Using multiple in vitro and in vivo models of HCC, we show for the first time that 5-Aza can impair HCC development via upregulation of miR-139-5p, which in turn downregulates the ROCK2/cyclin D1/E2F1/cyclin B1 pro-proliferative pathway and the ROCK2/MMP-2 pro-migratory pathway. The gene discussed is E2F1; the disease is hepatocellular carcinoma.