Irradiation of pediatric glioblastoma cells promotes radioresistance and enhances glioma malignancy via genome-wide transcriptome changes
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Hisham S. Alhajala1, Ha S. Nguyen2, Saman Shabani2, Benjamin Best2, Mayank Kaushal2, Mona M. Al-Gizawiy3, Eun-Young Erin Ahn7, Jeffery A. Knipstein4, Shama Mirza6, Kathleen M. Schmainda3,5, Christopher R. Chitambar1 and Ninh B. Doan7
1Department of Medicine, Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA
2Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI, USA
3Department of Radiology, Medical College of Wisconsin, Milwaukee, WI, USA
4Department of Pediatrics, Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA
5Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA
6Department of Chemistry and Biochemistry, University of Wisconsin, Milwaukee, WI, USA
7Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA
Ninh B. Doan, email: [email protected]
Keywords: pediatric glioblastoma; high-grade glioma; radioresistance; mRNA; ribonucleotide reductase
Abbreviations: GBM: Giloblastoma; PBS: phosphate-buffered; SJ-GBM2: radiation-naïve pediatric GBM; RR: ribonucleotide reductase; SJ-GBM2-10gy: stable radioresistant pediatric GBM
Received: May 25, 2018 Accepted: September 08, 2018 Published: September 25, 2018
Pediatric glioblastoma (GBM) is a relatively rare brain tumor in children that has a dismal prognosis. Surgery followed by radiotherapy is the main treatment protocol used for older patients. The benefit of adjuvant chemotherapy is still limited due to a poor understanding of the underlying molecular and genetic changes that occur with irradiation of the tumor. In this study, we performed total RNA sequencing on an established stable radioresistant pediatric GBM cell line to identify mRNA expression changes following radiation. The expression of many genes was altered in the radioresistant pediatric GBM model. These genes have never before been reported to be associated with the development of radioresistant GBM. In addition to exhibiting an accelerated growth rate, radioresistant GBM cells also have overexpression of the DNA synthesis-rate-limiting enzyme ribonucleotide reductase, and pro-cathepsin B. These newly identified genes should be concertedly studied to better understand their role in pediatric GBM recurrence and progression after radiation. It was observed that the changes in multiple biological pathways protected GBM cells against radiation and transformed them to a more malignant form. These changes emphasize the importance of developing a treatment regimen that consists of a multiple-agent cocktail that acts on multiple implicated pathways to effectively target irradiated pediatric GBM. An alternative to radiation or a novel therapy that targets differentially expressed genes, such as metalloproteases, growth factors, and oncogenes and aim to minimize oncogenic changes following radiation is necessary to improve recurrent GBM survival.
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