Zhao Xiaoya, Bao Linsen, Qian Yun, Zhou Shimeng, Chen Chen, Ma Zhuang, Xu Jiawen, Li Mengmeng, Niu Wenlu, Wang Bo, Wang Qiang, Wang Zhangding, Wang Shouyu, Wang Meng
Division of Gastric Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
Medical School of Nanjing University, Nanjing, China.
Oncogene. 2025 Jun 16. doi: 10.1038/s41388-025-03475-0.
Lymph node (LN) metastasis is a common feature of gastric adenocarcinoma (GAC) and is closely associated with a poor prognosis. Our previous study highlighted the pivotal role of nicotinamide N-methyltransferase (NNMT) in driving GAC carcinogenesis and malignant progression, primarily through its regulation of histone methylation. However, the mechanisms by which NNMT contributes to LN metastasis in GAC remain poorly understood. In this study, we demonstrated that elevated NNMT expression was positively correlated with LN metastasis and a poor prognosis in GAC patients. Gain- and loss-of-function experiments further revealed that NNMT accelerated GAC-related lymphangiogenesis, migration, and invasion in vitro and facilitated LN metastasis in vivo. Mechanistically, NNMT promoted the degradation of NR4A3 mRNA by diminishing its mA methylation, which diminished the binding of NR4A3 protein to the promoters of fibroblast growth factor 2 (FGF2) and hepatocyte growth factor (HGF), leading to increased expression of FGF2 and HGF, which in turn enhanced lymphangiogenesis and facilitated lymphatic metastasis in GAC. Collectively, our findings suggest that NNMT plays an oncogenic role in GAC and may serve as a valuable prognostic biomarker and therapeutic target for treating LN-metastatic GAC. NNMT promotes NR4A3 mRNA degradation by diminishing its m6A methylation, consequently promoting lymphangiogenesis and lymphatic metastasis in GAC.
淋巴结（LN）转移是胃腺癌（GAC）的常见特征，且与预后不良密切相关。我们之前的研究强调了烟酰胺N-甲基转移酶（NNMT）在驱动GAC致癌和恶性进展中的关键作用，主要是通过其对组蛋白甲基化的调控。然而，NNMT促进GAC中LN转移的机制仍知之甚少。在本研究中，我们证明NNMT表达升高与GAC患者的LN转移和不良预后呈正相关。功能获得和功能丧失实验进一步表明，NNMT在体外加速了GAC相关的淋巴管生成、迁移和侵袭，并在体内促进了LN转移。机制上，NNMT通过减少NR4A3 mRNA的m⁶A甲基化促进其降解，从而减少NR4A3蛋白与成纤维细胞生长因子2（FGF2）和肝细胞生长因子（HGF）启动子的结合，导致FGF2和HGF表达增加，进而增强GAC中的淋巴管生成并促进淋巴转移。总体而言，我们的研究结果表明NNMT在GAC中起致癌作用，可能作为治疗LN转移GAC的有价值的预后生物标志物和治疗靶点。NNMT通过减少NR4A3 mRNA的m⁶A甲基化促进其降解，从而促进GAC中的淋巴管生成和淋巴转移。
