SERPINE1 Alternative Polyadenylation Influences Gastric Cancer Prognosis via N6-Methyladenosine Modification.

Alternative polyadenylation (APA) and N6-methyladenosine (m6A) methylation are critical post-transcriptional regulators in cancer, yet their synergistic role in gastric cancer (GC) remains poorly understood. By integrating RNA-seq and MeRIP-seq data from paired GC tumor and adjacent normal tissues, we identified 9769 distinct APA events and 3117 differentially methylated sites. Concurrent 3'UTR length and methylation alterations were observed in 165 genes. Among these, SERPINE1 emerged as an independent prognostic factor; its high expression correlated with advanced TNM stages and poor survival across multiple independent cohorts. Moreover, elevated plasma SERPINE1 protein levels in an in-house cohort of 263 GC patients were significantly associated with worse overall and disease-specific survival. Mechanistically, the APA factor CSTF2 and the m6A reader IGF2BP1 were found to physically interact and cooperatively regulate SERPINE1 3'UTR selection. Silencing either factor shifted expression toward the long 3'UTR isoform and reduced SERPINE1 protein levels. Functional assays further confirmed that the short SERPINE1 isoform promotes GC cell proliferation, migration, and invasion more potently than the long isoform. Collectively, this study reveals that CSTF2 and IGF2BP1 synergistically drive SERPINE1 3'UTR shortening to enhance GC malignancy, highlighting SERPINE1 as a promising prognostic biomarker and potential therapeutic target.