Role of PPARγ in the hematogenous spread of hepatocellular carcinoma after hepatic ischemia reperfusion in mice / 中华肝胆外科杂志

ABSTRACT

Objective To investigate the role of peroxisome proliferator-activated receptor γ (PPARγ) in hematogenous spread of hepatocellular carcinoma after hepatic ischemia reperfusion in mice and its mechanism.Methods One hundred and sixty mice were randomly divided into 4 groups,sham,control,Rosiglitazone(R group) and Rosiglitazone + GW9662 (R + GW).The mice models with hepatic ischemia reperfusion combined with portal vein metastasis of hepatocellular carcinoma were well established.Serum ALT level,expressions of MMP-9,NF-κB and PPARγ,hepatic replacement area (HRA) and survival of mice were compared.Results (1) The median survival in sham group was 16.3 d,R group 12.1 d,control group 9.6 d,R + GW group 8.7 d.(2) Impact on portal venous metastasiscompared with left hepatic lobe (ischemic hepatic lobe) of control group,the HRA was significantly decreased in the left hepatic lobe of sham group (29.1％ vs.13.2％,P ＜0.05).Tumor load was higher in control group than R group (29.1％ vs.13.0％,P ＜ 0.05).(3) Serum ALT levelafter 2 h,8 h and 24 h hepatic ischemia reperfusion injury (HIRI),the ALT levels in control group [(1 134.2 ± 320.5) U/L],R group [(1 017.3 ± 365.9)U/L] and R + GW group [(1 344.0 ± 304.3) U/L] were all higher than sham group [(20.6 ± 7.8) U/L],P ＜0.05.With 8 and 24 h HIRI,ALT levels were highest in R + GW group [(4 101.7 ± 462.2) U/L,(3 730.8 ± 582.7) U/L],following by control group [(3 649.1 ± 440.1) U/L,(2 226.7 ± 442.7) U/L],andRgroup [(1691.9±398.6)U/L,(1 109.2±237.4)U/L],P＜0.05.(4) MMP-9 expressionafter 8 h HIRI,MMP-9 expression level was predominantly elevated in control group than R group [(41.3 ± 10.7) vs.(4.7 ± 1.1),P ＜ 0.05].Similarly,MMP-9 expression was higher in R + GW group than both control and R groups [(166.9 ± 7.9) vs.(41.3 ± 10.7) and (4.7 ± 1.1),P ＜ 0.05].(5) Expressions of PPARγand NF-κBin the control group,PPARγ expression emerged after 2 h HIRI,and reached the peak with 8 h HIRI,decreased significantly with 24 h HIRI.NF-κB expression elevated with time,and at the peak with 24 h HIRRI.In R + GW group,the PPARγ expression was similar to control group and high expression of NF-κB were detected at all three endpoints.In R group,marked expression of PPARγ was observed after 2 h HIRI,and reached to peak after 24 h HIRI.NF-κB showed weakly positive expression after 2 h HIRI.Conclusions Rosiglitazone could significantly reduce hematogenous spread of hepatocellular carcinoma after hepatic ischemia reperfusion in mice.This may be attributed to NF-κB expression inhibition by PPARγ up-regulation and decreased MMP-9 production after pretreatment with Rosiglitazone.