Exosome-derived miR-182-5p promoted cholangiocarcinoma progression and vasculogenesis by regulating ADK/SEMA5a/PI3K pathway.

ABSTRACT

BACKGROUND AND AIMS: Increasing evidence suggested that miRNAs regulated the expression of pivotal genes involved in oncogenesis and malignant phenotype. In this project, the purpose was to make an inquiry to the effect and mechanism of miR-182-5p in the progression of cholangiocarcinoma. METHODS: By analysing TCGA and GEO databases, combined with tissue expression levels, miR-182-5p was identified as one of the most valuable miRNAs for research. The function and relationships between miR-182-5p and downstream target genes were both verified by in vitro and in vivo experiments. Methylation-specific PCR and bisulphite sequencing were used to detect the methylation level changes of downstream gene promoter. RESULTS: We found that miR-182-5p could be taken up by exosomes secreted from cholangiocarcinoma. Moreover, exosomal derived miR-182-5p promoted vascular endothelial cell proliferation and migration and induced angiogenesis by targeting ADK/SEMA5a. Subsequently, the PI3K/AKT/mTOR signalling pathway was activated and ultimately caused resistance to gemcitabine and cisplatin. CONCLUSIONS: Our findings suggested that the miR-182-5p/ADK/SEMA5a axis might serve as a potential therapeutic target for cholangiocarcinoma.