Objective To investigate the effect and mechanism of osteopontin (OPN) in hepatoma cell migration through galectin-3 binding protein ( LGALS3BP) . Methods Human hepatoma cell lines SMMC-7721, SMMC-P ( stably transfected with empty eukaryotic expression vectors) , and SMMC-OPN ( stably transfected with the OPN gene) were cultured. mRNA expression levels of OPN and LGALS3BP were measured by RT-qPCR. Western blot assays were used to analyze the relative protein expression of OPN and LGALS3BP and PI3K / AKT pathway. Wound healing assays were performed to explore the cell migration ability. After transfection with LGALS3BP-targeting small interfering RNA ( siLGALS3BP) or negative control small RNA ( si-NC) into SMMC-OPN cells, cell migration and relative expression of PI3K / AKT pathway-related proteins were assessed. Results Compared with SMMC-7721 and SMMC-P, the migratory ability of SMMC-OPN cells was significantly reinforced, and expression of LGALS3BP was obviously upregulated at both mRNA and protein levels. Moreover, relative expression of p-PI3K / PI3K and p-AKT / AKT proteins was significantly increased. Wound healing assays showed that the si-LGALS3BP obviously suppressed the migratory ability of SMMC-OPN cells. Furthermore, relative expression of p-PI3K / PI3K and p-AKT / AKT proteins in SMMC-OPN cells was significantly decreased after transfection of si-LGALS3BP. Conclusions OPN activates the PI3K / AKT pathway by upregulating LGALS3BP expression to promote hepatoma cell migration.