Identification of miRNA signatures associated with radiation-induced late lung injury in mice

Abstract

Acute radiation exposure of the thorax can lead to late serious, and even life-threatening, pulmonary and cardiac damage. Sporadic in nature, late complications tend to be difficult to predict, which prompted this investigation into identifying non-invasive, tissue-specific biomarkers for the early detection of late radiation injury. Levels of circulating microRNA (miRNA) were measured in C3H and C57Bl/6 mice after whole thorax irradiation at doses yielding approximately 70% mortality in 120 or 180 days, respectively (LD 70/120 or 180). Within the first two weeks after exposure, weight gain slowed compared to sham treated mice along with a temporary drop in white blood cell counts. 52% of C3H (33 of 64) and 72% of C57Bl/6 (46 of 64) irradiated mice died due to late radiation injury. Lung and heart damage, as assessed by computed tomography (CT) and histology at 150 (C3H mice) and 180 (C57Bl/6 mice) days, correlated well with the appearance of a local, miRNA signature in the lung and heart tissue of irradiated animals, consistent with inherent differences in the C3H and C57Bl/6 strains in their propensity for developing radiation-induced pneumonitis or fibrosis, respectively. Radiation-induced changes in the circulating miRNA profile were most prominent within the first 30 days after exposure and included miRNA known to regulate inflammation and fibrosis. Importantly, early changes in plasma miRNA expression predicted survival with reasonable accuracy (88-92%). The miRNA signature that predicted survival in C3H mice, including miR-34a-5p,-100-5p, and-150-5p, were associated with pro-inflammatory NF-κB-mediated signaling pathways, whereas the signature identified in C57Bl/6 mice (miR-34b-3p,-96-5p, and-802-5p) was associated with TGF-β/SMAD signaling. This study supports the hypothesis that plasma miRNA profiles could be used to identify individuals at high risk of organ-specific late radiation damage, with applications for radiation oncology clinical practice or in the context of a radiological incident.

Long non‑coding RNA nuclear paraspeckle assembly transcript 1 regulates ionizing radiation‑induced pyroptosis via microRNA‑448/gasdermin E in colorectal cancer cells

“…Gene expression omnibus (GEO) and the cancer genome atlas (TCGA) data analyses. LncRNA NEAT1 and miR-448 expression data were obtained from PubMed GEO (https://www.ncbi.nlm.nih.gov/geo/) (GSE65292, GSE8704, GSE43310, GSE137013) and NCBI Sequence Read Archive (SRA, http://www.ncbi.nlm.nih.gov/Traces/sra) (PRJNA644335) databases or from supplementary data from Rogers et al (34). Expression and overall survival analyses for NEAT1 and GSDME in colon adenocarcinoma (COAD) from TCGA database (http://gepia.cancer-pku.cn) were performed using the Gene Expression Profiling Interactive Analysis online tool (http://gepia.cancer-pku.cn/) (35).…”

Thal protects against paraquat‐induced lung injury through a microRNA‐141/HDAC6/IκBα‐NF‐κB axis in rat and cell models

“…Aberrant expression of miRNAs is closely associated with inflammatory responses including lung injury development. [46][47][48] A miRNA microarray analysis was applied to explore the potential molecules involved in the events mediated by thalidomide. miR-141 was identified as the mostly significantly upregulated miRNA after thalidomide treatment.…”

Long and short non-coding RNA and radiation response: a review

“…100 In the plasma of C3H (13.92 Gy) and C57BL/6 mice exposed to whole thorax irradiation, Rogers et al demonstrated the upregulation of miR-34a-5p (day 5, both strains), miR-34b-3p (day 2, C57BL/6 only), and miR-802-5p (day 2, C57BL/2 only) and the downregulation of miR-199a-5p (day 5, C57Bl/6 only), miR-199b-5p (day 2, C3H only), miR-150-5p (days 2 and 5, C3H only), and miR-122-5p (day 5, C57BL/2 only). 101 Additionally, they showed that miR-34a-5p, miR-100-5p, and miR-150-5p forecasted survival in C3H mice while miR-34b-3p, miR-96-5p, and miR-802-5p forecasted survival in C57BL/6 mice. 101 Although the miRNAs differed between strains, KEGG analysis predicted MAPK signaling, regulation of actin cytoskeleton, and fatty acid metabolism were altered in both strains.…”

“…101 Additionally, they showed that miR-34a-5p, miR-100-5p, and miR-150-5p forecasted survival in C3H mice while miR-34b-3p, miR-96-5p, and miR-802-5p forecasted survival in C57BL/6 mice. 101 Although the miRNAs differed between strains, KEGG analysis predicted MAPK signaling, regulation of actin cytoskeleton, and fatty acid metabolism were altered in both strains. This study demonstrated important differences between models used and considerations for translation into human models.…”