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

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.

Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma

“…et al, 2016). In a radioresistant GB model, the total RNA was sequenced and it was found that there was a positive regulation of macrophage chemotaxis following radiation (Doan et al, 2018). Also, in a murine glioma model, an increase in SDF-1a at the tumor invasion front after radiotherapy was correlated with the recruitment of TAMs and radioresistance (Wang et al, 2013).…”

Elevated HDAC activity and altered histone phospho-acetylation confer acquired radio-resistant phenotype to breast cancer cells

“…A radiosensitivity signature, comprising of DNA repair and cell cycle-related genes (identified in breast cancer cell lines and validated in an independent patient dataset) was successful in predicting local recurrence [10]. Another study reported an increase in expression of genes involved in epithelial-to-mesenchymal (EMT) transition, angiogenesis, and proliferation in a highly radio-resistant tumor, glioblastoma [11]. Also, a study of genomic alterations in breast cancer patients revealed an association of phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation with loco-regional recurrence in case of breast cancer [12].…”

Irradiation of pediatric glioblastoma cells promotes radioresistance and enhances glioma malignancyviagenome-wide transcriptome changes

“…Yet the molecular and genomic changes post-radiation in pediatric GBM have not been well examined. We have recently identified many radiation-responsive genes in adult radioresistant GBM cells that explain the radioresistance and increased malignant features of recurrent GBM [ 4 ]. However, adult and pediatric GBMs are distinct from each other at both molecular and genetic levels [ 2 ].…”