We indicate that miR-129-2 inhibits tumor migration and invasion in vitro and vivo. Mechanistically, we suggest that miR-129-2 is downregulated by DNA methylation and functions as a tumor suppressor by targeting HMGB1 in HCC cells, which in turn results in the dephosphorylation of AKT on Ser473 and decreased expression of MMP2/9. This evidence concerns the gene HMGB1 and hepatocellular carcinoma.