Exosomal microRNA-4800-3p in portal vein blood promotes liver metastasis in pancreatic cancer by targeting PLAA.

This study aimed to identify exosomal microRNAs (exo-miRNAs) in portal vein blood (PVB) linked to liver metastasis in pancreatic cancer (PC) and elucidate the related molecular mechanisms. Exo-miRNAs were extracted from peripheral blood (PB) and PVB samples collected intraoperatively from patients with PC. Microarray analysis revealed that the exo-miRNA profiles associated with PC liver metastasis differed between PVB and PB. miR-4800-3p emerged as a potential exo-miRNA involved in liver metastasis and was highly expressed in PVB but not in PB. The overexpression (OE) of miR-4800-3p enhanced cell migration, invasion, and epithelial‒mesenchymal transition in vitro. mRNA sequencing revealed phospholipase A2 activating protein (PLAA) as a target mRNA regulated by miR-4800-3p. PLAA inhibits ubiquitination and prevents the degradation of methyltransferase like-3 protein, thereby enhancing the G protein-coupled receptor class C group 5 member A oncogene in vitro. In the in vivo PC liver metastasis model, the number of tumor nodules markedly increased in the miR-4800-3p OE group. Immunostaining of clinical samples revealed significantly lower PLAA expression in liver metastases than in lung metastases. These findings underscore the importance of PVB as a liquid sample for investigating liver metastasis-specific mechanisms that are undetectable using conventional PB analysis.