Tang Lei, Ji Yang, Ni Chuangye, Xu Zhenggang, Shen Yanjun, Lu Hao, Zhang Chuanyong, Yang Shikun
Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), No. 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China.
Medical College, Yangzhou University, Yangzhou, Jiangsu, 225009, China.
Adv Sci (Weinh). 2025 Apr;12(14):e2411869. doi: 10.1002/advs.202411869. Epub 2025 Feb 18.
Mounting research indicates that circRNAs are pivotal elements in tumorigenesis and progression. Understanding the mechanisms by which circRNAs function in tumors is crucial for identifying undiscovered diagnostic and treatment targets. This research centers on unraveling the mechanisms by which the novel circRNA, circFADS1, influences hepatocellular carcinoma (HCC) progression. CircFADS1 shows elevated expression in HCC and is linked to unfavorable prognosis. Functionally, circFADS1 overexpression accelerates HCC progression through inducing HCC proliferation and inhibited apoptosis. Mechanistically, RNA-seq analysis demonstrates its connection to the Wnt/β-catenin pathway. Moreover, circFADS1 interacts with GSK3β and promotes its ubiquitination and degradation by recruiting the ubiquitin ligase RNF114 while EIF4A3 facilitates the biogenesis of circFADS1. Additionally, circFADS1 is closely linked to lenvatinib resistance. Overall, this study reveals that circFADS1 regulates GSK3β function, influencing the progression of hepatocellular carcinoma. The EIF4A3/circFADS1/GSK3β/β-catenin axis is discovered to hold promise as a novel therapeutic target for hepatocellular carcinoma, while circFADS1 is also a significant factor in lenvatinib resistance.
越来越多的研究表明，环状RNA（circRNAs）是肿瘤发生和发展的关键因素。了解circRNAs在肿瘤中发挥作用的机制对于确定未被发现的诊断和治疗靶点至关重要。本研究聚焦于揭示新型circRNA——circFADS1影响肝细胞癌（HCC）进展的机制。circFADS1在HCC中表达升高，且与不良预后相关。在功能上，circFADS1过表达通过诱导HCC增殖和抑制凋亡来加速HCC进展。从机制上讲，RNA测序分析表明其与Wnt/β-连环蛋白通路有关。此外，circFADS1与糖原合成酶激酶3β（GSK3β）相互作用，并通过招募泛素连接酶RNF114促进其泛素化和降解，而真核翻译起始因子4A3（EIF4A3）促进circFADS1的生物合成。此外，circFADS1与乐伐替尼耐药密切相关。总体而言，本研究揭示了circFADS1调节GSK3β功能，影响肝细胞癌的进展。发现EIF4A3/circFADS1/GSK3β/β-连环蛋白轴有望成为肝细胞癌的新型治疗靶点，而circFADS1也是乐伐替尼耐药的重要因素。
