Nectin-4 promotes osteosarcoma progression and metastasis through activating PI3K/AKT/NF-κB signaling by down-regulation of miR-520c-3p

Abstract Purpose Nectin-4 was specifically up-regulated in various tumors, exerted crucial effects on tumor occurrence and development. Nevertheless, the role and molecular mechanism of Nectin-4 in osteosarcoma (OS) were rarely studied. Methods The expression of Nectin-4 and its relationship with clinical characteristics of OS were investigated using OS clinical tissues, tissue microarrays, TCGA and GEO databases. Moreover, the effect of Nectin-4 on cell proliferation, migration, and invasion abilities were detected by in vitro functional assays, respectively. The RT-qPCR, Western blotting and luciferase reporter assays were performed to explore molecular mechanism which Nectin-4 mediated the expression of miR-520c-3p, thereby modulating PI3K/AKT/NF-κB signaling. In vivo mice models were used to validate the functional roles of Nectin-4 and miR-520c-3p. Results Nectin-4 displayed a higher expression in OS tissues compared with normal tissues. We also found that Nectin-4 overexpression was positively associated with tumor stage and metastasis in OS patients. Besides, the miR-520c-3p was negatively correlated with Nectin-4, and its low expression is closely related with tumor metastasis in OS patients. Functionally, Nectin-4 enhanced cells proliferation and cell mobility in vitro. Moreover, mice models with subcutaneous xenograft and lung metastasis confirmed that knockdown of Nectin-4 could suppress the tumorigenesis and tumor metastasis in vivo. Mechanistically, Nectin-4 promoted epithelial-mesenchymal transition (EMT) by activating PI3K/AKT/NF-κB signaling through down-regulation of miR-520c-3p. Conclusions This study firstly clarified that Nectin-4 promoted OS progression and metastasis through activating PI3K/AKT/NF-κB signaling mediated by negative regulation of miR-520c-3p, which would open a novel avenue for identifying potential therapeutic target to improve patient outcomes.