TGF-β Signal Transduction via MAPK in Hepatocellular Carcinoma and Therapeutic Application

大多数患有慢性肝炎的患者归因于丙型肝炎病毒（HCV）感染，发展为肝纤维化，具有肝细胞癌的高风险。然而，关于慢性炎症同时引起进行性肝纤维化和肝细胞癌的分子机制的信息很少。另一方面，转化生长因子β（TGF-β）不仅激活TGF-β I型受体（TβRI），还激活c-Jun N-末端激酶（JNK），将未磷酸化的Smad 3转变为其磷酸化亚型：C-末端磷酸化的Smad 3（pSmad 3C）和连接子磷酸化的Smad 3（pSmad 3L）。TβRI/pSmad 3C通路通过上调p21^转录而发挥抑瘤作用<WAF1>，而JNK/pSmad 3L介导的信号通路部分通过增加纤溶酶原激活物抑制剂1（派-1）而促进细胞外基质沉积。随着HCV感染的肝脏从慢性肝炎经肝硬化进展为肝细胞癌，肝细胞中pSmad 3L/派-1逐渐增加，而pSmad 3C/p21 - 1<WAF1>降低，导致上皮稳态的丧失和侵袭性间充质表型的获得。由促炎细胞因子白细胞介素-1 β激活的JNK通过增加肝细胞中可用于纤维化作用的pSmad 3C/派-1的水平，同时降低pSmad 3C/p21 β的TGF-β依赖性肿瘤抑制活性，充当TGF-β信号传导的调节剂<WAF1>。总之，随着肝病的进展，HCV感染相关的慢性炎症将人类肝脏TGF-β信号从肿瘤抑制转变为纤维化，从而加速肝纤维化，增加肝细胞癌的风险。

Most patients suffered from chronic hepatitis attributed to hepatitis C virus (HCV) infection develop liver fibrosis with a high risk for hepatocellular carcinoma. However, little information is available on the molecular mechanisms by which chronic inflammation causes progressive liver fibrosis and hepatocellular carcinoma simultaneously. On the other hand, transforming growth factor β(TGF-β) activates not only TGF-β type I receptor (TβRI) but also c-Jun N-terminal kinase (JNK), changing unphosphorylated Smad3 to its phosphoisoforms : C-terminally phosphorylated Smad3 (pSmad3C) and linker phosphorylated Smad3 (pSmad3L). TβRI/pSmad3C pathway involves tumor suppressive action by up-regulating p21^<WAF1> transcript, whereas JNK/pSmad3L-mediated signaling promotes extracellular matrix deposition, in part, by increasing plasminogen activator inhibitor 1 (PAI-1). As the HCV-infected livers progressed from chronic hepatitis through cirrhosis to hepatocellular carcinoma, pSmad3L/PAI-1 gradually increased while pSmad3C/p21^<WAF1> decreased in the hepatocytes, leading to loss of epithelial homeostasis and acquisition of an invasive, mesenchymal phenotype. JNK activated by pro-inflammatory cytokine interleukin-1β acted as a regulator of TGF-β signaling by increasing the level of pSmad3L/PAI-1 available for fibrogenic action in the hepatocytes, in the meantime reducing TGF-β-dependent tumor suppressive activity of pSmad3C/p21^<WAF1>. In conclusion, chronic inflammation associated with HCV infection shifts human hepatic TGF-β signaling from tumor suppression to fibrogenesis with the progress of liver diseases, thereby accelerating liver fibrosis with higher risk for hepatocellular carcinoma.