Genistein inhibits tumor invasion by suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells

Background: Genistein (Gen) exhibits anti-mutagenic and anti-metastatic activities in hepatoma cell lines. Gen has suppressive effects on tumor growth and angiogenesis in nude mice. Gen suppresses the enzymatic activity of matrix metalloproteinase (MMP)-9; however, the mechanism underlying its anti-invasive activity on hepatocellular carcinoma (HCC) cells is unclear. Methods: In this study, the possible mechanisms underlying Gen-mediated reduction of 12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced cell invasion and inhibition of secreted and cytosolic MMP-9 production in human hepatoma cells (HepG2, Huh-7, and HA22T) and murine embryonic liver cells (BNL CL2) were investigated. Results: Gen suppressed MMP-9 transcription by inhibiting activator protein (AP)-1 and nuclear factor-kappa B (NF-kappa B) activity. Gen suppressed TPA-induced AP-1 activity through inhibitory phosphorylation of extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways, and TPA-stimulated inhibition of NF-kappa B nuclear translocation through I kappa B inhibitory signaling pathways. Moreover, Gen suppressed TPA-induced activation of ERK/phosphatidylinositol 3-kinase/Akt upstream of NF-kappa B and AP-1. Conclusions: Gen and its inhibition of multiple signal transduction pathways can control the invasiveness and metastatic potential of HCC.