Beta-catenin signaling involves HGF-enhanced HepG2 scattering through activating MMP-7 transcription.
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.
Pan
Fei-Yan
FY
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210046, China.
Zhang
Sheng-Zhou
SZ
Xu
Na
N
Meng
Fan-Li
FL
Zhang
Hong-Xia
HX
Xue
Bin
B
Han
Xiao
X
Li
Chao-Jun
CJ
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*
D015820:Cadherins; D051153:Wnt Proteins; D051176:beta Catenin; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D020783:Matrix Metalloproteinase 7