Scharf J-G, Braulke T
Department of Medicine, Georg-August-Universität, Göttingen, Germany.
Horm Metab Res. 2003 Nov-Dec;35(11-12):685-93. doi: 10.1055/s-2004-814151.
Primary hepatocellular carcinoma (HCC) is one of the most common forms of malignant cancer with the fourth highest mortality rate worldwide. Major risk factors for the development of HCC include chronic infections with the hepatitis B or C virus, alcohol consumption, exposure to dietary aflatoxin B1, hereditary liver disease or liver cirrhosis of any etiology. Recent studies have discovered changes in the insulin-like growth factor (IGF) axis that affect the molecular pathogenesis of HCC, including the autocrine production of IGFs, IGF binding proteins (IGFBPs), IGFBP proteases, and IGF receptor expression. Characteristic alterations detected in HCC and hepatoma cell lines comprise the overexpression of IGF-II and the IGF-I receptor emerging as critical events in malignant transformation and growth of tumors. Simultaneous reduction of IGFBP expression and the increase in proteolytic cleavage of IGFBPs result in an excess of bioactive IGFs. Finally, defective functions of the IGF-II/mannose 6-phosphate receptor involved in degradation of IGF II, the activation of the growth inhibitor TGF-beta1, and the lysosomal targeting of cathepsin proteases capable to degrade extracellular matrix proteins may contribute to the development of HCC.
原发性肝细胞癌（HCC）是最常见的恶性肿瘤形式之一，在全球死亡率排名第四。HCC发生的主要风险因素包括慢性乙型或丙型肝炎病毒感染、饮酒、接触膳食黄曲霉毒素B1、遗传性肝病或任何病因引起的肝硬化。最近的研究发现胰岛素样生长因子（IGF）轴的变化会影响HCC的分子发病机制，包括IGF的自分泌产生、IGF结合蛋白（IGFBP）、IGFBP蛋白酶和IGF受体表达。在HCC和肝癌细胞系中检测到的特征性改变包括IGF-II的过表达以及IGF-I受体的出现，这是肿瘤恶性转化和生长中的关键事件。IGFBP表达的同时降低以及IGFBP蛋白水解切割的增加导致生物活性IGF过量。最后，参与IGF II降解的IGF-II/甘露糖6-磷酸受体的功能缺陷、生长抑制剂TGF-β1的激活以及能够降解细胞外基质蛋白的组织蛋白酶的溶酶体靶向作用可能有助于HCC的发生。
