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<p>Hepatocellular carcinoma (HCC) remains a global health challenge with a high recurrence rate, highlighting the need to decipher its underlying molecular mechanisms. While circular RNAs (circRNAs) are known to regulate gene expression, the landscape of competitive splicing—the dynamic balance between back-splicing and linear splicing—during HCC initiation and recurrence remains largely unexplored. Leveraging rRNA-zero RNA-seq data from GSE169289 (comprising 34 primary, recurrent, and non-recurrent HCC samples with paired controls), this study utilized an upgraded SUVA pipeline to systematically profile circRNA-associated alternative splicing events. By integrating four distinct algorithms, we identified 9,652 high-confidence circRNAs. Our analysis revealed extensive differential splicing events distinguishing tumor from normal tissues, and notably, recurrent from non-recurrent tumors, with host genes enriched in chromatin remodeling and ubiquitin-dependent pathways. Specifically, we observed a conserved attenuation in the competitive splicing of the LARP1B circRNA in tumor tissues, which correlated with host gene downregulation and poor prognosis. In the context of recurrence, circ-KLHL8 exhibited specific splicing suppression; in silico modeling suggests a potential mechanism where circ-KLHL8 loss relieves the sponging of miRNAs, thereby suppressing the tumor suppressor GLYCTK. Furthermore, RBP-circRNA co-regulatory network analysis implicated HNRNPU and CPSF4 as potential upstream regulators of initiation-related splicing, and DKC1 as a modulator of recurrence-associated events. Collectively, this study provides the first systematic characterization of the competitive splicing landscape in HCC, proposing a novel theoretical framework and candidate targets for diagnostic and therapeutic interrogation.</p>

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Dysregulated competitive splicing between circular and linear RNAs characterizes hepatocellular carcinoma tumorigenesis and recurrence

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月14日

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  • Sunlu Jiang,
  • Ning Cui,
  • Lei Nie,
  • Jian Shen,
  • Xianmin Zhu,
  • Hong Li

摘要

Hepatocellular carcinoma (HCC) remains a global health challenge with a high recurrence rate, highlighting the need to decipher its underlying molecular mechanisms. While circular RNAs (circRNAs) are known to regulate gene expression, the landscape of competitive splicing—the dynamic balance between back-splicing and linear splicing—during HCC initiation and recurrence remains largely unexplored. Leveraging rRNA-zero RNA-seq data from GSE169289 (comprising 34 primary, recurrent, and non-recurrent HCC samples with paired controls), this study utilized an upgraded SUVA pipeline to systematically profile circRNA-associated alternative splicing events. By integrating four distinct algorithms, we identified 9,652 high-confidence circRNAs. Our analysis revealed extensive differential splicing events distinguishing tumor from normal tissues, and notably, recurrent from non-recurrent tumors, with host genes enriched in chromatin remodeling and ubiquitin-dependent pathways. Specifically, we observed a conserved attenuation in the competitive splicing of the LARP1B circRNA in tumor tissues, which correlated with host gene downregulation and poor prognosis. In the context of recurrence, circ-KLHL8 exhibited specific splicing suppression; in silico modeling suggests a potential mechanism where circ-KLHL8 loss relieves the sponging of miRNAs, thereby suppressing the tumor suppressor GLYCTK. Furthermore, RBP-circRNA co-regulatory network analysis implicated HNRNPU and CPSF4 as potential upstream regulators of initiation-related splicing, and DKC1 as a modulator of recurrence-associated events. Collectively, this study provides the first systematic characterization of the competitive splicing landscape in HCC, proposing a novel theoretical framework and candidate targets for diagnostic and therapeutic interrogation.