Abstract
Circular RNAs (circRNAs) are increasingly recognized as having a role in cancer development. Their expression is modified in numerous cancers, including hepatocellular carcinoma (HCC); however, little is known about the mechanisms of their regulation. The aim of this study was to identify regulators of circRNAome expression in HCC. Using publicly available datasets, we identified RNA binding proteins (RBPs) with enriched motifs around the splice sites of differentially expressed circRNAs in HCC. We confirmed the binding of some of the candidate RBPs using ChIP-seq and eCLIP datasets in the ENCODE database. Several of the identified RBPs were found to be differentially expressed in HCC and/or correlated with the overall survival of HCC patients. According to our bioinformatics analyses and published evidence, we propose that NONO, PCPB2, PCPB1, ESRP2, and HNRNPK are candidate regulators of circRNA expression in HCC. We confirmed that the knocking down the epithelial splicing regulatory protein 2 (ESRP2), known to be involved in the maintenance of the adult liver phenotype, significantly changed the expression of candidate circRNAs in a model HCC cell line. By understanding the systemic changes in transcriptome splicing, we can identify new proteins involved in the molecular pathways leading to HCC development and progression.
Highlights
Circular RNAs are a newly identified class of RNA molecules that have various roles, such as sponging miRNAs and RNA binding proteins (RBPs), modulating RBP function, having protein-coding potential, and regulating gene expression. [1]
We knocked down the expression of an identified RBP, epithelial splicing regulatory protein 2 (ESRP2), in a model hepatocellular carcinoma (HCC) cell line, and we showed that this modulated the expression levels of candidate circRNAs
We propose that ESRP2 is one of the RBPs driving the differential expression of circRNAs in HCC
Summary
Circular RNAs (circRNAs) are a newly identified class of RNA molecules that have various roles, such as sponging miRNAs and RNA binding proteins (RBPs), modulating RBP function, having protein-coding potential, and regulating gene expression. [1]. Though the biogenesis of circRNAs is a well-described mechanism, the regulation of their expression is not yet fully understood. The best-described mechanism of circRNA biogenesis is through the pairing of orientation-opposite complementary sequences (especially Alu repetitive elements) in the introns flanking the circRNA sequence, thereby bringing back-splice splicing sites to proximity. The accumulation of short interspersed nuclear repetitive DNA elements (SINEs) positively correlates with increased circRNA variety and number in more complex organisms [5]. Other mechanisms, such as the presence of long flanking introns, have been shown to drive the biogenesis of a class of circRNAs [6]
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