Circular RNAs: A Promising Biomarker for Endometrial Cancer

Abstract

Endometrial cancer (EC) is one of the most common malignant tumors of the female reproductive tract. EC patients have high morbidity and mortality rates and remain an important cause of cancer-related morbidity and mortality worldwide. More and more studies have shown that a large number of non-coding RNAs (such as microRNAs and long non-coding RNAs) are associated with the occurrence of diseases. Circular RNAs (circRNAs) is an endogenous non-coding RNA. It has a unique covalent structure. Many studies in recent years have found circRNAs differential expression in a variety of tumor tissues compared to matched normal tissues. In endometrial carcinoma, there also are multiple circRNAs differentially expressed and therefore circRNAs perhaps can be used as a diagnostic and prognosis biomarkers of EC. In this review, we described the biogenesis, function and characteristics of circRNAs, and the circRNAs with potential influence and clinical significance on the development of EC were summarized. Adenocarcinoma is the most common form of EC, so this review focuses on endometrioid adenocarcinoma.

Keywords: back-splicing; biogenesis; biomarker; circRNA; endometrial cancer; function.

Figure 1

Lariat-driven circularization: due to the exon skipping mechanism, back-splicing can occur, which leads to the formation of a lariat. The 3 ‘end splice donor of exon 1 is covalently bound to the 5ʹ splice acceptor of exon 4, and then the introns are excised to form circRNA. And finally three different products are synthesized: a circRNA, a mRNA with skipped exon, and a lariat structure.

Figure 2

Intronic lariats can form intronic circRNAs (ciRNAs).

Figure 3

Intron pairing-driven circularization: introns are paired by base pairing to form a circular structure, which promotes 3ʹ downstream splice donor connecting to the 5ʹ upstream splice acceptor, then the introns are excised to form circRNA.

Figure 4

RNA binding proteins (RBP) bind to introns on both sides of the exon that forms circRNA. RBP dimerization promotes the back splicing process.

Figure 5

(A) The functions of circRNAs: (B) CircRNA can act as a microRNA sponge by combining with miRNA and inhibiting its function. (C) CircRNA may bind to Pol II to enhance transcription of their parental genes. (D) By binding proteins, circRNA can act as a protein sponge to regulate gene expression. In addition, circRNAs can also be scaffolds for protein interactions. (E) As a template for protein synthesis. CircRNA containing internal ribosomal entry site (IRES) elements and an open reading frame can be translated into proteins or polypeptide.