MiR‐124‐3p signaling in the control of metastasis‐related cytoskeleton organization, cell junctions and adhesion

Our recent studies using novel bioengineered miR-124-3p molecules have demonstrated the functions of miR-124-3p in the inhibition of human osteosarcoma cell invasiveness in vitro and lung metastasis in vivo. This study is to investigate the molecular and cellular mechanisms by which miR-124-3p controls tumor metastasis. LC-MS-based proteomics study identified a set of proteins selectively and significantly downregulated by bioengineered miR-124-3p, which were assembled into multiple biological pathways critical for cancer, such as cell junctions and focal adhesion. Among these proteins, we identified and verified plectin (PLEC) as a new direct target for miR-124-3p that links cytoskeleton to intercellular junctions. Associated with significantly lower levels of PLEC, ITGB1, IQGAP1 and CDH2 proteins in miR-124-3p-treated human osteosarcoma 143B and MG63 cells as well as NSCLC A549 cells, cytoskeleton was remodeled and cell-cell junctions were sharply inhibited. Furthermore, miR-124-3p decreased the ability of cells to form focal adhesion complexes and plaques, leading to much lower levels of cell adhesion capacity. Together, our results connect miR-124-3p-PLEC to other known elements in the control of cytoskeleton, cell adhesion and junctions essential for cancer cell invasion and extravasation towards metastasis.