Evolutionarily conserved serum microRNAs predict radiation-induced fatality in nonhuman primates

Abstract

Effective planning for the medical response to a radiologic or nuclear accident is complex. Due to limited resources for medical countermeasures, the key would be to accurately triage and identify victims most likely to benefit from treatment. We had used a mouse model system to provide evidence that serum microRNAs (miRNAs) may effectively predict the impact of radiation on long-term viability of animals. Here we use non-human primates (NHPs) to demonstrate that this concept is conserved and serum miRNA signatures have the potential to serve as prediction biomarkers for radiation-induced fatality in a human population. We identified a signature of seven miRNAs that are altered by irradiation in both mice and NHPs. Genomic analysis of these conserved miRNAs revealed that there is a combination of seven transcription factors that are predicted to regulate these miRNAs in human, mice, and NHPs. Moreover, a combination of three miRNAs (miR-133b, miR-215, and miR-375) can identify, with nearly complete accuracy, NHPs exposed to radiation versus unexposed NHPs. Consistent with historical data, female macaques appeared to be more sensitive to radiation, but the difference was not significant. Sex-based stratification allowed us to identify an interaction between gender and miR-16-2 expression, which affected the outcome of radiation exposure. Moreover, we developed a classifier based on two miRNAs (miR-30a and miR-126) that can reproducibly predict radiation-induced mortality. Altogether, we have obtained a 5-miRNA composite signature that can identify irradiated macaques and predict their probability of survival.

Nonhuman primates as models for the discovery and development of radiation countermeasures

“…[13]. In addition, recent studies showed that seven microRNAs are altered by irradiation in NHPs (mir-150, miR-215, miR-30A, miR-126, miR-133a, miR-375, and miR-133b) [123] Furthermore, the genomic studies revealed that there is a combination of seven transcription factors that are predicted to regulate these miRNAs in mice, NHPs, and humans. Studies showed that a combination of three microRNAs (miR-133b, miR-215, and miR-375) can be used to identify NHPs exposed to radiation versus unexposed NHPs, and that females appeared to be more sensitive to radiation.…”

“…Biomarkers may also be used to correlate with the mechanism by which the radiation countermeasure ameliorates the injury or to correlate with the desired clinical result (reduction in morbidity and mortality). Three microRNAs (miR-30a, miR-126, and miR-375) have recently been demonstrated as biomarkers for the radioprotective efficacy of γ-tocotrienol as a countermeasure [123]. …”

Ionizing radiation-induced altered microRNA expression as biomarkers for assessing acute radiation injury

“…The majority of studies have been conducted using the rhesus macaque, although there is also a report with baboons exposed to radiation. A recently conducted study using rhesus macaques identified a signature of seven significantly altered miRNAs (miR-150–5p, miR-215– 5p, miR-30a-5p, miR-126–5p, miR-133a-3p, miR-133b-3p, and miR-375–3p) 24 h following exposure to ionizing radiation [5]. Differences in the expression of three miRNAs (miR-133b, miR-215, and miR-375) were able to distinguish irradiated versus un-irradiated NHPs with complete accuracy.…”

“…A promising radiation countermeasure under advanced development, γ-tocotrienol (GT3), was able to revert it to preirradiation levels in mice as well as in NHPs [5,14]. In fact, three miRNAs (miR-30a, miR-126, and miR-375) correlated with the radioprotective efficacy of GT3; these miRNA in GT3-treated irradiated NHPs resembled the unirradiated animals.…”

“…This will be critical for the timely use of radiation countermeasures to mitigate impact of radiation exposure. There are several studies using rodent and nonhuman primate (NHP) models suggesting that miRNAs can predict both the extent of radiation injury and outcome for survival/mortality, and they may serve as an ideal biomarker choice [1,5–8]. …”