). We used Affymetrix whole-genome microarray expression analysis to analyze alterations in gene expression and identified a variety of CTS-1 regulated genes involved in cancer-linked processes. 313 genes were differentially expressed in Adeno-CTS-1 (Ad-CTS-1)-infected and 700 genes in uninfected 229R cells compared to matching parental cells. Ingenuity Pathway Analysis (IPA) determined a variety of differentially expressed genes in Ad-CTS-1-infected cells that were members of the intracellular networks with central tumor-involved players such as nuclear factor kappa B (NF-κB), protein kinase B (PKB/AKT) or transforming growth factor beta (TGF-β). Differentially regulated genes include secreted factors as well as intracellular proteins and transcription factors regulating not only cell death, but also processes such as tumor cell motility and immunity. This work gives an overview of the pathways differentially regulated in the resistant versus parental glioma cells and might be helpful to identify candidate genes which could serve as targets to develop novel glioma specific therapy strategies.
Insights
Chimeric tumor suppressor (CTS)-1, a modified p53, induces cell death in resistant glioblastoma cells. Gene expression analysis revealed CTS-1 regulates key cancer pathways, offering potential therapeutic targets for glioblastoma multiforme.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain cancer often resistant to standard treatments.
- The tumor suppressor p53 regulates genes critical for controlling cancer growth and promoting cell death.
- Existing p53 therapies are limited by inactivation mechanisms, necessitating alternative approaches.
Purpose of the Study:
- To investigate the anti-tumor properties of a novel p53-based chimeric tumor suppressor (CTS)-1.
- To identify genes and pathways regulated by CTS-1 in glioblastoma cells resistant to therapy.
- To explore potential novel therapeutic targets for glioblastoma.
Main Methods:
- Generation of a CTS-1-resistant glioblastoma cell line (229R).
- Whole-genome microarray expression analysis to compare gene expression profiles.
- Ingenuity Pathway Analysis (IPA) to identify regulated biological networks and pathways.
Main Results:
- CTS-1 significantly altered the expression of numerous genes in resistant glioblastoma cells.
- Differentially expressed genes were involved in critical cancer-related processes including cell death, motility, and immunity.
- IPA identified CTS-1-regulated genes within networks involving key cancer players like NF-κB, AKT, and TGF-β.
Conclusions:
- CTS-1 demonstrates potential in modulating gene expression to induce cell death in resistant glioblastoma.
- The study identified novel CTS-1-regulated genes and pathways relevant to glioblastoma.
- These findings may guide the development of new therapeutic strategies targeting glioblastoma.
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