Tu Linshuang, Luo Jiefu, Yin Ya, Yu Huihong
Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Front Pharmacol. 2025 Apr 28;16:1516534. doi: 10.3389/fphar.2025.1516534. eCollection 2025.
Splicing factor 3b subunit 6(SF3B6), a subunit of the SF3B complex, regulates the process of RNA splicing by recognizing the branch point adenosine in pre-mRNA and facilitating the interaction between U2 snRNA and the branch point sequence. Currently, there is no systematic multi-omics study exploring the diagnostic, prognostic, and immunotherapy predictive value of SF3B6 in pan-cancer, nor is its role in hepatocellular carcinoma (HCC) clear.
We utilized various databases to systematically examine the expression and genetic variation of SF3B6 across multiple cancer types, assessing its relationship with diagnosis, prognosis, immune infiltration, immunotherapy response, and associated signaling pathways. Additionally, we investigated the correlation between SF3B6 and prognosis, clinicopathological features, and treatment responses in HCC, as well as the roles of its related alternative splicing isoforms. Finally, we conducted experiments to validate the effects of SF3B6 on the proliferation, migration, invasion, apoptosis, and cell cycle progression of liver cancer cells.
Results indicate that SF3B6 was highly expressed in various cancers and regulated by copy number variations and DNA methylation. The elevated expression of SF3B6 demonstrated predictive value for cancer diagnosis, prognosis, and responses to immunotherapy. Functional enrichment analysis suggests that SF3B6 was closely associated with pathways related to tumor immunity, tumor metabolism, and cell cycle. Additionally, high SF3B6 expression was an independent risk factor for overall survival and correlated with poor alpha-fetoprotein levels, pathological grading, clinical staging, and reduced responses to sorafenib and transarterial chemoembolization treatment in HCC. Interestingly, SF3B6 was associated with variant splicing isotypes of genes involved in the G2M checkpoint and DNA repair pathways, including NEIL3, NEK2, KIF4A, TROAP, and FANCD2. Moreover, SF3B6 was highly expressed in liver cancer cells, promoting the proliferation, migration, and invasion of cancer cells, inhibiting apoptosis, and regulating the transition from the S phase to the G2M phase of the cell cycle.
We emphasize that SF3B6 has the potential to serve as a biomarker for predicting cancer diagnosis, prognosis, and immunotherapy responses, especially in HCC. SF3B6 and its related alternative splicing isoforms promote the occurrence and progression of HCC and may serve as potential therapeutic targets.
剪接因子3b亚基6（SF3B6）是SF3B复合体的一个亚基，通过识别前体mRNA中的分支点腺苷并促进U2 snRNA与分支点序列之间的相互作用来调节RNA剪接过程。目前，尚无系统的多组学研究探索SF3B6在泛癌中的诊断、预后及免疫治疗预测价值，其在肝细胞癌（HCC）中的作用也尚不明确。
我们利用各种数据库系统地研究了SF3B6在多种癌症类型中的表达和基因变异，评估其与诊断、预后、免疫浸润、免疫治疗反应及相关信号通路的关系。此外，我们还研究了SF3B6与HCC预后、临床病理特征及治疗反应之间的相关性，以及其相关可变剪接异构体的作用。最后，我们进行实验验证了SF3B6对肝癌细胞增殖、迁移、侵袭、凋亡及细胞周期进程的影响。
结果表明，SF3B6在多种癌症中高表达，并受拷贝数变异和DNA甲基化调控。SF3B6表达升高对癌症诊断、预后及免疫治疗反应具有预测价值。功能富集分析表明，SF3B6与肿瘤免疫、肿瘤代谢和细胞周期相关通路密切相关。此外，高SF3B6表达是总生存的独立危险因素，且与HCC中不良的甲胎蛋白水平、病理分级、临床分期以及对索拉非尼和经动脉化疗栓塞治疗反应降低相关。有趣的是，SF3B6与参与G2M检查点和DNA修复通路的基因的可变剪接异构体有关，包括NEIL3、NEK2、KIF4A、TROAP和FANCD2。此外，SF3B6在肝癌细胞中高表达，促进癌细胞的增殖、迁移和侵袭，抑制凋亡，并调节细胞周期从S期到G2M期的转变。
我们强调，SF3B6有潜力作为预测癌症诊断、预后及免疫治疗反应的生物标志物，尤其是在HCC中。SF3B6及其相关可变剪接异构体促进HCC的发生和发展，可能成为潜在的治疗靶点。
