Circular RNAs and gastrointestinal cancers: Epigenetic regulators with a prognostic and therapeutic role

Abstract

Both environmental and genetic factors are involved in the initiation and development of gastrointestinal cancer. Covalent closed circular RNAs (circRNAs) are produced by a mechanism called "back-splicing" from mRNAs. They are highly stable and show cell and tissue specific expression patterns. Although some functions such as "microRNA sponge" and "RNA binding protein sponge" have been reported for a small number of circRNAs, the function of thousands of other circRNAs is still unknown. Dysregulation of circRNAs has been reported in many GI cancers and are involved in metastasis and invasion. CircRNAs have been reported to be useful as prognostic markers and targets for developing new treatments. We first describe the properties and biogenesis of circRNAs. We then summarize recent reports about circRNA functions, expression status, and their potential to be used as biomarkers in GI cancers including, gastric cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, gallbladder cancer and pancreatic cancer.

Keywords: Biomarkers; Circular RNAs; Gastrointestinal cancers; Prognostic indicator; Signaling pathways; microRNA sponge.

Figure 1.. CircRNAs biogenesis.

Exons are shown as rectangles with different colors, and introns are depicted as black lines. Exon-derived circRNA (ecRNA) contains only exons (A and B), while circular intronic RNA (ciRNA) comprises only introns (D). In exon–intron circRNA (EIciRNA), an intron is introduced between two exons (C). The pathway by which mature ecRNAs are exported into the cytoplasm is still unclear. Some circRNAs are assumed to pass through the nuclear membrane via a nuclear pore complex.

Figure 2.. Schematic illustration of circRNA functions.

(A) CircRNAs might function as miRNA sponges by competing for binding of miRNA sequences, lessening the impact of miRNA-mediated regulationon gene expression. (B) CircRNAs might function as protein sponges, by binding to other RNA-binding proteins (RBPs). (C) Some circRNAs might control the expression of proteins by sequestering mRNA translation start sites. (D) CircRNAs might be translated to create functional proteins. (E) CircRNAs (e.g., EIciRNAs and ciRNAs) might interact with transcription complexes and increase the expression of their parental genes.