血管细胞黏附因子-1在小鼠肝脏缺血再灌注损伤并肝癌细胞血行转移模型中的作用

Role of Vascular Cell Adhesion Molecule-1 in the Mouse Model of Hepatic Ischemia /Reperfusion and the Hematogenic Metastasis

目的观察肝脏缺血再灌注损伤对Balb/C小鼠肿瘤细胞门静脉转移的影响及可能的分子学机制。方法建立Balb/C小鼠肝脏部分缺血再灌注并肝癌细胞门静脉转移模型。建模后14 d比较各组肿瘤生长情况,检测谷丙转氨酶、谷草转氨酶和血管细胞黏附因子-1(VCAM-1)等的表达情况。结果肝脏缺血再灌注2 h后,缺血45 min组和缺血30 min组的谷丙转氨酶、谷草转氨酶水平均显著高于假手术组(P均<0.05),且缺血45 min组较缺血30 min组谷丙转氨酶、谷草转氨酶水平变化更加明显(P均<0.05)。假手术组术后谷丙转氨酶及谷草转氨酶均一过性轻度升高,缺血45 min组和缺血30 min组谷丙转氨酶和谷草转氨酶水平在再灌注8 h时表达均较2 h时高(P均<0.05);术后7 d缺血45 min组左肝叶的肿瘤负荷较缺血30 min组和假手术组高(P=0.013,P=0.007),但假手术组右肝叶(无缺血肝叶)的肿瘤负荷与缺血30 min组右肝叶相比差异无统计学意义(P=0.089)。缺血30 min组与假手术组比较生存时间差异有统计学意义(P=0.041),缺血30 min组与缺血45 min组比较生存时间差异无统计学意义(P=0.055)。再灌注8 h,缺血45 min组的VCAM-1表达较缺血30 min组和假手术组高(P=0.003,P<0.001),并与肝脏受侵犯面积呈正相关(r=0.491,P=0.045)。结论肝脏缺血再灌注能够诱导肝癌细胞门静脉转移,部分分子学机制可能与VCAM-1的表达上调有关。

Objective To investigate the effect of ischemia/reperfusion （I/R） on tumor metastasis in a experimental mouse model of hematogenous metastasis after I/R and to quantify expression of vascular cell adhesion molecule-1 （VCAM-1） during I/R.Methods An experimental mouse model of metastasis after partial hepatic I/R was designed to determine the effects of I/R on tumor metastasis to liver.Tumor loads were valued 14 days after operation.In addition,the expressions of alanine transaminase （ALT）,aspartate transaminase （AST）,and VCAM-1 were detected.Results Two hours after hepatic reperfusion,ALT and AST levels in ischemia 45-minute group and ischemia 30-minute group were significantly higher than in the sham group （all P ＜ 0.05）.Also,the changes of ALT and AST were more obvious in the ischemia 45-minute group than in ischemia 30-minute group （all P ＜ 0.05）.In the sham group,both ALT and AST slightly and transiently increased.ALT and AST in the ischemia 45-minute group and ischemia 30-minute group at 8 hours were both significantly higher than those at 2 hours reperfusion （P ＜ 0.05）.The tumor load （valued by hepatic replacement area） and the expression of VCAM-1 in ischemic lobe were significantly larger in the ischemia 45-minute group than in the ischemia 30-minute group and sham group （P =0.013,P =0.007）.However,there was no statistical difference on tumor load between the right lobe of sham operated mice and the right lobe （nonischemic lobes） of mice subjected to I/R （P =0.089）.Mouse survivals were significantly longer in the sham group than in the ischemia 30-minute group （P =0.041） but were not significantly different between the ischemia 45-minute group and ischemia 30-minute group （P =0.055）.VCAM-1 expression in ischemia 45-minute group was significantly higher than in ischemia 30-minute group and sham group （P =0.003,P ＜0.001）,and it was positively correlated with the hepatic replacement area （r =0.491,P =0.045）.Conclusion Hepatic I/R promotes liver hematogenic metastasis of hepatocellular carcinoma in mice and at least in part,through the induction of VCAM-1 expression.