Circular RNAs and Their Role in Pediatric Disease Pathogenesis

Abstract

Circular RNA (circRNA) and long non-coding RNA (lncRNA) play a crucial role in gene regulation through microRNA (miRNA) pathways. Initially viewed as a molecular curiosity or a byproduct of RNA splicing processes, circRNAs were largely overlooked. Their biological relevance and diversity were only realised with the advent of high-throughput sequencing technologies in the 2010s. In this review manuscript, the role of circular RNA will be further evaluated in pediatric disease pathogenesis. Recent studies emphasise the importance of circRNA and lncRNA in competing endogenous RNA (ceRNA) networks in pediatric cancer. Circular RNA (circRNA) is a single-stranded RNA molecule that forms a closed loop structure, lacking 3' and 5' ends found in linear RNA. CircRNA has unique properties, including resistance to degradation and stability in cells. Some circRNAs are derived from protein-coding genes and have been shown to regulate gene expression. They have also been associated with diseases like cancer. In eukaryotes, genes are split by non-coding introns, and during RNA splicing, introns are removed, leaving only exons in the mature mRNA. Alternative splicing allows for different protein products from one RNA transcript. Exon scrambling, a non-canonical splicing event, can lead to different exon arrangements, impacting gene expression. Alu elements in flanking introns influence circRNA formation, and RNA editing can affect circRNA synthesis. CircRNAs can act as miRNA sponges, regulating gene expression. Genome-wide studies have identified circRNAs in various species, and their functions are still being explored. In recent years, circular RNAs (circRNAs) have emerged as key players in regulating cellular processes. Studies have identified specific circRNAs associated with NB progression. For instance, circAGO2 and circ-CUX1 have been linked to promoting growth and invasion of cancer cells by interacting with specific proteins.  Moreover, Circ0093740 was identified as upregulated in WT samples, promoting proliferation and migration by sponging miR-136/145 and upregulating DNMT3A. Researchers found that SMN circ4-2b-3, detected in patient-derived serum exosomes, was associated with a strong response to Nusinersen in a subset of patients (Guerra et al. 2024). This suggests that SMN circ4-2b-3 could be a useful biomarker for predicting treatment response in type I SMA patients. Targeting circRNAs can be achieved using antisense oligonucleotides and silencing RNAs, with nanotechnology offering innovative delivery methods. CircRNAs are more stable than linear RNAs and have longer half-lives. They are predominantly found in the cytoplasm and may play roles in gene regulation and disease. Evolutionarily conserved circRNA mechanisms suggest their functional significance across species. CDR1as/CiRS-7 is an example of a circRNA that acts as a miRNA sponge, regulating gene expression. Wilms' tumour (WT) accounts for 6% of childhood tumours and 95% of pediatric kidney tumours. CircSLC7A6 was found to be upregulated in WT tumour samples, increasing cell apoptosis and repressing migration and invasion by targeting miR-107 and upregulating ABL2 expression. It was concluded that CircRNAs, stable and specific molecules involved in physiological processes and implicated in cancer, offer potential as clinical biomarkers and therapeutic targets in pediatric oncology.