Wang Jiaqi, Zhou Kai, He Tao, Hu Qihang, Liu Jianquan, Li Pingang, Shi Yan, Song Jun, Yu Peiwu
Department of General Surgery, The First Affiliated Hospital of Army Medical University, 30 Gaotanyan Street, Chongqing, 400038, China.
Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, China.
Cell Oncol (Dordr). 2025 Aug 5. doi: 10.1007/s13402-025-01094-1.
Gastric cancer (GC) is one of the most common malignant tumor worldwide. Metastasis is leading cases of cancer-related death of GC. It has been found that N-methylguanosine (m7G) modifications play an important role in cancer. However, the role of m7G modifications within mRNA and its "writer" METTL1 and WDR4 in tumors, particularly GC, has not been revealed.
RT-qPCR, WB and IHC were used to detect the expression of METTL1 and WDR4 in GC cells and tissues. Function-based experiments were performed using METTL1-WDR4 knockdown and overexpression cell lines in vitro and in vivo, including CCK8, colony formation, transwell and nude mice models. Mechanistically, RNA-seq, MeRIP-seq, MeRIP-qPCR, western blot, dot blot, co-IP, ChIP and IHC stainings were performed.
METTL1 and WDR4 were upregulated in GC patients. High expression of METTL1 and WDR4 were associated with poor prognosis. Silencing METTL1-WDR4 inhibited GC cell migration and proliferation in vitro and vivo. Mechanistically, METTL1-WDR4 can enhance the mRNA stability of PIK3C2B and AKT by promoting their m7G levels, which leading the overexpression of p-AKT. Interestingly, we also found that on the one hand, the transcription factor YY1 can promote the mRNA transcription expression of METTL1 and WDR4 at the same time, and on the other hand, METTL1-WDR4 can promote YY1 expression by increasing the level of m7G. This regulation presents positive feedback. Above all, METTL1 and WDR4 ultimately up-regulate the level of m7G and promote the malignant progression of GC.
These findings suggest that METTL1-WDR4 might serve as a potential diagnostic and prognostic biomarker and a therapeutic target for GC treatment by regulating m7G level.
胃癌（GC）是全球最常见的恶性肿瘤之一。转移是胃癌相关死亡的主要原因。已发现N-甲基鸟苷（m7G）修饰在癌症中起重要作用。然而，m7G修饰在mRNA及其“书写器”METTL1和WDR4在肿瘤，特别是胃癌中的作用尚未揭示。
采用RT-qPCR、WB和IHC检测METTL1和WDR4在胃癌细胞和组织中的表达。使用METTL1-WDR4敲低和过表达细胞系在体外和体内进行基于功能的实验，包括CCK8、集落形成、transwell和裸鼠模型。从机制上，进行了RNA-seq、MeRIP-seq、MeRIP-qPCR、western blot、斑点印迹、co-IP、ChIP和IHC染色。
METTL1和WDR4在胃癌患者中上调。METTL1和WDR4的高表达与不良预后相关。沉默METTL1-WDR4在体外和体内抑制胃癌细胞迁移和增殖。机制上，METTL1-WDR4可通过提高PIK3C2B和AKT的m7G水平来增强其mRNA稳定性，从而导致p-AKT的过表达。有趣的是，我们还发现，一方面，转录因子YY1可同时促进METTL1和WDR4的mRNA转录表达，另一方面，METTL1-WDR4可通过增加m7G水平促进YY1表达。这种调节呈现正反馈。综上所述，METTL1和WDR4最终上调m7G水平并促进胃癌的恶性进展。
这些发现表明，METTL1-WDR4可能作为一种潜在的诊断和预后生物标志物，以及通过调节m7G水平作为胃癌治疗的靶点。
