Pathogenic mechanisms and the potential clinical value of circFoxo3 in cancers

Abstract

Circular RNAs (circRNAs) are covalently closed circular structures that can function in various physiological and pathological processes by acting as microRNA (miRNA) sponges, RNA-binding protein (RBP) sponges, mRNA transcriptional regulators, and protein translational templates. circFoxo3 is one of the most studied circRNAs and is generated from the tumor suppressor gene Foxo3. Increasing studies have demonstrated the multiple functions of circFoxo3 in the pathogenesis of different cancer types. circFoxo3 plays important roles in cancer development mainly by binding to various miRNAs. The diagnostic potential of circFoxo3 has been revealed in several cancers. Some research results have been found to contradict the results of other studies, and this may be due to insufficient sample sizes and inconsistencies in the experimental and nomenclature methods. In this review, we systematically summarize current knowledge about the biogenesis and functions of circRNAs, elucidate the roles of circFoxo3 in different cancers, and explore the clinical applications of circFoxo3.

Keywords: action modes; biogenesis; cancer pathogenesis; circFoxo3; circular RNAs; clinical application.

Graphical abstract

Figure 1

Biogenesis models and the underlying action mechanisms of circRNAs (A) Lariat-driven circularization model dependent on the splice donor and acceptor can produce exonic circRNAs (ecRNAs). (B) Intron pairing-driven circularization indicated by the pairing of RNA base motifs (e.g., Alu repeats, red arrows) in introns can generate ecRNAs or exon-intron circRNAs (EIciRNAs). (C) RNA-binding proteins (RBPs) can bridge with pre-mRNAs to produce ecRNAs or EIciRNAs. (D) Circular intronic RNA (ciRNA) is generated by a back-splicing process. (E) circRNAs can bind to miRNAs to influence their function. (F) circRNAs can associate with RBPs to regulate the subsequent pathways. (G) circRNAs can encode proteins assisted by internal ribosome entry site (IRES38100136525000000) elements or m⁶A modifications (blue pin-2730572390000000). (H) ciRNAs and EIciRNAs can regulate the expression of parental genes by binding to RNA polymerase II (Pol II).

Figure 2

circFoxo3 participates in various types of cancers through different pathways circFoxo3 can suppress the pathogenesis of non-small cell lung cancer, prostate cancer, breast cancer, esophageal squamous cell cancer, and bladder cancer. On the contrary, circFoxo3 can promote the pathogenesis of gastric carcinoma, glioblastoma, prostate cancer, and hepatocellular carcinoma. In particular, circFoxo3 was reported to have the opposite effect in two studies on prostate cancer.