The Expression, Functions and Mechanisms of Circular RNAs in Gynecological Cancers

Abstract

Circular RNAs (circRNAs) are covalently closed, endogenous non-coding RNAs and certain circRNAs are linked to human tumors. Owing to their circular form, circRNAs are protected from degradation by exonucleases, and therefore, they are more stable than linear RNAs. Many circRNAs have been shown to sponge microRNAs, interact with RNA-binding proteins, regulate gene transcription, and be translated into proteins. Mounting evidence suggests that circRNAs are dysregulated in cancer tissues and can mediate various signaling pathways, thus affecting tumorigenesis, metastasis, and remodeling of the tumor microenvironment. First, we review the characteristics, biogenesis, and biological functions of circRNAs, and describe various mechanistic models of circRNAs. Then, we provide a systematic overview of the functional roles of circRNAs in gynecological cancers. Finally, we describe the potential future applications of circRNAs as biomarkers for prognostic stratification and as therapeutic targets in gynecological cancers. Although the function of most circRNAs remains elusive, some individual circRNAs have biologically relevant functions in cervical cancer, ovarian cancer, and endometrial cancer. Certain circRNAs have the potential to serve as biomarkers and therapeutic targets in gynecological cancers.

Keywords: biomarker; cancer diagnosis; cancer treatment; circular RNA; gynecological cancer; non-coding RNA.

Figure 1

Functional mechanisms of circular RNAs (circRNAs). CircRNAs, like mRNAs, are transcribed from protein-coding genes by RNA polymerase II (Pol II). However, they are spliced in a non-canonical splicing process known as back-splicing. Following biogenesis, the majority of circRNAs are exported to the cytoplasm in a size-dependent manner. (a) CircRNAs may act as microRNA (miRNA) sponges by binding to miRNAs and inhibiting their functions, thereby releasing downstream target genes from miRNA-mediated repression. (b) CircRNAs that harbor binding sites for RNA-binding proteins (RBPs) may function as protein sponges and thus regulate gene expression. In addition, circRNAs may work as scaffolds in the assembly of protein complexes. (c) CircRNAs may associate with Pol II to enhance the transcription of their parental genes. (d) CircRNAs may compete with their linear counterparts against canonical pre-mRNA splicing, thus suppressing the expression of their parent genes. (e) CircRNAs that contain internal ribosomal entry site (IRES) elements and open reading frame may be translated into protein or polypeptide.

Figure 2

Summary of literature search, screening and selection.

Figure 3

The circRNA-miRNA-mRNA regulatory networks and an HPV E7 oncoprotein-encoding circRNA play crucial roles in controlling CC progression, angiogenesis and chemoresistance. Red circles: oncogenic circRNAs; green circles: tumor-suppressive circRNAs.

Figure 4

The circRNA-miRNA-mRNA regulatory networks play essential roles in mediating ovarian cancer progression, angiogenesis and chemoresistance. Red circles: oncogenic circRNAs; green circles: tumor-suppressive circRNAs.