MiR-151-3p transferred by cancer-associated fibroblast-derived extracellular vesicles promotes osteosarcoma progression through the CHL1/integrin 1β/TGF-β axis

microRNA-151-3p (miR-151-3p) is a widely reported oncogene with a documented role in tumorigenesis and cancer progression. miRNAs are potent regulators of gene expression that are transferred between cells by extracellular vesicles (EVs). However, there is limited data about the role of EV-derived miR-151-3p in osteosarcoma (OS) progression, or the possible effects of miR-151-3p on the paracrine activity of cancer-associated fibroblasts (CAFs) in OS. To fill this gap of knowledge, we isolated CAF-derived EVs (CAF-EVs) from examined their up-take by human MG63 OS cells and their effects on MG63 biology. We found high expression of miR-151-3p in OS tissues, and miR-151-3p derived from CAF-EVs promoted the process of epithelial-mesenchymal transition (EMT), migration, and invasion of MG63 cells. Notably, bioinformatics analysis, RIP, and dual luciferase report test determined that CHL1 was the direct binding target of miR-151-3p. CAF-EVs mediated the CHL1/integrin 1 beta axis through miR-151-3p to regulate the TGF-beta pathway and then promoted the proliferation, migration, invasion, and EMT of OS cells. Our in vivo results confirmed that EV secretion of miR-151-3p activated the TGF-beta pathway through the CHL1/integrin 1 beta axis to promote the proliferation of OS cells and increase tumor volume and weight. Other effects were to upregulate E-Cadherin and downregulate the expression of N-Cadherin and beta-catenin. Hence, our data reveal a potential functional axis mediated by EVs in the tumor microenvironment of OS and suggest potential candidate therapy targets.

Automated summary

miR-151-3p plays a crucial role in osteosarcoma progression by promoting EMT, migration, and invasion of MG63 cells through EVs-mediated transfer. By modulating the CHL1/integrin 1 beta axis, CAF-EVs derived miR-151-3p activates the TGF-beta pathway, leading to increased proliferation and tumor growth in OS cells.