Emerging roles of exosomal circRNAs in non-small cell lung cancer

Abstract

Despite the prevalence of non-small cell lung cancer (NSCLC) is high, the limited early detection and management of these tumors are restricted since there is an absence of reliable and precise diagnostic biomarkers and therapeutic targets. Exosomes transport functional molecules for facilitating intercellular communication, especially in the tumor microenvironment, indicating their potential as cancer biomarkers and therapeutic targets. Circular RNA (circRNA), a type of non-coding RNA possessing a covalently closed loop structure, substantial abundance, and tissue-specific expression patterns, is stably enriched in exosomes. In recent years, significant breakthroughs have been made in research on exosomal circRNA in NSCLC. This review briefly introduces the biogenesis, characterizations, and functions of circRNAs and exosomes, and systematically describes the biological functions and mechanisms of exosomal circRNAs in NSCLC. In addition, this study summarizes their role in the progression of NSCLC and discusses their clinical significance as biomarkers and therapeutic targets for NSCLC.

Keywords: Biomarker; CircRNAs; Exosomal circRNAs; Exosomes; Non-small cell lung cancer; Therapeutic target.

Fig. 1

Biogenesis and functions of circRNAs. CircRNAs form EIciRNAs, EcircRNAs, and CiRNAs through four hypothesized mechanisms: intron pairing-driven circulation, RNA-driven circularization, lariat-driven circularization and circularization intronic RNA. Reverse direct splicing or RNA-binding proteins (RBPs) bind to specific motifs in flanking introns, promoting RNA-driven circularization. Splicing intermediates known as lariat precursors, which result from intronic lariat precursors that elude the debranching stage of canonical linear splicing or from an exon-skipping event during linear splicing, can also produce circRNAs. CiRNAs are generated by the retention of a 7 nt GU-rich element and an 11 nt C-rich element. CircRNAs can be sponges, interact with proteins, regulate gene expression, and translate proteins. They serve as biomarkers, therapeutic targets, and therapeutic agents. Detailed information on circRNAs was sourced from Lingling Chen

Fig. 2

Bioactive molecules on exosomes, the mechanisms of circRNAs’ entry into exosomes, and the therapy strategies of exosomes. Various bioactive molecules on exosomes can be used as biomarkers for disease. They can be roughly divided into two categories: protein biomarkers such as CD9, CD63, CD81, CEA (carcinoembryonic antigen), Her2 (human epidermal growth factor receptor-2), and EpCAM (epithelial cell adhesion molecule); nucleic acid biomarkers. Exosomes play a role in gene therapy, targeted therapy, drug delivery, immune regulation, etc. The mechanisms by which circRNAs enter exosomes include (A) RNA-binding protein mediated mechanism, (B) miRNA-mediated mechanism, (C) mechanisms mediated by RNA modification, and (D) mechanisms under cellular stress. In RNA-binding protein-mediated mechanism, circRHOBTB3 can be specifically sorted into exosomes by interacting with SNF8, a member of the ESCRT-II complexes, via its distinctive components. CircCCAR1, circ-CDYL and circNEIL3 can be packaged into exosomes by hnRNPA2B. In miRNA-mediated mechanism, exosomes with miR-7 mimics can effectively decrease the levels of competing endogenous spongy circCDR1as, and miR-671-AGO2 mediates the degradation of circCDR1as in source cells. In mechanism mediated by RNA modification, the structure and function of circRNAs may be affected by RNA modifications. M⁶A modification of circ-CDYL can promote the sorting of circ-CDYL into exosomes. In addition, when cells are exposed to external stimuli or stress conditions, the integration of circRNAs into exosomes is also affected. Exosome therapy strategies primarily include drug delivery, targeted therapy, gene therapy, and immune regulation

Fig. 3

Diagram of the functions of exosomal circRNAs in various aspects of NSCLC. The functions of exosomal circRNAs in NSCLC include lung cancer proliferation, metastasis, angiogenesis and apoptosis, in addition to playing roles in metabolism, tumor immune microenvironment, and chemoresistance, making exosomal circRNAs potential biomarkers and therapeutic targets