title: 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.
abstract: 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.
authors.affiliation: School of Chinese Medicine, China Medical University.
authors.forename: Tran Duc
authors.initials: TD
authors.lastname: Dung
authors.forename: Chih-Chung
authors.initials: CC
authors.lastname: Feng
authors.forename: Wei-Wen
authors.initials: WW
authors.lastname: Kuo
authors.forename: Peiying
authors.initials: P
authors.lastname: Pai
authors.forename: Li-Chin
authors.initials: LC
authors.lastname: Chung
authors.forename: Sheng-Huang
authors.initials: SH
authors.lastname: Chang
authors.forename: Hsi-Hsien
authors.initials: HH
authors.lastname: Hsu
authors.forename: Fuu-Jen
authors.initials: FJ
authors.lastname: Tsai
authors.forename: Yueh-Min
authors.initials: YM
authors.lastname: Lin
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D019319:Okadaic Acid / Q000494:pharmacology; D010936:Plant Extracts / Q000494:pharmacology*; D010960:Plasminogen Activators / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays; D032106:Zanthoxylum / Q000737:chemistry*
chemical_list: D010936:Plant Extracts; D019714:Tissue Inhibitor of Metalloproteinases; D019319:Okadaic Acid; D054648:Protein Phosphatase 2; D010960:Plasminogen Activators; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9