Genome-wide Analysis of Ovarian Cancer-specific circRNAs in Alternative Splicing Regulation

Background: Ovarian cancer (OC) is a fatal female reproductive system cancer with a high mortality rate and is hard to detect at an early stage. Recent studies have indicated that alternative splicing plays an important role in OC progression by activating genes and pathways involved in tumorigenesis. Circular RNAs (circRNAs) have also been found to play as regulatory roles in tumor progression and present their potential ability in regulating alternative splicing. However, the underlying mechanism by which circRNAs regulate alternative splicing events (ASEs) in OC remains unclear. Methods: In this study, we performed a comprehensive transcriptomic study on the RNA-seq data of our collected tumor and normal samples from OC patients, aiming to investigate the regulatory roles of OC-specific circRNAs in aberrant splicing events and their underlying pathways in tumorigenesis. Results: The results of this study indicated that OC-specific circRNAs might indirectly regulate groups of ASEs through splicing factors (SFs), rather than through direct interaction. We conducted a genome-wide regulatory network with strong correlations from 300 differentially expressed (DE) circRNAs and 1,150 aberrant ASEs, mediated by 31 DE SFs. Analyses of this network revealed that dysregulation of circRNAs may lead to aberrant ASEs that are closely involved in ovarian tumorigenesis. In addition, two crucial circRNAs, circ_AKT3 (hsa_circ_0000199) and circ_GSK3B (hsa_circ_0008797), were identified due to their significant roles in the network and associations with multiple tumor-related functional pathways. Conclusion: This study provides novel insights into the regulatory pathways by which circRNAs are involved in OC progression, offering clues for discovering diagnostic biomarkers and therapeutic targets. conclusion: This study provides novel insights into the regulatory pathways by which circRNAs are involved with OC progression, offering clues for discovering diagnostic biomarkers and therapeutic targets.