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

丙型肝炎病毒感染所致的慢性肝炎患者大多发生肝纤维化，发生肝细胞癌的风险较高。然而，关于慢性炎症同时导致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(转化生长因子β)不仅能激活转化生长因子β的I型受体(TβRI)，还能激活c-jun氨基末端激酶(JNK)，将未磷酸化的Smad3转变为磷酸化的Smad3：C-末端磷酸化的Smad3(PSmad3C)和连接蛋白磷酸化的Smad3(PSmad3L)。TβRI/pSmad3C途径通过上调p21和pSmad3L的转录参与肿瘤抑制作用，而JNK/pSmad3L介导的信号部分通过增加纤溶酶原激活物抑制物1(PAI-1)促进细胞外基质沉积。随着感染丙型肝炎的肝脏从慢性肝炎到肝硬变再到肝细胞癌的进展，肝细胞中pSmad3L/PAI-1逐渐增加，而pSmad3C/p21^&lt；WAF1&gt；减少，导致上皮动态平衡的丧失，并获得侵袭性的间质表型。促炎症细胞因子IL-1β激活的JNK通过增加肝细胞中可用于纤维化作用的pSmad3L/PAI-1的水平，同时降低依赖于转化生长因子-β的肿瘤抑制活性，从而调节转化生长因子-β信号转导通路。总之，随着肝病的进展，丙型肝炎病毒感染相关的慢性炎症使人肝脏转化生长因子-β信号从肿瘤抑制转变为纤维化，从而加速了肝纤维化，并增加了发生肝细胞癌的风险。

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.