AI Insight
This study developed a new algorithm to identify both canonical and noncanonical circular RNAs (circRNAs) independent of genome annotation. Research in lung cancer cells revealed that noncanonical circRNAs, which originate from regions outside typical exon-intron boundaries, comprise over two-thirds of all circRNAs and are more abundantly expressed than canonical forms. The researchers validated 65 noncanonical circRNAs experimentally, demonstrating that they are genuine cellular products rather than artifacts, may be translated into proteins, are conserved across species, and directly influence cancer cell viability.
Why it matters
These findings challenge the previous dismissal of noncanonical circRNAs as mere noise and reveal a largely unexplored layer of gene regulation. The discovery that these molecules affect cancer cell behavior and show tissue-specific expression patterns in lung cancer patients suggests potential applications in cancer diagnosis, prognosis, and therapeutic targeting.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Circular RNAs (circRNAs) are ubiquitous in eukaryotes; dysregulated circRNA expression is linked to diseases, including lung cancer. In contrast to canonical circRNAs arising from exon-intron boundaries, noncanonical circRNAs originating within exonic, intronic, and intergenic regions have typically been dismissed as transcriptional noise or technical artifacts. To explore circRNA diversity and appreciate their functions, we developed an algorithm to identify both canonical and noncanonical circRNAs without relying on genome annotation, enabling the identification of circRNAs of all types and in newly sequenced or poorly annotated species. Results from lung cancer cells revealed that noncanonical circRNAs constituted over two-thirds of the circRNA population and were expressed more abundantly than canonical circRNAs, and genes with fewer and shorter exons were hotspots for noncanonical circRNA and circRNA isoform production. Further analyses showed that many noncanonical circRNAs were indeed endogenous circRNAs transcribed within cells rather than experimental artifacts, were potentially translated into proteins or peptides, and were conserved across species. Moreover, we validated 65 noncanonical circRNAs in NCI-H23 cells using multiple bioassays and demonstrated that both exonic and intergenic noncanonical circRNAs influenced cell viability. CircRNA profiles in tumor and tumor-adjacent tissues of lung cancer patients revealed tissue-specific expression and differentially expressed canonical and noncanonical circRNAs from cognate genes involved in cancer-related pathways, indicating their potential clinical relevance. This study confirmed the authenticity of noncanonical circRNAs and provided the first experimental evidence that noncanonical circRNAs influence cancer cell phenotypes. These findings broaden our understanding of circRNA biology, highlighting their widespread genomic distribution, diverse functions, and potential clinical relevance.