miRNA-34a-5p is a novel biomarker and modulator of the radioresponse in esophageal adenocarcinoma

Poor pathological response to neoadjuvant chemoradiotherapy (neo-CRT) remains a major clinical challenge in esophageal adenocarcinoma (EAC), contributing to treatment resistance and poor patient outcomes. Identification of novel predictive biomarkers of treatment resistance and therapeutic targets to enhance treatment response are crucial to improving patient outcomes. In this study, we investigated the role of miR-34a-5p in EAC treatment response using both cell line models and clinical tumor samples. We observed reduced miR-34a-5p expression across multiple cell line models of radioresistant EAC. Overexpression of miR-34a-5p enhanced radiosensitivity, impaired DNA damage repair, and altered cell cycle following irradiation, accompanied by changes in the expression of DNA damage response and cell cycle-related genes. Consistent with these findings, analysis of pre-treatment tumor biopsies from EAC patients demonstrated that reduced miR-34a-5p expression was associated with poor response to neo-CRT, advanced pathological T stage, and worse clinical outcomes. This study demonstrates for the first time, a role for miR-34a-5p as a potential biomarker of treatment response and an independent predictor of survival outcomes in EAC patients. Furthermore, we identify miR-34a-5p as a radiosensitizer in EAC, highlighting a novel therapeutic approach to enhance the efficacy of radiation therapy in EAC.