miR-378d suppresses gastric cancer metastasis by targeting METTL4 to inhibit epithelial-mesenchymal transition

Abstract

Metastasis is a major determinant of prognosis in gastric cancer (GC), and microRNAs (miRNAs) play crucial roles in driving the metastatic process. This study aimed to identify key miRNAs involved in GC metastasis and elucidate their underlying mechanisms. GC tissues from patients with and without metastasis were subjected to miRNA sequencing to identify differentially expressed miRNAs. Expression differences between GC and normal tissues, as well as their correlation with patient survival, were analyzed using data from The Cancer Genome Atlas and an internal cohort. miR-378d expression was measured by RT-qPCR in the internal cohort, and its association with clinicopathological features and prognosis was analyzed. Gene Set Enrichment Analysis (GSEA) was performed to investigate the potential mechanisms by which miR-378d influences GC metastasis. The findings were validated through in vitro wound healing, transwell assays, western blotting, and immunofluorescence, as well as in vivo models. MiRNA sequencing identified miR-378d as significantly downregulated in GC tissues and associated with poor prognosis. GSEA showed that miR-378d was negatively correlated with epithelial-mesenchymal transition (EMT). In vitro and in vivo experiments demonstrated that upregulation of miR-378d inhibited GC cell migration and invasion. Mechanistically, miR-378d suppressed EMT by downregulating METTL4 expression. miR-378d inhibits GC metastasis by suppressing EMT through the downregulation of METTL4, offering novel insights into the role of miRNAs in GC progression and highlighting potential therapeutic targets for intervention.