Suppression of plasminogen activators and the MMP-2/-9 pathway by a Zanthoxylum avicennae extract to inhibit the HA22T human hepatocellular carcinoma cell migration and invasion effects in vitro and in vivo via phosphatase 2A activation

Biosci Biotechnol Biochem. 2013;77(9):1814-21. doi: 10.1271/bbb.130060. Epub 2013 Sep 7.


This study shows that the ECM degradation-associated pathway, including uPA and tPA and the downstream MMP-2/-9 protein, was significantly suppressed in HA22T cells treated with a Zanthoxylum avicennae extract (YBBE). The endogenous inhibitors, including TIMP-1/-2 and PAI-1, were enhanced in HA22T cells by the YBBE treatment. The expression of MMP-2/-9 and TIMP-1/-2 was respectively assessed by using RT-PCR and a zymography assay. The mRNA levels and enzymatic activity of MMP-2/-9 were down-regulated by the YBBE treatment in a dose-dependent manner, while the TIMP-1/-2 levels were conversely markedly increased. The PP2A siRNA or PP2A inhibitor totally reversed the YBBE effects, confirming the essential role of PP2A in YBBE inhibiting the HA22T cell migration and invasion effects. Xenografted animal experiments on nude mice demonstrated similiar results to the in vitro system. Both the in vitro and in vivo models clearly demonstrate that YBBE inhibited the highly metastatic HA22T liver cancer cell migration and invasion effects through PP2A activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / pathology*
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Down-Regulation / drug effects
  • Enzyme Activation / drug effects
  • Humans
  • Liver Neoplasms / pathology
  • Male
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinases / metabolism*
  • Mice
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Okadaic Acid / pharmacology
  • Plant Extracts / pharmacology*
  • Plasminogen Activators / metabolism*
  • Protein Phosphatase 2 / deficiency
  • Protein Phosphatase 2 / genetics
  • Protein Phosphatase 2 / metabolism*
  • Tissue Inhibitor of Metalloproteinases / biosynthesis
  • Xenograft Model Antitumor Assays
  • Zanthoxylum / chemistry*


  • Plant Extracts
  • Tissue Inhibitor of Metalloproteinases
  • Okadaic Acid
  • Protein Phosphatase 2
  • Plasminogen Activators
  • Matrix Metalloproteinases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9