CircRNAs and RNA-Binding Proteins Involved in the Pathogenesis of Cancers or Central Nervous System Disorders

Abstract

Circular RNAs (circRNAs), a newly recognized group of noncoding RNA transcripts, have established widespread attention due to their regulatory role in cell signaling. They are covalently closed noncoding RNAs that form a loop, and are typically generated during the splicing of precursor RNAs. CircRNAs are key post-transcriptional and post-translational regulators of gene expression programs that might influence cellular response and/or function. In particular, circRNAs have been considered to function as sponges of specific miRNA, regulating cellular processes at the post-transcription stage. Accumulating evidence has shown that the aberrant expression of circRNAs could play a key role in the pathogenesis of several diseases. Notably, circRNAs, microRNAs, and several RNA-binding proteins, including the antiproliferative (APRO) family proteins, could be indispensable gene modulators, which might be strongly linked to the occurrence of diseases. In addition, circRNAs have attracted general interest for their stability, abundance in the brain, and their capability to cross the blood-brain barrier. Here, we present the current findings and theragnostic potentials of circRNAs in several diseases. With this, we aim to provide new insights to support the development of novel diagnostic and/or therapeutic strategies for these diseases.

Keywords: APRO family protein; RNA binding protein; circular RNA; poly(A)-binding protein; translational regulator.

Figure 1

Illustration of the general functions of circular RNAs (circRNAs). Functions of circRNAs have been proposed in several diseases including cancers, brain or CNS disorders, several types of diabetes mellitus, bone-related diseases, and polycystic ovary syndrome. Consequently, certain circRNAs could be diagnostic and/or therapeutic tools for these diseases. The arrowhead means stimulation and/or augmentation, whereas the hammerhead represents inhibition.

Figure 2

Schematic representation of circRNA- and/or miRNA-mediated functional inhibition of mRNA translation. The AGO2 protein interacts with GW182 constructing the miRNA-loaded RNA-induced silencing complex (miRISC), which may facilitate the deadenylation and/or mRNA degradation process by CAF1/CCR4/NOT1 with the PABP and APRO protein complex. Consequently, the circRNA and/or miRNA could play an active role in regulating post-transcriptional gene expression via the decapping, translational inhibition, deadenylation, and degradation of mRNA. The CAF1/CCR4/NOT1 complex is recruited to the 3′ UTR of specific mRNAs through an interaction with the PABP protein. APRO family proteins might also interact with PABP to recruit the CAF1/CCR4/NOT1 complex. The arrowhead means stimulation, and the hammerhead represents inhibition. Note that some critical pathways have been omitted for clarity. Abbreviations: ORF, open reading frame; miRISC, microRNA-induced silencing complex, “?” means for our speculation.