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.