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

Abstract

Once thought of as arising from "junk DNA," noncoding RNAs (ncRNAs) have emerged as key molecules in cellular processes and response to stress. From diseases such as cancer, coronary artery disease, and diabetes to the effects of ionizing radiation (IR), ncRNAs play important roles in disease progression and as biomarkers of damage. Noncoding RNAs regulate cellular processes by competitively binding DNA, mRNA, proteins, and other ncRNAs. Through these interactions, specific ncRNAs can modulate the radiosensitivity of cells and serve as diagnostic and prognostic biomarkers of radiation damage, whether from incidental exposure in radiotherapy or in accidental exposure scenarios. Analysis of RNA expression after radiation exposure has shown alterations not only in mRNAs, but also in ncRNAs (primarily miRNA, circRNA, and lncRNA), implying an important role in cellular stress response. Due to their abundance and stability in serum and other biofluids, ncRNAs also have great potential as minimally invasive biomarkers with advantages over current biodosimetry methods. Several studies have examined changes in ncRNA expression profiles in response to IR and other forms of oxidative stress. Furthermore, some studies have reported modulation of radiosensitivity by altering expression levels of these ncRNAs. This review discusses the roles of ncRNAs in the radiation response and evaluates prior research on ncRNAs as biomarkers of radiation damage. Future directions and applications of ncRNAs in radiation research are introduced, including the potential for a clinical ncRNA assay for assessing radiation damage and for the therapeutic use of RNA interference (RNAi).

Figure 1.

Diagram representing the ways lncRNAs and miRNAs regulate cellular processes by binding mRNA, proteins, DNA, and other ncRNAs. lncRNA can pair with DNA to modify chromatin and transcription. lncRNAs can direct cellular processes by scaffolding/guiding for epigenetic or transcriptional factors. lncRNA and miRNA can both bind to homologous mRNA sequences to repress translation. Lastly, lncRNA can regulate miRNA by molecular sponging.

Figure 2.

Schematic depicting the method of 3 selected lncRNAs, HOTAIR, TUG1, and GAS5. HOTAIR has been shown to sponge miR-218 and miR-449b-5p to increase radioresistance. TUG1 has been shown to sponge miR-139-5p and target the mRNA HMGB1 to increase radioresistance. GAS5 has been shown to sponge miR-106b and miR-205-5p.

Figure 3.

Pathways of miRNA regulation of PTEN. miR-21, miR-221, and miR-222 target PTEN to decrease its expression. By utilizing anti-miR-221 and anti-miR-222, the expression of miR-221 and miR-222 was decreased, preventing the inhibition of PTEN and resulting in increased radiosensitivity.^, Another study has shown that ionizing radiation induces miR-21 to target PTEN, which leads to radiation-induced epithelial to mesenchymal transition (EMT), representing another response to radiation

Figure 4.

Schematic depicting the pathways of 3 circRNAs, circRNA_100367, circPITX1, circTUBD1, in modulating radiation response. circRNA_100367 sponges miR-217, which prevents miR-217 from targeting the Wnt pathway resulting in increased radioresistance. By silencing circPITX1, its target miR-329-3p can target Nek2 and results in increased radiosensitivity. By silencing circTUBD1, which is upregulated after irradiation, its target miR-146a-5p can target TRL4, which leads to increased apoptosis and decreased pro-inflammatory cytokines.

Figure 5.

Application of molecular biomarkers into the medical triage model for healthcare providers, adapted from Sullivan et al. Initially (T1), Crisis Standards of Care will dominate, and healthcare providers must determine which patients require medical care (T2) and are eligible for limited point-of-care (POC) diagnostics (T3). Here, for example, the absence or presence of certain ncRNAs can efficiently determine non-exposed, worried-well from patients eligible for high throughput screening (HTS, T4). In HTS, further RNAs can more accurately predict dose and guide medical providers with decision making. Eventually, as resources recover, organ specific ncRNA markers (T5) can be assayed to predict and mitigate immediate, delayed or minimal injury. This allows medical providers to tailor treatment to an individual’s specific injuries.