Perspective and Therapeutic Potential of the Noncoding RNA-Connexin Axis

Abstract

Noncoding RNAs (ncRNAs) are a class of nucleotide sequences that cannot be translated into peptides. ncRNAs can function post-transcriptionally by splicing complementary sequences of mRNAs or other ncRNAs or by directly engaging in protein interactions. Over the past few decades, the pervasiveness of ncRNAs in cell physiology and their pivotal roles in various diseases have been identified. One target regulated by ncRNAs is connexin (Cx), a protein that forms gap junctions and hemichannels and facilitates intercellular molecule exchange. The aberrant expression and misdistribution of connexins have been implicated in central nervous system diseases, cardiovascular diseases, bone diseases, and cancer. Current databases and technologies have enabled researchers to identify the direct or indirect relationships between ncRNAs and connexins, thereby elucidating their correlation with diseases. In this review, we selected the literature published in the past five years concerning disorders regulated by ncRNAs via corresponding connexins. Among it, microRNAs that regulate the expression of Cx43 play a crucial role in disease development and are predominantly reviewed. The distinctive perspective of the ncRNA-Cx axis interprets pathology in an epigenetic manner and is expected to motivate research for the development of biomarkers and therapeutics.

Keywords: connexin; disease; lncRNA; microRNA; noncoding RNA.

Figure 1

Diagram of the ncRNA–Cx axis. miRNAs act as translation suppressors by inhibiting transcription or inducing mRNA degradation. miRNAs bind to the 3′ untranslated regions of connexin mRNAs, preventing the Cx mRNAs from being translated, thereby contributing to disease development. lncRNAs, including circRNAs, act as sponges to abolish miRNA function, abrogating the miRNA-induced inhibition of Cx mRNAs. Moreover, miRNAs and lncRNAs interact with various proteins or serve as scaffolds to influence Cx function and distribution. tsRNAs and piRNAs regulate gene expression; however, how they regulate Cx remains unclear. Notably, (1) gap junctions particularly assembled from Cx43 provide pathways for the intercellular transport of miRNAs between cancer cells; (2) lncRNA CCRR’s reaction with CIP85 interrupts the binding of CIP85 and Cx43, thereby preventing the removal of Cx43 from the myocardial cell membrane; and (3) extracellular vesicles equipped with hemichannels have been implicated in the delivery of miRNAs to distant cells. However, supporting evidence for this mechanism is currently limited. The interaction between tsRNAs, piRNAs, and connexins needs to be further investigated. Cx, connexin; lncRNA, long noncoding RNA; circRNA, circular RNA; miRNA, microRNA; tsRNAs, transfer RNA (tRNA)-derived small RNAs; piRNAs, PIWI-interacting RNAs; nt, nucleotide; PPI, protein–protein interaction.