Integrative Bioinformatic Analysis of Transcriptomic Data Identifies Conserved Molecular Pathways Underlying Ionizing Radiation-Induced Bystander Effects (RIBE)

Efstathios-Iason Vlachavas,Constantinos Vorgias,Eleftherios Pilalis,Aristotelis Chatziioannou,Constantinos Yeles,Alexandros Georgakilas,Olga Papadodima

doi:10.3390/cancers9120160

Abstract

Ionizing radiation-induced bystander effects (RIBE) encompass a number of effects with potential for a plethora of damages in adjacent non-irradiated tissue. The cascade of molecular events is initiated in response to the exposure to ionizing radiation (IR), something that may occur during diagnostic or therapeutic medical applications. In order to better investigate these complex response mechanisms, we employed a unified framework integrating statistical microarray analysis, signal normalization, and translational bioinformatics functional analysis techniques. This approach was applied to several microarray datasets from Gene Expression Omnibus (GEO) related to RIBE. The analysis produced lists of differentially expressed genes, contrasting bystander and irradiated samples versus sham-irradiated controls. Furthermore, comparative molecular analysis through BioInfoMiner, which integrates advanced statistical enrichment and prioritization methodologies, revealed discrete biological processes, at the cellular level. For example, the negative regulation of growth, cellular response to Zn2+-Cd2+, and Wnt and NIK/NF-kappaB signaling, thus refining the description of the phenotypic landscape of RIBE. Our results provide a more solid understanding of RIBE cell-specific response patterns, especially in the case of high-LET radiations, like α-particles and carbon-ions.

Highlights

Over the past years, novel approaches in radiation biology and therapy have emphasized the importance of the study of systemic phenomena that represent non-targeted [1] radiation-induced bystander effects (RIBE) [2].In detail, ionizing radiation (IR) damages the cellular genome directly or indirectly through the generation of reactive oxygen and nitrogen species (ROS/RNS) [3,4]
It has been illustrated that RIBE are linked to distinct molecular mechanisms, such as cell growth [7], micronuclei formation [8], cell cycle delay [7,9], and repair [5], along with the transformation of non-irradiated cells [10], inflammation, and DNA damage [5]
"linker genes", represent critical players in various distinct biological processes, enabling a systemic perspective of the disease under investigation we demonstrated that the modularity of the RIBE systemic response elicits differentiated biological responses according to the particular type of radiation, while operating through conserved biological circuits, which exert their effect through common differentially expressed genes, such as IL1A, IL1B, NFKBIZ, SAT1, and TNFAIP3, in the majority of the datasets

Summary

Introduction

In detail, ionizing radiation (IR) damages the cellular genome directly or indirectly through the generation of reactive oxygen and nitrogen species (ROS/RNS) [3,4]. Cancers 2017, 9, 160 demonstrated in various in-vitro and in-vivo studies that targeted irradiation of cytoplasm with α-particles IR induces mutations in the genome of the irradiated cells [5] In this phenomenon, non-irradiated cells, adjacent to the irradiated cells, namely bystander cells, manifest stress responses as a result of signals derived from adjacent directly irradiated cells [6]. Various “omics”-technologies (microarrays, Generation Sequencing (NGS)) have generated numerous transcriptomic datasets for the interrogation of the systemic character of the above phenomena

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