首页|Integration of exosomal miR-106a and mesothelial cells facilitates gastric cancer peritoneal dissemination
Integration of exosomal miR-106a and mesothelial cells facilitates gastric cancer peritoneal dissemination
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NSTL
Elsevier
Background: Metastatic organotropism is considered the end stage of malignancy with the mechanism still have some mysteries that have not been disclosed. Although the role of miR-106a is well studied, its involvement in the formation of peritoneal metastasis transported by exosomes is less discussed.Methods: Gastric cancer (GC)-derived exosomes were identified by transmission electron microscopy and the integration with peritoneal mesothelial cells (PMC) was confirmed by PKH-26 staining. Cell phenotype was assessed by EdU and flow cytometry. MiR-106a and its targets were authenticated by luciferase reporter assay. The mesothelial-to-mesenchymal transition (MMT) and extracellular matrix (ECM) degeneration were deter-mined and morphological transformation was measured by transwell assay. Immunodeficient mouse was con-ducted to investigate the tumorigenesis and tumor growth. The final was tissue analysis.Results: MiR-106a enrichment in GC-exosomes can be delivered and integrated into PMC to establish a proper pre-metastatic niche (PMN). We found that PMC could internalize exosomal-miR-106a and lead to increased apoptotic rate and decreased proliferative vitality. The direct target Smad7 and TIMP2 were proved to be effectively reduced by translocation of exosomal miR-106a. We confirmed that exosomal miR-106a was able to induce MMT and accelerate ECM through targeting Smad7 and TIMP2 to activate TGF-beta pathway. Animal model investigated that the tumorigenesis and tumor growth could be influenced by exosomes, and exosomal-miR-106a could promote the formation of xenograft tumor. Tissue analysis verified the ectopic miR-106a expression in gastric cancer metastasis.Conclusion: Our data suggest that exosomal miR-106a facilitates gastric cancer peritoneal dissemination by integrating PMC to destroy mesothelial barrier.
NSTL
Elsevier
