miR-6855-5p Enhances Radioresistance and Promotes Migration of Pancreatic Cancer by Inducing Epithelial-Mesenchymal Transition via Suppressing FOXA1: Potential of Plasma Exosomal miR-6855-5p as an Indicator of Radiosensitivity in Patients with Pancreatic Cancer.

ABSTRACT

BACKGROUND: Whether radiation should be added to neoadjuvant treatment remains controversial, and liquid biopsy has not been reported to predict radioresistance in pancreatic cancer (PC). We aimed to identify microRNAs (miRNAs) governing radioresistance in PC by utilizing peripheral plasma exosome samples and to verify their usefulness as biomarkers. METHODS: miRNA microarray analysis was conducted using pretreatment peripheral plasma exosomes from 10 patients with PC receiving neoadjuvant chemoradiotherapy (NACRT) in the discovery cohort. Patients were categorized into two groups (good and poor responders) based on treatment responses, and candidate miRNAs exhibiting differential expression between the two groups were identified. The radiosensitivity of PC cells was examined after miR-6855-5p overexpression. Next-generation sequencing (NGS) and TargetScan were used to explore the mechanisms of radioresistance. We investigated the correlation between miR-6855-5p expression levels in the pretreatment peripheral plasma exosomes of 28 patients in the validation cohort and the response to NACRT. RESULTS: miR-6855-5p expression was higher in poor responders than in good responders. miR-6855-5p induces radioresistance in PC cells. NGS showed that epithelial-mesenchymal transition (EMT) was involved in miR-6855-5p-related radioresistance. Forkhead box protein A1 (FOXA1) was identified as a direct target of miR-6855-5p using NGS and TargetScan. Clinical examination of samples from the validation cohort revealed a tendency for patients with higher expression of miR-6855-5p in peripheral plasma exosomes to exhibit increased radioresistance (r = -0.5964). CONCLUSIONS: miR-6855-5p regulates the radioresistance of PC by inducing EMT via suppressing FOXA1, and miR-6855-5p in peripheral plasma exosomes may be a biomarker for radioresistance of PC.