It is well accepted that cell scattering (dispersion of clustered cells into single cells) is the initial step of tumor metastasis, and the downregulation of E-cadherin is associated with metastatic potential of tumor cells; however, the molecular mechanisms underlying loss of E-cadherin during tumor development are still poorly understood. Here, we report that hepatocyte growth factor (HGF) induced E-cadherin downregulation and cell scattering are attributed to the activation of Wnt/beta-catenin signaling and transcriptional activation of matrix metalloproteinase MMP-7. Furthermore, the increased MMP-7 is secreted into the medium and cleaves the ectodomain of E-cadherin. Inhibition of HGF signal by siRNA of c-Met, blocking the beta-catenin transcriptional activity through a dominant negative form of TCF4, MMP-7 knockdown by siRNA or suppression of MMP-7 enzymatic activity with a neutralization antibody allowed inhibition of HGF-induced loss of E-cadherin and HepG2 scattering. Our data presented here revealed the intrinsic mechanism of HGF activated Wnt/beta-catenin signaling regulation of HepG2 cell scattering through MMP-7 transcription activation and E-cadherin degradation. The results suggest that the blocking of HGF/c-Met/beta-catenin/MMP-7/E-cadherin signaling pathway might present a practical therapeutic target for interference with hepatocellular carcinoma metastasis.