circVAPA-rich small extracellular vesicles derived from gastric cancer promote neural invasion by inhibiting SLIT2...

Area of Science:

• Oncology
• Cell Biology
• Molecular Biology

Background:

• Gastric cancer (GC) is a prevalent malignancy with poor prognosis often linked to neural invasion (NI).
• Small extracellular vesicles (sEVs) are crucial mediators of intercellular communication, but their role in GC-NI is unknown.
• Understanding GC-NI mechanisms is vital for developing effective treatments.

Purpose of the Study:

• To investigate the role of sEVs in mediating gastric cancer neural invasion (GC-NI).
• To identify specific molecules within sEVs involved in GC-NI.
• To elucidate the molecular mechanisms by which sEVs promote GC-NI.

Main Methods:

• Inhibition of sEV release to assess its effect on GC-NI potential.
• Investigating the role of Muscarinic receptor M3 in sEV-neuronal cell interaction.
• Serum high-throughput sEV-circRNA sequencing and analysis of clinical samples.
• In vitro and in vivo experiments to evaluate the pro-NI effects of sEV-circVAPA.
• Mechanistic studies involving miR-548p, TGIF2, eIF4G1, and SLIT2 expression.

Main Results:

• Inhibiting sEV release reduced the NI potential of GC cells.
• GC-derived sEVs are preferentially absorbed by neuronal cells via Muscarinic receptor M3.
• sEV-circVAPA was enriched in the serum of NI-positive GC patients.
• sEV-circVAPA significantly promoted GC-NI in vitro and in vivo.
• sEV-circVAPA downregulates SLIT2 expression by targeting the miR-548p/TGIF2 pathway and inhibiting SLIT2 translation via eIF4G1.

Conclusions:

• This study reveals a novel mechanism of GC-derived sEVs preferential absorption by neurons.
• GC-derived sEV-circVAPA plays a critical role in promoting GC-NI.
• sEV-circRNAs represent potential biomarkers for diagnosing NI-positive GC.
• Targeting sEV-circRNA pathways offers a promising therapeutic strategy for GC-NI.