NNMT-mediated N6-methyladenosine modification of NR4A3 mRNA facilitates lymphatic metastasis of gastric adenocarcinoma.

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 m6A 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.