title: Beta-catenin signaling involves HGF-enhanced HepG2 scattering through activating MMP-7 transcription.
abstract: 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.
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210046, China.
authors.forename: Fei-Yan
authors.initials: FY
authors.lastname: Pan
authors.forename: Sheng-Zhou
authors.initials: SZ
authors.lastname: Zhang
authors.forename: Na
authors.initials: N
authors.lastname: Xu
authors.forename: Fan-Li
authors.initials: FL
authors.lastname: Meng
authors.forename: Hong-Xia
authors.initials: HX
authors.lastname: Zhang
authors.forename: Bin
authors.initials: B
authors.lastname: Xue
authors.forename: Xiao
authors.initials: X
authors.lastname: Han
authors.forename: Chao-Jun
authors.initials: CJ
authors.lastname: Li
mesh_terms: D015820:Cadherins / Q000096:biosynthesis*; D015536:Down-Regulation; D004789:Enzyme Activation; D056945:Hep G2 Cells; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D009362:Neoplasm Metastasis / Q000503:physiopathology; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D051153:Wnt Proteins / Q000502:physiology; D051176:beta Catenin / Q000502:physiology*
chemical_list: D015820:Cadherins; D051153:Wnt Proteins; D051176:beta Catenin; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D020783:Matrix Metalloproteinase 7