Role of Circular RNAs in Pulmonary Fibrosis

Abstract

Pulmonary fibrosis is a chronic progressive form of interstitial lung disease, characterized by the histopathological pattern of usual interstitial pneumonia. Apart from aberrant alterations of protein-coding genes, dysregulation of non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs (circRNAs), is crucial to the initiation and progression of pulmonary fibrosis. CircRNAs are single-stranded RNAs that form covalently closed loops without 5' caps and 3' tails. Different from canonical splicing of mRNA, they are produced from the back-splicing of precursor mRNAs and have unique biological functions, as well as potential biomedical implications. They function as important gene regulators through multiple actions, including sponging microRNAs and proteins, regulating transcription, and splicing, as well as protein-coding and translation in a cap-independent manner. This review comprehensively summarizes the alteration and functional role of circRNAs in pulmonary fibrosis, with a focus on the involvement of the circRNA in the context of cell-specific pathophysiology. In addition, we discuss the diagnostic and therapeutic potential of targeting circRNA and their regulatory pathway mediators, which may facilitate the translation of recent advances from bench to bedside in the future.

Keywords: circRNA; pulmonary fibrosis; silicosis.

Figure 1

Pathophysiology of pulmonary fibrosis. Underlying pathophysiology of pulmonary fibrosis involves repetitive epithelial injury, epithelial-to-mesenchymal transition, macrophage activation, polarization, persistent fibroblast activation, and fibroblast-to-myofibroblast transition and subsequent excessive deposition of extracellular matrix.

Figure 2

Overview of research history of circRNA. The discovery of circRNA starts with identification of viroids, which was published in 1976. Subsequent investigations and novel technologies revealed the biogenesis and properties of circRNA. (see Refs. [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25]).

Figure 3

Biogenesis, trafficking, and degradation of circRNA. Different from the canonical splicing that joins an upstream 5′ splice site with a downstream 3′ splice site; circRNA are produced from back-splicing of precursor mRNA, in which a downstream 5′ splice site joins an upstream 3′ splice site in reverse order. In addition, intron lariats from conventional splicing can retain a circular form when escape debranching. Apart from biogenesis, trafficking and degradation also regulate the abundance of circRNA. Nuclear export of circRNAs to the cytoplasm occurs in a length-dependent manner and requires multiple proteins, such as spliceosome RNA helicase DDX39B (for long circRNAs) and ATP-dependent RNA helicase DDX39A (for short circRNAs). CircRNA also can be degraded by endonucleases or further exported to extracellular vesicles.

Figure 4

Biological functions of circRNA. CircRNAs function as important gene regulators through multiple actions, including miRNA or protein sponges or decoys, templates for translation, protein scaffolding, and recruitment or enhancer of protein function.

Figure 5

circRNAs in pulmonary fibrosis and their influence on biological processes. CircRNA dysregulation intrigues a complex interplay of signaling pathways in endothelial-to-mesenchymal transition, epithelial-to-mesenchymal transition, macrophage activation, and fibroblast-to-myofibroblast transition.