Identification of SLC2A3 as a Downstream Target of METTL1- mediated N7-methylguanosine Modification During MNNG-induced Gastric Carcinogenesis.

INTRODUCTION Methyl-N'-nitro-N-nitrosoguanidine (MNNG) is an environmental carcinogen that induces Gastric Cancer (GC). N7-methylguanosine (m7G) is a prevalent RNA modification closely linked to cancer onset and progression. However, the role of m7G in regulating gene expression during MNNG-induced gastric carcinogenesis remains unclear. This study aims to investigate the role of m7G modification in MNNG-induced GC and to identify potential downstream regulatory genes.

Methods

Cell proliferation and migration were evaluated using CCK-8 and scratch assays in Malignant transformed cells (MC) and GC cells with different METTL1 expression levels. The m7G MeRIP-seq and whole-transcriptome sequencing were integrated to screen potential genes regulated by m7G modification in MC-30 cells. GO and KEGG analyses were performed for gene function. Candidate gene expression was screened and validated in MC and GC cells by RT-qPCR. Finally, we validated SLC2A3 by analyzing gene expression using the TCGA STAD cohort and 24 pairs of clinical GC samples.

Results

METTL1 knockdown significantly inhibited proliferation and migration by about 25% (p < 0.001). Sequencing analysis identified SLC2A3 as a key METTL1 downstream target, with significantly altered m7G modification levels (fold change > 2, p < 0.05) and enrichment in cancer-related pathways. Clinically, SLC2A3 expression was significantly up-regulated in GC tissues versus normal controls (FC = 2.52, p < 0.001) and was significantly associated with tumor stage and prognosis in GC patients (p < 0.05).

Conclusion

Our study revealed that m7G methyltransferase METTL1 plays an oncogenic role in MNNG-induced gastric carcinogenesis. SLC2A3 is a key downstream target of METTL1, which is associated with clinical progression in GC patients. These findings may provide evidence for developing prognostic biomarkers for GC.