Huang Min, Zhang Zhengrong, Yan Wenwu, Cheng Zhengwu, Wang Jinguo
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, No. 2 Zheshan West Road, Wuhu 241000, Anhui Province, China.
The First Affiliated Hospital of Wannan Medical College.
Crit Rev Eukaryot Gene Expr. 2025;35(5):59-68. doi: 10.1615/CritRevEukaryotGeneExpr.2025058741.
Gastric cancer (GC) is a highly prevalent malignancy with significant morbidity and mortality rates. N4-acetylcytidine (ac4C), an emerging RNA modification, has been implicated in tumorigenesis of GC. NAT10, an enzyme responsible for ac4C modification, has garnered attention for its potential role in cancer progression. This study investigates the role of NAT10 in GC. We analyzed NAT10 expression in GC tissues and cell lines using Rt-qPCR, immunohistochemistry and Western blotting. Functional studies were conducted using shRNA and overexpression models in vitro and in vivo. The molecular mechanisms underlying NAT10-mediated GRB7 regulation were elucidated through ac4C modification assays. Our findings revealed that NAT10 is overexpressed in GC tissues and cells and predicted poor prognosis of GC patients. Inhibition of NAT10 suppressed the proliferation, migration, and invasion of GC cells. Mechanistically, NAT10-mediated ac4C modification enhanced expression of GRB7 by promoting its mRNA stability. Overexpression of GRB7 antagonized the effects of NAT10 shRNA and promoted the malignant behaviors of GC. In vivo studies showed that NAT10 knockdown reduced tumor growth. Collectively, our study highlights the crucial roles of NAT10 and ac4C modification in GC progression through the regulation of GRB7. Therefore, targeting NAT10/GRB7 axis may be a novel strategy for GC.
胃癌（GC）是一种高度流行的恶性肿瘤，发病率和死亡率都很高。N4-乙酰胞苷（ac4C）是一种新出现的RNA修饰，与GC的肿瘤发生有关。NAT10是一种负责ac4C修饰的酶，因其在癌症进展中的潜在作用而受到关注。本研究调查了NAT10在GC中的作用。我们使用逆转录定量聚合酶链反应（Rt-qPCR）、免疫组织化学和蛋白质免疫印迹法分析了GC组织和细胞系中NAT10的表达。在体外和体内使用短发夹RNA（shRNA）和过表达模型进行了功能研究。通过ac4C修饰试验阐明了NAT10介导的生长因子受体结合蛋白7（GRB7）调控的分子机制。我们的研究结果显示，NAT10在GC组织和细胞中过表达，并预测GC患者预后不良。抑制NAT10可抑制GC细胞的增殖、迁移和侵袭。机制上，NAT10介导的ac4C修饰通过促进GRB7的信使核糖核酸（mRNA）稳定性增强其表达。GRB7的过表达拮抗了NAT10 shRNA的作用，并促进了GC的恶性行为。体内研究表明，敲低NAT10可减少肿瘤生长。总的来说，我们的研究突出了NAT10和ac4C修饰通过调控GRB7在GC进展中的关键作用。因此，靶向NAT10/GRB7轴可能是GC的一种新策略。
