Gene expression profiling and the isocitrate dehydrogenase mutational landscape of temozolomide‑resistant glioblastoma

Chen,Wu-Fu; Chuang,Jimmy Ming‑Jung; Yang,San-Nan; Chen,Nan-Fu; Bhattacharya,Manojit; Liu,Hsin-Tzu; Dhama,Kuldeep; Chakraborty,Chiranjib; Wen,Zhi-Hong

doi:10.3892/ol.2024.14511

Gene expression profiling and the isocitrate dehydrogenase mutational landscape of temozolomide‑resistant glioblastoma

Authors:
- Wu-Fu Chen
- Jimmy Ming‑Jung Chuang
- San-Nan Yang
- Nan-Fu Chen
- Manojit Bhattacharya
- Hsin-Tzu Liu
- Kuldeep Dhama
- Chiranjib Chakraborty
- Zhi-Hong Wen
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Affiliations: Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan, R.O.C., Department of Pediatrics, E‑DA Hospital, School of Medicine, College of Medicine I‑Shou University, Kaohsiung 82445, Taiwan, R.O.C., Division of Neurosurgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan, R.O.C., Department of Zoology, Fakir Mohan University, Balasore, Odisha 756089, India, Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970374, Taiwan, R.O.C., Division of Pathology, Indian Council of Agriculture Research‑Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh 243122, India, Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Kolkata, West Bengal 700126, India, Department of Marine Biotechnology and Resources, National Sun Yat‑sen University, Kaohsiung 80424, Taiwan, R.O.C.
Published online on: June 17, 2024 https://doi.org/10.3892/ol.2024.14511
Article Number: 378
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Glioblastoma multiforme (GBM) is an aggressive brain cancer that occurs more frequently than other brain tumors. The present study aimed to reveal a novel mechanism of temozolomide resistance in GBM using bioinformatics and wet lab analyses, including meta‑Z analysis, Kaplan‑Meier survival analysis, protein‑protein interaction (PPI) network establishment, cluster analysis of co‑expressed gene networks, and hierarchical clustering of upregulated and downregulated genes. Next‑generation sequencing and quantitative PCR analyses revealed downregulated [tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 1 (TIE1), calcium voltage‑gated channel auxiliary subunit α2Δ1 (CACNA2D1), calpain 6 (CAPN6) and a disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6)] and upregulated [serum amyloid (SA)A1, SAA2, growth differentiation factor 15 (GDF15) and ubiquitin specific peptidase 26 (USP26)] genes. Different statistical models were developed for these genes using the Z‑score for P‑value conversion, and Kaplan‑Meier plots were constructed using several patient cohorts with brain tumors. The highest number of nodes was observed in the PPI network was for ADAMTS6 and TIE1. The PPI network model for all genes contained 35 nodes and 241 edges. Immunohistochemical staining was performed using isocitrate dehydrogenase (IDH)‑wild‑type or IDH‑mutant GBM samples from patients and a significant upregulation of TIE1 (P<0.001) and CAPN6 (P<0.05) protein expression was demonstrated in IDH‑mutant GBM in comparison with IDH‑wild‑type GBM. Structural analysis revealed an IDH‑mutant model demonstrating the mutant residues (R132, R140 and R172). The findings of the present study will help the future development of novel biomarkers and therapeutics for brain tumors.

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