Cancer Cell-Derived Exosomal miR-519a/522-5p Promotes Pancreatic Cancer Progression by Enhancing Warburg Effect.

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

Exosomal microRNAs (exo-miRNAs) isolated from serum samples of 92 PDAC patients and 44 healthy subjects were detected by small RNA sequencing, and their diagnostic performance and prognostic value were evaluated. In vitro experiments and orthotopic PDAC mouse model were conducted to investigate the effect of miR-519a/522-5p. Integrated transcriptomics and metabolomics were used to explore the underlying mechanism of miR-519a/522-5p dysregulation.

RESULTS

Compared with 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. 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 experiments 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 cancer 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 SESN2.

CONCLUSIONS

Serum exo-miRNAs could be promising candidates for precise diagnosis and treatment of PDAC. Exo-miR-519a/522-5p promotes PDAC cellular invasiveness by enhancing Warburg effect through intercellular transportation.