MiR-519a/522-5p from pancreatic cancer-secreted exosomes promotes tumor invasion by enhancing Warburg effect

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with poor prognosis. Exploring novel serum biomarkers and the underlying mechanism is crucial for the early diagnosis and precise therapy of PDAC.Methods: Exosomes were isolated from serum samples of 92 PDAC patients and 44 healthy subjects. Serum exosomal microRNAs (exo-miRNAs) were detected by small RNA sequencing, verified by qRT-PCR, and their diagnostic performance and prognostic value were evaluated. In vitro experiments and orthotopic tumor mouse models were conducted to investigate the effect of miR-519a/522-5p on PDAC. Integrated transcriptomics and metabolomics were used to explore the underlying mechanism of miR-519a/522-5p.Results: Compared to the healthy control, all three PDAC subgroups (stage I-III) displayed a specific deregulated serum exo-miRNA profile. A panel of 3 serum exo-miRNAs (let-7g-3p, miR-490-5p, and miR-519a/522-5p) was established as novel diagnostic biomarkers for PDAC, which exhibited high sensitivity and specificity in clinical cohort. Among the three exo-miRNAs, miR-519a/522-5p was found to be an independent prognostic factor for PDAC and associated with tumor features particularly invasion/metastasis. In vitro and in vivo experiment confirmed that miR-519a/522-5p promoted invasiveness/metastasis of PDAC cells. Moreover, miR-519a/522-5p could be effectively delivered via exosomes and increased the invasiveness of recipient PDAC cells. Multi-omics analysis showed a comprehensive miR-519a/522-5p-regulated molecular network, in which glycolysis played a central role. We further validated that miR-519a/522-5p enhanced glycolysis by targeting sestrin2.Conclusion: Serum exo-miRNAs could be novel and promising candidates for precise diagnosis and treatment of PDAC. Tumor-derived exo-miR-519a/522-5p promotes PDAC cellular invasiveness by enhancing Warburg effect.