Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
Exp Cell Res. 2024 Sep 1;442(1):114219. doi: 10.1016/j.yexcr.2024.114219. Epub 2024 Aug 23.
N6-methyladenosine (mA) modification plays an important role in RNA molecular functions, therefore affecting the initiation and development of hepatocellular carcinoma (HCC). Herein, multiple datasets were applied to conduct a comprehensive analysis of DEGs within HCC and the analysis revealed significant dysregulation of numerous genes. Functional and signaling pathway enrichment analyses were performed. Further, TP53RK binding protein (TPRKB) emerged as a significant factor, exhibiting high expression level within HCC tissue samples and cells which could predict HCC patients' poor OS. Knockdown investigations of TPRKB in vitro demonstrated the effect of TPRKB knockdown on attenuating the aggressiveness of HCC cells by suppressing the viability, colony formation, invasive ability, and migratory ability, inducing cell cycle arrest, and facilitating the apoptosis of HCC cells. Investigations in vivo revealed that TPRKB knockdown significantly suppressed tumor growth in mice model. Additionally, the study identified methyltransferase 5, N6-adenosine (METTL5) as a potential regulator of TPRKB expression via mA modification, positively regulating TPRKB expression by enhancing TPRKB mRNA stability. The dynamic effects of METTL5 and TPRKB upon the phenotypes of HCC cells further confirmed that TPRKB overexpression partially abolished the anti-cancer effects of METTL5 knockdown upon the aggressiveness of HCC cells. Conclusively, our findings uncover that TPRKB, significantly overexpressed in HCC, exerts a critical effect on promoting tumor aggressiveness, and its expression shows to be positively regulated by METTL5 via mA methylation. These insights deepen the understanding of HCC pathogenesis and open new avenues for targeted therapies, highlighting that METTL5-TPRKB axis is an underlying new therapeutic target in HCC management.
N6-甲基腺苷（mA）修饰在 RNA 分子功能中发挥重要作用，因此影响肝癌（HCC）的发生和发展。在此，应用多个数据集对 HCC 中的差异表达基因（DEGs）进行全面分析，分析显示大量基因显著失调。进行了功能和信号通路富集分析。进一步发现，TP53RK 结合蛋白（TPRKB）是一个重要的因素，在 HCC 组织样本和细胞中表现出高表达水平，可预测 HCC 患者的 OS 不良。体外 TPRKB 敲低研究表明，TPRKB 敲低通过抑制 HCC 细胞的活力、集落形成、侵袭能力和迁移能力，诱导细胞周期停滞，并促进 HCC 细胞凋亡，从而影响 HCC 细胞的侵袭性。体内研究表明，TPRKB 敲低显著抑制了小鼠模型中的肿瘤生长。此外，研究还发现甲基转移酶 5、N6-腺苷（METTL5）通过 mA 修饰作为 TPRKB 表达的潜在调节剂，通过增强 TPRKB mRNA 稳定性正向调节 TPRKB 表达。METTL5 和 TPRKB 对 HCC 细胞表型的动态影响进一步证实，TPRKB 过表达部分消除了 METTL5 敲低对 HCC 细胞侵袭性的抗癌作用。总之，我们的研究结果表明，在 HCC 中高度表达的 TPRKB 对促进肿瘤侵袭性具有重要作用，其表达受 METTL5 通过 mA 甲基化的正向调节。这些发现加深了对 HCC 发病机制的理解，并为靶向治疗开辟了新的途径，突出了 METTL5-TPRKB 轴是 HCC 治疗的一个潜在新的治疗靶点。
