Exosomal miR-4644 Targets SPRY3 to Promote Proliferation and Invasion of Pancreatic Cancer.

BACKGROUND

Tumor-derived exosomes (TDEs) can carry diverse genetic material that modulates pancreatic cancer (PC) proliferation and invasion. Despite this, the involvement of microRNAs (miRNAs) in TDE-mediated tumor progression in PC remains inadequately explored.

METHODS

Ultracentrifugation was used to isolate exosomes derived from AsPC-1 and BxPC-3 cells. Cell proliferation was assessed by cell counting kit-8 (CCK-8) and plate colony formation assays. Cell migration and invasion were evaluated using Transwell assays. Real-time polymerase chain reaction (RT-PCR) was performed to detect the expression levels of miR-4644 and Sprouty RTK Signaling Antagonist 3 (SPRY3). A dual-luciferase reporter assay was conducted to verify the binding site between miR-4644 and SPRY3. Orthotopic PC xenografts were established to validate the effects of SPRY3 and miR-4644. Finally, the relative expression levels of SPRY3 were validated using PC tissue and matched adjacent non-tumor tissue samples.

RESULTS

MiR-4644 was enriched in TDEs, and the inhibition of miR-4644 reduced the proliferation, migration, and invasion of PC cells. SPRY3 was identified as a direct target of miR-4644, which bound to the 3'-UTR of SPRY3 and suppressed its expression. The inhibitory effects of SPRY3 on PC cell proliferation, migration, and invasion were partially counteracted by miR-4644. Importantly, clinical data analysis revealed that SPRY3 expression was significantly downregulated in PC tissues (p < 0.05). Mechanistically, miR-4644 targeted SPRY3 and promoted PC cell proliferation, migration, and invasion through the Ras-Raf-MAPK signaling pathway.

CONCLUSIONS

MiR-4644 is upregulated in PC TDEs and promotes PC cell progression by suppressing SPRY3 expression; high expression of exosomal miR-4644 correlates with poor patient prognosis.