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Exosomal miR-4644 Targets SPRY3 to Promote Proliferation and Invasion of Pancreatic Cancer
Xiangyu Chu1,2, Dongqi Li3, Fusheng Zhang3
1Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, State Key Lab of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing, China.
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.
