FAM117A and PIGU regulate the trilogy of gastric carcinogenesis.

Gastric cancer (GC) develops through a multistep process; however, the molecular mechanisms driving the progression from normal gastric mucosa to precancerous lesions and ultimately to GC remain incompletely understood. Here, this study performed whole-transcriptome sequencing and ATAC-seq on normal gastric mucosa (N), gastric precancerous lesions (P), and gastric tumor tissues (T) to profile chromatin accessibility, lncRNAs, miRNAs, and mRNAs. Differential expression and KEGG pathway analyses identified key hub genes driving gastric carcinogenesis. A core competing endogenous RNA (ceRNA) network revealed critical regulatory lncRNAs for H19 and SNHG3. Through integrative analysis of ATAC-seq and whole-transcriptome sequencing, FAM117A and PIGU were identified as potential key regulatory factors. Experimental validation, including western blot, RT-qPCR, plasmid transfection and immunohistochemistry, confirmed FAM117A and PIGU as pivotal targets. Functional assays demonstrated that FAM117A and PIGU regulate the p53 signaling pathway and modulate cell adhesion molecules (N-cadherin and E-cadherin), highlighting their involvement in abnormal proliferation and tumor metastasis during GC progression. These findings identify FAM117A and PIGU as novel biomarkers and potential therapeutic targets, providing mechanistic insights into gastric carcinogenesis.