Functional role of circular RNAs in cancer development and progression

Abstract

Circular RNAs (circRNAs) are a large class of endogenously expressed non-coding RNAs formed by covalently closed loops through back-splicing. High throughput sequencing technologies have identified thousands of circRNAs with high sequence conservation and cell type specific expression in eukaryotes. CircRNAs play multiple important roles in cellular physiology functioning as miRNA sponges, transcriptional regulators, RBP binding molecules, templates for protein translation, and immune regulators. In a clinical context, circRNAs expression is correlated with patient's clinicopathological features in cancers including breast, liver, gastric, colorectal, and lung cancer. Additionally, distinct properties of circRNAs, such as high stability, exonuclease resistance, and existence in body fluids, show promising role for circRNAs as molecular biomarkers for tumor diagnosis, non-invasive monitoring, prognosis, and therapeutic intervention. Therefore, it is critical to further understand the molecular mechanism underlying circRNAs interaction in tumors and the recent progress of this RNA species in cancer development. In this review, we provide a detailed description of biological functions, molecular role of circRNAs in different cancers, and its potential role as biomarkers in a clinical context.

Keywords: Circrnas; cancer; carcinogenesis; circRNAs functions; miRNA sponge; tumor.

Figure 1.

Key functions of circRNAs. (A) CircRNA serves as miRNA sponge that harbors multiple miRNA binding sites that indirectly controls gene expression; (B) CircRNA functions as a transcriptional regulator via binding to RNA polymerase II; (C) CircRNAs act as a protein interactome. In human and Drosophila, RBP (MBL) binds to circRNA to compete with linear alternative splicing; In mouse, cell cycle related proteins bind to circRNAs to strengthen p21/CDK2 interaction and block cell cycle progression; (D) CircRNA that contains open reading frame (ORF) and in-frame stop codon is translated into proteins in a splicing-dependent, cap-independent manner.

Figure 2.

Roles of circRNAs. (A) Aberrant circRNAs expression associates with different cancer outcome. (B) Immune signaling, such as Toll-like receptor, induces the production of host circRNAs (left). Foreign circRNAs evoke RIG-I mediated immune responses via intron identity (right). (C) CircRNAs expression associates with cellular functions. (D) Hypoxia induces circRNAs expression.