Summary:
Introduction
The use of high Linear Energy Transfer (LET) Ionizing Radiation (IR) is progressively being incorporated in Radiation Therapy (RT) due to its precise dose localization and high relative biological effectiveness, also associated with the induction of highly complex DNA damage. At the same time, these benefits of particle radiation become a high risk in the case of inevitable, cosmic radiation exposure for astronauts. Nonetheless, DNA Damage Response (DDR) activated via complex DNA damage on healthy tissue, occurring from such types of radiation, may be instrumental in the induction of various chronic and late effects. A method of approach for better understanding the possible complicated underlying response mechanisms, is studying alterations in gene expression after exposure to high-LET IR with the use of bioinformatics.
Methods
To this end, human samples irradiated with high LET IR and non-irradiated (control) were selected and gene expression was determined using cDNA microarray data analysis. Raw data from various studies were downloaded from GEO and ArrayExpress public databases. Pre-processing and differential expression analysis was performed using R programming language. Differentially expressed genes were subjected to functional enrichment analysis to identify Gene Ontology (GO) terms and biological pathways related to high LET IR effects as well as associated diseases, using WebGestalt and Enrichr, respectively. A bibliographical research was performed using GO and Protein to Protein Interaction (PPI) network construction via STRING, to select a group of genes of interest, regarding DDR. Finally, we expanded our study in search of possible comorbidities for heavy ion (HZE) exposure, combining gene-disease associations from DisGeNET platform and disease networks from DISNOR.
Results-Discussion
Our findings suggest the induction of a differential biological response for high-LET radiations, in comparison to low-LET IR, mainly through an enhanced inflammatory response, including several mechanisms associated with the adaptive immune system. Activation of JAK-STAT signaling pathway further upholds this premise. In addition, apoptotic mechanisms seem to be inhibited, further supported by stimulation of focal adhesion, which may imply the induction of cellular senescence. By expanding our study in search of possible comorbidities for HZE particle exposure, functional enrichment analysis suggests the involvement of mechanisms, tightly correlated with neurodegenerative disorders through Wnt and Calcium signaling pathways as well as amyloid fibrils formation. NOTCH signaling pathway activation, also supported by the up-regulation of SIRT1 at a systems biology level, is indicative of a connection to cardiovascular disease. Finally, through dysregulation in the expression of PLA2G4A, inflammatory metabolic diseases are suggested.
Keywords:
ionizing radiation, cosmic radiation, high LET, complex DNA damage response, systems biology, bioinformatics, microarrays, R-Bioconductor, differential gene expression, functional enrichment, biological networks, comorbidities, cancer
