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Comparative Transcriptomic Analysis of Temozolomide Resistant Primary GBM Stem-Like Cells and Recurrent GBM Identifies Up-Regulation of the Carbonic Anhydrase CA2 Gene as Resistance Factor

1
Department of Neurosurgery, UKGM, Philipps University Marburg, Baldingerstraße, 35033 Marburg, Germany
2
Department of Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany
3
Department of Neuropathology, UKGM, Philipps University Marburg, Baldingerstraße, 35033 Marburg, Germany
4
Genomics Core Facility, Philipps University Marburg, Hans-Meerwein-Straße 3, 35043 Marburg, Germany
5
Institute of Molecular Oncology, member of the German Center for Lung Research (DZL), Philipps University Marburg, Hans-Meerwein-Straße 3, 35043 Marburg, Germany
6
Institute for Neuropathology, Justus-Liebig University Gießen, Arndtstr. 16, 35392 Gießen, Germany
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(7), 921; https://doi.org/10.3390/cancers11070921
Received: 3 June 2019 / Revised: 24 June 2019 / Accepted: 28 June 2019 / Published: 30 June 2019
(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)
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Abstract

About 95% of patients with Glioblastoma (GBM) show tumor relapse, leaving them with limited therapeutic options as recurrent tumors are most often resistant to the first line chemotherapy standard Temozolomide (TMZ). To identify molecular pathways involved in TMZ resistance, primary GBM Stem-like Cells (GSCs) were isolated, characterized, and selected for TMZ resistance in vitro. Subsequently, RNA sequencing analysis was performed and revealed a total of 49 differentially expressed genes (|log2-fold change| > 0.5 and adjusted p-value < 0.1) in TMZ resistant stem-like cells compared to their matched DMSO control cells. Among up-regulated genes, we identified carbonic anhydrase 2 (CA2) as a candidate gene correlated with glioma malignancy and patient survival. Notably, we describe consistent up-regulation of CA2 not only in TMZ resistant GSCs on mRNA and protein level, but also in patient-matched clinical samples of first manifest and recurrent tumors. Co-treatment with the carbonic anhydrase inhibitor Acetazolamid (ACZ) sensitized cells to TMZ induced cell death. Cumulatively, our findings illustrate the potential of CA2 as a chemosensitizing target in recurrent GBM and provide a rationale for a therapy associated inhibition of CA2 to overcome TMZ induced chemoresistance. View Full-Text
Keywords: glioblastoma; GBM Stem-like cells; temozolomide; chemoresistance; GBM recurrence; transcriptomics; acetazolamide; carbonic anhydrase 2 glioblastoma; GBM Stem-like cells; temozolomide; chemoresistance; GBM recurrence; transcriptomics; acetazolamide; carbonic anhydrase 2
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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MDPI and ACS Style

Hannen, R.; Selmansberger, M.; Hauswald, M.; Pagenstecher, A.; Nist, A.; Stiewe, T.; Acker, T.; Carl, B.; Nimsky, C.; Bartsch, J.W. Comparative Transcriptomic Analysis of Temozolomide Resistant Primary GBM Stem-Like Cells and Recurrent GBM Identifies Up-Regulation of the Carbonic Anhydrase CA2 Gene as Resistance Factor. Cancers 2019, 11, 921.

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