Zou Lingxiao, Zhang Meng, He Shan, Zhuang Minhui, Jia Wenjing, Wang Yulan, Liu Jingjing, Wang Yixuan, Song Xiaofeng, Zhao Jian
Department of Biomedical Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing, 211106, China.
School of Mathematics and Statistics Science, Ludong University, Yantai, 264025, China.
Funct Integr Genomics. 2025 Sep 2;25(1):185. doi: 10.1007/s10142-025-01687-x.
Ovarian cancer (OC) is a highly lethal gynecologic malignancy that lacks reliable early biomarkers. Numerous long non-coding RNAs (lncRNAs) have been found to play critical regulatory roles in OC, yet the mechanisms underlying most of them remain unclear. Recently, lncRNAs have emerged as key regulators of RNA splicing, while splicing dysregulation is widespread and plays critical roles in cancer. In addition, genetic variants of splicing regulators have been shown to contribute to disease etiology. In this study, we comprehensively analyzed 202 °C samples and characterized 21,129 lncRNA splicing quantitative trait loci (sQTLs) involving both event-level and transcript-level. We found that lncRNA sQTLs differ significantly from lncRNA expression quantitative trait loci (eQTLs), and genes regulated by lncRNA sQTLs are involved in cancer hallmark pathways and associated with immune cell infiltration and drug sensitivity. Additionally, these lncRNA sQTLs are significantly enriched in histone markers, transcription factor (TF) binding sites, and RNA-binding protein (RBP) binding sites, including several critical splicing factors (SF) in OC. Based on SF binding and partial correlation analysis, a potential lncRNA-SF-mRNA regulatory network was constructed. Finally, by integrating GWAS data, we elucidated that a specific lncRNA sQTL rs1549334 generates different isoforms by regulating the splicing of the HOXD3 gene and thus impacting OC risk. Our study provides new insights into the mechanisms of splicing regulation in OC involving lncRNA sQTL and reveals potential biomarkers for early detection and clinical treatment of OC.
卵巢癌（OC）是一种极具致死性的妇科恶性肿瘤，缺乏可靠的早期生物标志物。已发现众多长链非编码RNA（lncRNA）在OC中发挥关键调控作用，但其大多数潜在机制仍不清楚。最近，lncRNA已成为RNA剪接的关键调节因子，而剪接失调普遍存在且在癌症中起关键作用。此外，剪接调节因子的基因变异已被证明与疾病病因有关。在本研究中，我们全面分析了202个样本，并对涉及事件水平和转录本水平的21,129个lncRNA剪接定量性状位点（sQTL）进行了表征。我们发现lncRNA sQTL与lncRNA表达定量性状位点（eQTL）有显著差异，且由lncRNA sQTL调控的基因参与癌症特征通路，并与免疫细胞浸润和药物敏感性相关。此外，这些lncRNA sQTL在组蛋白标记、转录因子（TF）结合位点和RNA结合蛋白（RBP）结合位点中显著富集，包括OC中的几个关键剪接因子（SF）。基于SF结合和偏相关分析，构建了一个潜在的lncRNA-SF-mRNA调控网络。最后，通过整合全基因组关联研究（GWAS）数据，我们阐明了一个特定的lncRNA sQTL rs1549334通过调节HOXD3基因的剪接产生不同的异构体，从而影响OC风险。我们的研究为涉及lncRNA sQTL的OC剪接调控机制提供了新见解，并揭示了OC早期检测和临床治疗的潜在生物标志物。
