Identification of novel drug resistance mechanisms by genomic and transcriptomic profiling of glioblastoma cells with mutation-activated EGFR
| Autor: | Shaymaa Azawi, Kristin Mrasek, Mohamed E.M. Saeed, Onat Kadioglu, Nuha Mahmoud, Thomas Efferth, Thomas Liehr |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Down-Regulation Biology medicine.disease_cause 030226 pharmacology & pharmacy General Biochemistry Genetics and Molecular Biology Transcriptome 03 medical and health sciences 0302 clinical medicine Cell Line Tumor medicine Humans Gene Regulatory Networks Protein Interaction Maps General Pharmacology Toxicology and Pharmaceutics Gene Transcription factor Metaphase Chromosome Aberrations Mutation medicine.diagnostic_test Brain Neoplasms Gene Expression Profiling General Medicine Genomics Up-Regulation Gene expression profiling ErbB Receptors Gene Expression Regulation Neoplastic 030104 developmental biology Drug Resistance Neoplasm Cancer research Carcinogenesis Glioblastoma Comparative genomic hybridization Fluorescence in situ hybridization Signal Transduction |
| Zdroj: | Life sciences. 284 |
| ISSN: | 1879-0631 |
| Popis: | Aims Epidermal growth factor receptor (EGFR) is not only involved in carcinogenesis, but also in chemoresistance. We characterized U87.MGΔEGFR glioblastoma cells with constitutively active EGFR due to deletion at the ligand binding domain in terms of gene expression profiling and chromosomal aberrations. Wild-type U87.MG cells served as control. Materials and methods RNA sequencing and network analyses (Ingenuity Pathway Analysis) were performed to identify novel drug resistance mechanisms related to expression of mutation activated EGFR. Chromosomal aberrations were characterized by multicolor fluorescence in situ hybridization (mFISH) and array comparative genomic hybridization (aCGH). Key findings U87.MGΔEGFR cells presented much more chromosomal aberrations, amplifications and deletions than wild-type U87.MG cells. Both cell lines were near-triploid. Numerous genes were overexpressed in U87.MGΔEGFR cells, some of which have been already linked to drug resistance. PXDN, which is associated with epithelial mesenchymal transition, was the most upregulated gene (901.8-fold). TENM1 was 331.6-fold upregulated, and it was previously reported to modulate neural development. EGFR-AS1 (161.2-fold upregulated) has been reported to increase the EGFR mRNA stability and its expression - in accordance with that of EGFR - was upregulated (85.5-fold). In addition to well-known resistance genes, numerous novel genes and genomic aberrations were identified. ANGPT2 upregulation and CPM downregulation were validated by Western blotting. Significance Transcriptomics and genomics analyses in U87.MGΔEGFR cells unraveled a range of novel drug resistance mechanisms including apoptosis, DNA repair, ferroptosis, glutathione related gene activities, heat shock, oxidative stress, transcription factor activities, which may have important implications for future treatment strategies. |
| Databáze: | OpenAIRE |
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