PPARgamma inhibits hepatocellular carcinoma metastases in vitro and in mice

BACKGROUND: We have previously demonstrated that peroxisome proliferator-activated receptor (PPAR gamma) activation inhibits hepatocarcinogenesis. We aim to investigate the effect of PPARg on hepatocellular carcinoma (HCC) metastatic potential and explore its underlying mechanisms. METHODS: Human HCC cells (MHCC97L, BEL-7404) were infected with adenovirus-expressing PPARg (Ad-PPAR gamma) or Ad-lacZ and treated with or without PPARg agonist (rosiglitazone). The effects of PPARg on cell migration and invasive activity were determined by wound healing assay and Matrigel invasive model in vitro, and in an orthotopic liver tumour metastatic model in mice. RESULTS: Pronounced expression of PPAR gamma was demonstrated in HCC cells (MHCC97L, BEL-7404) treated with Ad-PPAR gamma, rosiglitazone or Ad-PPAR gamma plus rosiglitazone, compared with control (Ad-LacZ). Such induction markedly suppressed HCC cell migration. Moreover, the invasiveness of MHCC97L and BEL-7404 cells infected with Ad-PPAR gamma, or treated with rosiglitazone was significantly diminished up to 60%. Combination of Ad-PPAR gamma and rosiglitazone showed an additive effect. Activation of PPAR gamma by rosiglitazone significantly reduced the incidence and severity of lung metastasis in an orthotopic HCC mouse model. Key mechanisms underlying the effect of PPAR gamma in HCC include upregulation of cell adhesion genes, E-cadherin and SYK (spleen tyrosine kinase), extracellular matrix regulator tissue inhibitors of metalloproteinase (TIMP) 3, tumour suppressor gene retinoblastoma 1, and downregulation of pro-metastatic genes MMP9 (matrix metallopeptidase 9), MMP13, HPSE (heparanase), and Hepatocyte growth factor (HGF). Direct transcriptional regulation of TIMP3, MMP9, MMP13, and HPSE by PPAR gamma was shown by ChIP-PCR. CONCLUSION: Peroxisome proliferator-activated receptor-gamma exerts an inhibitory effect on the invasive and metastatic potential of HCC in vitro and in vivo, and is thus, a target for the prevention and treatment of HCC metastases. British Journal of Cancer (2012) 106, 1486-1494. doi:10.1038/bjc.2012.130 www.bjcancer.com Published online 3 April 2012 (C) 2012 Cancer Research UK