RNA结合蛋白(RBPs)-调控的基因表达在各种病理过程中发挥着重要作用，包括癌症的进展。然而，在肝细胞癌(HCC)中，RBP的作用仍然很不明确。本研究旨在探讨RBP CCDC137在HCC发展中的贡献。我们分析了数据库和HCC样本中CCDC137的表达水平的改变以及其临床意义。我们使用体外细胞实验和体内自发小鼠模型评估了CCDC137的功能。最后，我们探究了CCDC137如何调节基因表达并促进HCC的分子机制。CCDC137在HCC中异常上调，并与HCC患者的不良临床结局相关。CCDC137显著促进了HCC在体外和体内的增殖和进展。在机制上，CCDC137与FOXM1、JTV1、LASP1和FLOT2 mRNAs结合，通过APOBEC1介导的分析发现，增加它们的细胞质定位，从而增强它们的蛋白表达。FOXM1、JTV1、LASP1和FLOT2的上调随后协同激活AKT信号通路并促进HCC。有趣的是，我们发现CCDC137与微处理器蛋白DGCR8结合，而DGCR8在mRNA亚细胞定位中具有一种新型的非经典功能，它调节了由CCDC137调控的mRNA的细胞质分布。我们的结果确定了CCDC137在增殖中的关键作用，并揭示了HCC进展中CCDC137/DGCR8/mRNA定位/AKT轴的新颖机制，为HCC治疗提供了潜在的靶点。© 2023年，意大利国家癌症研究所“Regina Elena”。

RNA binding proteins (RBPs)-regulated gene expression play a vital role in various pathological processes, including the progression of cancer. However, the role of RBP in hepatocellular carcinoma (HCC) remains much unknown. In this study, we aimed to explore the contribution of RBP CCDC137 in HCC development.We analyzed the altered expression level and clinical significance of CCDC137 in database and HCC specimens. In vitro cell assays and in vivo spontaneous mouse models were used to assess the function of CCDC137. Finally, the molecular mechanisms of how CCDC137 regulates gene expression and promotes HCC was explored.CCDC137 is aberrantly upregulated in HCC and correlates with poor clinical outcomes in HCC patients. CCDC137 markedly promoted HCC proliferation and progression in vitro and in vivo. Mechanistically, CCDC137 binds with FOXM1, JTV1, LASP1 and FLOT2 mRNAs, which was revealed by APOBEC1-mediated profiling, to increase their cytoplasmic localization and thus enhance their protein expressions. Upregulation of FOXM1, JTV1, LASP1 and FLOT2 subsequently synergistically activate AKT signaling and promote HCC. Interestingly, we found that CCDC137 binds with the microprocessor protein DGCR8 and DGCR8 has a novel non-canonical function in mRNA subcellular localization, which mediates the cytoplasmic distribution of mRNAs regulated by CCDC137.Our results identify a critical proliferation-related role of CCDC137 and reveal a novel CCDC137/DGCR8/mRNA localization/AKT axis in HCC progression, which provide a potential target for HCC therapy.© 2023. Italian National Cancer Institute ‘Regina Elena’.