Acidic bile salt‑induced DNA methylation promotes APE1 upregulation through miR‑128‑3p silencing in esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) is an aggressive malignancy with rapidly rising incidence in Western populations and a poor 5‑year survival rate of <20%. It commonly develops from Barrett's esophagus, a metaplastic condition driven by chronic exposure to acidic bile salts (ABS). Apurinic/apyrimidinic endonuclease 1 (APE1) serves a central role in this process by coordinating DNA repair and redox signaling pathways that promote tumor cell survival, inflammation and progression. Despite its importance, the upstream regulatory mechanisms controlling APE1 in EAC remain incompletely understood. The present study aimed to identify a novel epigenetic mechanism linking reflux‑induced stress to APE1 upregulation through microRNA (miR) regulation. Bioinformatics analysis of downregulated miRNAs in EAC and the 3'untranslated region of APE1 revealed that miR‑128‑3p has a predicted binding site within the APE1 3'untranslated region. Functional validation using luciferase reporter assays confirmed direct binding of miR‑128‑3p to APE1. Exposure to ABS resulted in marked suppression of miR‑128‑3p expression, concomitant with increased APE1 levels. Mechanistically, ABS induces DNA methyltransferase (DNMT1) expression, leading to hypermethylation of the CpG‑rich miR‑128‑3p promoter and transcriptional silencing. DNMT1 knockdown or inhibition reversed miR‑128‑3p suppression and decreased promoter methylation, restoring its regulatory effect on APE1. Collectively, these findings defined a DNMT1/miR‑128‑3p/APE1 regulatory pathway that links reflux‑induced epigenetic modifications to oncogenic signaling in EAC, highlighting potential therapeutic targets for this malignancy.