The crosstalk between alternative splicing and circular RNA in cancer: pathogenic insights and therapeutic implications.

Abstract

RNA splicing is a fundamental step of gene expression. While constitutive splicing removes introns and joins exons unbiasedly, alternative splicing (AS) selectively determines the assembly of exons and introns to generate RNA variants corresponding to the same transcript. The biogenesis of circular RNAs (circRNAs) is inextricably associated with AS. Back-splicing, the biogenic process of circRNA, is a special form of AS. In cancer, both AS and circRNA deviate from the original track. In the present review, we delve into the intricate interplay between AS and circRNAs in the context of cancer. The relationship between AS and circRNAs is intricate, where AS modulates the biogenesis of circRNAs and circRNAs in return regulate AS events. Beyond that, epigenetic and posttranscriptional modifications concurrently regulate AS and circRNAs. On the basis of this modality, we summarize current knowledge on how splicing factors and other RNA binding proteins regulate circRNA biogenesis, and how circRNAs interact with splicing factors to influence AS events. Specifically, the feedback loop regulation between circRNAs and AS events contributes greatly to oncogenesis and cancer progression. In summary, resolving the crosstalk between AS and circRNA will not only provide better insight into cancer biology but also provoke novel strategies to combat cancer.