Interactions between circRNAs and miR-141 in Cancer: From Pathogenesis to Diagnosis and Therapy

Abstract

The function of non-coding RNAs (ncRNAs) in the pathogenesis and development of cancer is indisputable. Molecular mechanisms underlying carcinogenesis involve the aberrant expression of ncRNAs, including circular RNAs (circRNAs), and microRNAs (miRNAs). CircRNAs are a class of single-stranded, covalently closed RNAs responsible for maintaining cellular homeostasis through their diverse functions. As a part of the competing endogenous RNA (ceRNAs) network, they play a central role in the regulation of accessibility of miRNAs to their mRNA targets. The interplay between these molecular players is based on the primary role of circRNAs that act as miRNAs sponges, and the circRNA/miRNA imbalance plays a central role in different pathologies including cancer. Herein, we present the latest state of knowledge about interactions between circRNAs and miR-141, a well-known member of the miR-200 family, in malignant transformation, with emphasis on the biological role of circRNA/miR-141/mRNA networks as a future target for novel anti-cancer therapies.

Keywords: cancer; circRNA; circRNA-miRNA-mRNA regulatory network; diagnosis; miR-141; microRNA; ncRNA; therapy.

Figure 1

Biogenesis of miRNAs (a) and circRNAs (b) and their interactions affecting the regulation of gene expression (c).

Figure 2

The biogenesis of circRNAs. (a) RNA-binding protein-driven circularization (RBPs): RBPs bind to specific flanking sequence motifs of upstream and downstream introns, bring flanking introns closer to each other and causing a formation of exonic-intronic circRNAs or exonic circRNAs. (b) The introns flanking inverted repeating elements (such as Alu elements) form exonic circRNAs or exonic-intronic circRNAs by base-pairing, where introns are removed or retained, respectively. (c) Exonic circRNAs and intronic circRNAs are created from splicing intermediates (lariat precursors): one mechanism is associated with exon-skipping when one or more exons of the mRNA transcript are skipped during linear splicing, and the second mechanism is based on intronic lariat precursors’ escape from the debranching step of the canonical linear splicing. (d) The formation of intronic circRNAs is dependent on 7-nt GU-rich and 11-nt C-rich elements: during direct back-splicing, two elements bind into a lariat-like intermediate which is sufficient to escape from debranching and exonucleolytic degradation. After the trimming of the 3′ tail, intronic circRNAs are generated.