肝细胞恶性转化过程中胰岛素样生长因子-I受体的动态表达与改变

Dynamic expression profile of the insulin-like growth factor-1 receptor during malignant transformation of hepatocytes

目的观察肝细胞恶性转化过程中胰岛素样生长因子-I受体(IGF-IR)的动态表达与改变特征。方法以2-乙酰氨基芴(2-FAA)喂饲雄性SD大鼠诱发肝癌发生,分别观察肝细胞形态学、肝及血IGF-1R的动态变化。以免疫组化法观察肝组织IGF-1R表达,以RT-PCR扩增IGF-1R mRNA表达片段并经测序证实,从基因转录和蛋白水平上分析与肝细胞恶性转化的相互关系。结果诱癌过程中肝细胞出现颗粒样变性、癌前病变到肝癌形成的动态变化,伴肝核酸代谢旺盛,肝IGF-IR表达异常;肝IGF-IR阳性率(%)、肝IGF-IR mRNA阳性率(%)、肝IGF-IR比浓度(ng/mg肝组织)和血IGF-IR(ng/ml)分别为:对照组0、0、0.63±0.17和1.33±0.47;变性组50、61.1、0.65±0.2和1.51±0.46;癌前组88.9、100、0.66±0.14和1.92±0.29;癌变组100、100、0.96±0.09和2.43±0.57。IGF-IR在转录或蛋白水平上呈梯度表达,癌变组显著高于其他组(P<0.01),且肝和血IGF-IR呈显著正相关(r=0.91,t=14.222,P<0.001)。结论 IGF-1R过表达参与肝细胞癌变,是肝细胞恶性转化的早期标志。

Objective To determine the dynamic expression pattern and investigate the mechanisms underlying modified expression of insulin-like growth factor-1 receptor（IGF-1R） during malignant transformation of hepatocytes.Methods The N-2-fluorenylacetamide-induced liver cancer model was established in male Sprague-Dawley rats.Uninduced rats served as controls.Morphological changes were observed in livers by histological analysis.Dynamic changes in liver and serum expression of IGF-1R were analyzed and quantitated by immunohistochemistry,immunoassays,and RT-PCR with DNA sequencing.The relation between IGF-1R expression and malignant transformation of hepatocytes was investigated at both the gene transcription and protein expression levels using rank correlation analysis.Results The 2-FAA-induced rat hepatocytes showed remarkable morphologic alterations,including granule-like degeneration and other features of precancerous to hepatoma formation,which paralleled with increases in IGF-1R expression.Comparison of the control rats,precancerous rats,degenerated rats,and hepatoma rats indicated differential profiles of liver IGF-IR（0,88.9%,50.0%,and 100%）,IGF-IR mRNA（0,100%,61.1%,and 100 %）,specific IGF-IR concentration（0.63±0.17,0.66±0.14,0.65±0.2,and 0.96±0.09,ng/mg wet liver）,and serum IGF-IR level（1.33±0.47,1.92±0.29,1.51±0.46,and 2.43±0.57 ng/ml）.The serum IGF-1R expression was significantly higher in the hepatoma group than in any of other groups（gene transcription and protein levels,P0.01）.A positive relationship was found between liver and sera levels of IGF-1R（r=0.91,t=14.222,P0.01）.Conclusion IGF-1R may participate in hepatocyte canceration.Overexpression of IGF-1R may represent a useful early marker to identify and monitor malignant transformation of hepatocytes.