Downregulation of cancer-associated fibroblast exosome-derived miR-29b-1-5p restrains vasculogenic mimicry and apoptosis while accelerating migration and invasion of gastric cancer cells via immunoglobulin domain-containing 1/zonula occluden-1 axis

Abstract

Background: Cancer-associated fibroblast (CAF) exosomal miRNAs have gradually a hot spot in cancer therapy. This study mainly explores the effect of CAF-derived exosomal miR-29b-1-5p on gastric cancer (GC) cells.Methods: CAFs and exosomes were identified by Western blot and transmission electron microscopy. CAF-derived exosomes-GC cells co-culture systems were constructed. Effects of CAF-derived exosomal miR-29b-1-5p on GC cells were determined by cell counting kit-8, flow cytometry, wound healing, Transwell assays and Western blot. The relationship between miR-29b-1-5p and immunoglobulin domain-containing 1 (VSIG1) was assessed by TargetScan, dual-luciferase reporter and RNA immunoprecipitation (RIP) experiments. The interaction between VSIG1 and zonula occluden-1 (ZO-1) was detected by co-immunoprecipitation. Expressions of miR-29b-1-5p, VSIG1 and ZO-1 were determined by quantitative real-time PCR. Vascular mimicry (VM) was detected using immunohistochemistry and tube formation assays. Rescue experiments and xenograft tumor assays were used to further determine the effect of CAF-derived exosomal miR-29b-1-5p/VSIG1 on GC.Results: VM structure, upregulation of miR-29b-1-5p, and downregulation of VSIG1 and ZO-1 were shown in GC tissues. MiR-29b-1-5p targeted VSIG1, which interacted with ZO-1. CAF-derived exosomal miR-29b-1-5p inhibitor suppressed the viability, migration, invasion and VM formation, but promoted the apoptosis of GC cells. MiR-29b-1-5p inhibitor increased levels of VSIG1, ZO-1 and E-cadherin, whilst decreasing levels of VE-cadherin, N-cadherin and Vimentin in vitro and in vivo, which however was partially reversed by shVSIG1. Downregulation of CAF-derived exosomal miR-29b-1-5p impeded GC tumorigenesis and VM structure in vivo by upregulating VSIG1/ZO-1 expression.Conclusion: Downregulation of CAF-derived exosomal miR-29b-1-5p inhibits GC progression via VSIG1/ZO-1 axis.