Identification and Integrated Analysis of circRNA and miRNA of Radiation-Induced Lung Injury in a Mouse Model

Abstract

Background Radiation-induced lung injury (RILI) is a main threat to patients who received thoracic radiotherapy. Thus, understanding the molecular mechanism of RILI is of great importance. Circular RNAs (circRNAs) have been found to act as a regulator of multiple biological processes, and the circRNA-microRNA (miRNA)-mRNA axis could play an important role in the signaling pathway of many human diseases including radiation injury. Methods First, the circRNA and miRNA of RILI in a mouse model were investigated. The mice received 12 Gy of thoracic irradiation, and the irradiated lung tissues at 48 hours after irradiation were analyzed by RNA sequencing (RNA-seq) compared with normal lung tissues. Then, Gene Ontology analysis of the target mRNAs of the significantly differently expressed circRNAs was performed. Results In the irradiated group, inflammatory changes in lungs were observed; 21 significantly up-regulated and 33 down-regulated significantly miRNAs were identified (p < 0.05). Among 27 differentially expressed circRNAs, 10 were down-regulated and 17 were up-regulated in the irradiated group [log2 (fold change) > 1 or < −1, p<0.05]. These differentially expressed miRNAs took part in a series of cellular processes, such as positive regulation of alpha-beta T-cell proliferation, interstitial matrix, collagen fibril organization, chemokine receptor activity, cellular defense response, and B-cell receptor signaling pathway. The differentially expressed circRNAs were related to Th1 and Th2 differentiation pathways, and the predicted mRNAs were verified. Conclusion This study revealed immune-related molecular pathways play an important role in the early response after radiotherapy. In the future, research on the target mechanism and early intervention of circRNAs with associated miRNAs such as circRNA5229, circRNA544, and circRNA3340, could benefit the treatment of RILI.

Functional roles of circular RNAs in lung injury

“…Furthermore, downregulated hsa_circRNA_102,927 and hsa_circRNA_100,562, and upregulated hsa_circRNA_101,523 were identified in the plasma samples of patients with traumatic lung injury ( Jiang et al, 2020 ). Radiation-induced lung injury (RILI) is a key threat to patients who undergo thoracic radiotherapy, in the thoracic irradiation-induced RILI mice, 10 circRNAs were downregulated and 17 were upregulated (including circRNA4146, circRNA4584, circRNA5229, circRNA544, circRNA1092, and circRNA3340), which are reported related to the Th1 and Th2 differentiation pathways ( Li et al, 2021 ). Those results suggest that circRNAs are involved in the process of lung injury caused by various etiologies but are limited to undefined specific pathology.…”

Microarray Analysis Reveals the Changes in Circular RNA Expression and Molecular Mechanisms in Mice With Ventilator-Induced Lung Injury

“…A large number of studies have confirmed that circRNAs mediate signal transduction pathways and regulate inflammation and oxidative stress, contributing to multiple diseases ( Yang et al, 2017 ; Saaoud et al, 2021 ; Xue et al, 2021 ). Furthermore, circRNAs have been reported to play important roles in lung injuries induced by PM2.5 ( Li et al, 2020 ), sepsis ( Jiang et al, 2020 ; Zhou et al, 2021a ), smoke ( Zhou et al, 2021b ), silica ( Fang et al, 2018 ), or radiation ( Li et al, 2021 ). In our study, we observed that there was differential expression of circRNAs in VILI.…”

Mesenchymal stem cells in radiation-induced lung injury: From mechanisms to therapeutic potential

“…The major upstream regulators of these genes are associated with angiotensinogen, IL-1, and transforming growth factor-β (TGF-β), indicating that these molecules play key roles in the progression of RILI. Radiation also causes discrepancies in circRNAs and miRNAs in contrast to normal pulmonary tissues ( Li et al, 2021 ). The main target mRNAs of these differentially expressed circRNAs and miRNAs are related to T cell proliferation, chemokine receptor activity, and the B-cell receptor signaling pathway.…”