Dysregulated microRNA expression profiles in cholangiocarcinoma cell-derived exosomes

Aim: Cholangiocarcinoma (CCA) is a malignant tumor of bile duct epithelial cells. The prognosis of CCA is poor due to lack of effective therapeutic targets and detection at an advanced stage. Exosomes are secreted nano-sized vesicles and contribute to the malignancy of several cancers via transferring their miRNAs between cells. Thus, exosomal miRNAs may serve as new therapeutic targets and potential biomarkers for CCA. Main methods: Exosomes were isolated from three different CCA cell lines and normal human cholangiocyte cells, followed by miRNA profiling analysis. Potential role of dysregulated miRNA was investigated by knockdown experiment. Key findings: We found that 38 and 460 miRNAs in CCA exosomes were significantly up-and down-regulated, respectively. Of these differentially expressed miRNAs, the hsa-miR-205-5p and miR-200 family members were markedly up-regulated for 600-1500 folds, whereas the miR-199 family members and their clustered miRNA, hsa-miR-214-3p, were down-regulated for 1000-2000 folds. The expression patterns of these representative exosomal miRNAs were similar to those observed in all types of CCA cells. The target genes of the top ten most up-and down-regulated miRNAs are significantly associated with well-characterized cancer-related pathways. Consistently, knockdown of the most up-regulated miRNA, miR-205-5p, reduced KKU-M213 cell invasion and migration. Significance: We have demonstrated the distinct miRNA signatures in exosomes released from CCA cells, compared to normal human cholangiocyte cells. These exosomal miRNAs may have the potential to be novel therapeutic targets and biomarkers for CCA.