Role of exosomal microRNA-125b-5p in conferring the metastatic phenotype among pancreatic cancer cells with different potential of metastasis.

Abstract Aims To explore the pro-metastatic role of exosomes derived from highly invasive pancreatic cancer cell and the associated aberrant expression of exosomal microRNAs (miRNAs). Main methods Weakly invasive PC-1 cells were treated with exosomes of highly invasive PC-1.0 cells to determine the pro-metastatic effect of PC-1.0 derived exosomes. The exosomal miRNA profile was further investigated using high-throughput sequencing. The level of miR-125b-5p in highly and weakly invasive pancreatic cancer cells was further determined. Pancreatic cancer cells transfected with miR-125b-5p mimic and inhibitor were used to explore the effect of miR-125b-5p on migration, invasion and epithelial-to-mesenchymal transition (EMT). Treatment with PC-1.0 derived exosome and Western blot assay were performed to validate STARD13 as a target of exosomal miR-125b-5p in pancreatic cancer. Key findings PC-1.0 derived exosomes promoted the migration and invasion of weakly invasive PC-1 cells. miRNA sequencing revealed 62 miRNAs upregulated in PC-1.0 derived exosomes. miR-125b-5p most significantly promoted migration and invasion and was associated with metastasis in pancreatic cancer. Further, miR-125b-5p was upregulated in highly invasive pancreatic cancer cells and increased migration, invasion, and EMT. Moreover, its upregulation was associated with activation of MEK2/ERK2 signaling. The tumor suppressor STARD13 was directly targeted by miR-125b-5p in pancreatic cancer, which was associated with good prognosis and was suppressed by exosomes derived from highly invasive cancer cells. Significance This study explored the pro-metastatic role of exosomes derived from highly invasive pancreatic cancer cells and the associated aberrant expression of exosomal miRNAs, which may help to elucidate the metastatic mechanism of pancreatic cancer.