Identification of radiation responsive genes and transcriptome profiling via complete RNA sequencing in a stable radioresistant U87 glioblastoma model

// Ninh B. Doan 1 , Ha S. Nguyen 1 , Hisham S. Alhajala 3 , Basem Jaber 5 , Mona M. Al-Gizawiy 2 , Eun-Young Erin Ahn 6 , Wade M. Mueller 1 , Christopher R. Chitambar 3 , Shama P. Mirza 7 and Kathleen M. Schmainda 2, 4 1 Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI, USA 2 Department of Radiology, Medical College of Wisconsin, Milwaukee, WI, USA 3 Department of Medicine, Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI, USA 4 Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA 5 Faculty of Medicine, University of Damascus, Damascus, Syria 6 Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA 7 Department of Chemistry and Biochemistry, University of Wisconsin, Milwaukee, WI, USA Correspondence to: Ninh B. Doan, email: ndoan@mcw.edu Keywords: glioblastoma; acid ceramidase; acid ceramidase inhibitors; carmofur; radioresistance Received: March 07, 2018      Accepted: April 08, 2018      Published: May 04, 2018 ABSTRACT The absence of major progress in the treatment of glioblastoma (GBM) is partly attributable to our poor understanding of both GBM tumor biology and the acquirement of treatment resistance in recurrent GBMs. Recurrent GBMs are characterized by their resistance to radiation. In this study, we used an established stable U87 radioresistant GBM model and total RNA sequencing to shed light on global mRNA expression changes following irradiation. We identified many genes, the expressions of which were altered in our radioresistant GBM model, that have never before been reported to be associated with the development of radioresistant GBM and should be concertedly further investigated to understand their roles in radioresistance. These genes were enriched in various biological processes such as inflammatory response, cell migration, positive regulation of epithelial to mesenchymal transition, angiogenesis, apoptosis, positive regulation of T-cell migration, positive regulation of macrophage chemotaxis, T-cell antigen processing and presentation, and microglial cell activation involved in immune response genes. These findings furnish crucial information for elucidating the molecular mechanisms associated with radioresistance in GBM. Therapeutically, with the global alterations of multiple biological pathways observed in irradiated GBM cells, an effective GBM therapy may require a cocktail carrying multiple agents targeting multiple implicated pathways in order to have a chance at making a substantial impact on improving the overall GBM survival.