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

TGF-β通过MAPK信号转导在肝细胞癌中的作用及其治疗应用

基本信息

批准号：
16590646
负责人：
MATSUZAKI Koichi
金额：
$ 2.56万
依托单位：
Kansai Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590646/
关键词：
Hepatocellular Carcinoma TGF-β Smad TGF-β

项目摘要

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.

大多数因丙型肝炎病毒（HCV）感染而患有慢性肝炎的患者会出现肝纤维化，并具有患肝细胞癌的高风险。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 (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 Smad3 转变为其磷酸异构体：C 末端磷酸化 Smad3 (pSmad3C) 和接头磷酸化 Smad3 (pSmad3L)。 TβRI/pSmad3C 通路涉及通过上调 p21^<WAF1> 转录物来抑制肿瘤的作用，而 JNK/pSmad3L 介导的信号传导部分通过增加纤溶酶原激活剂抑制剂 1 (PAI-1) 来促进细胞外基质沉积。随着HCV感染的肝脏从慢性肝炎、肝硬化发展到肝细胞癌，肝细胞中pSmad3L/PAI-1逐渐增加，而pSmad3C/p21^<WAF1>减少，导致上皮稳态丧失并获得侵袭性间质表型。促炎细胞因子白细胞介素-1β激活的 JNK 通过增加可用于肝细胞纤维化作用的 pSmad3L/PAI-1 水平，充当 TGF-β 信号传导的调节剂，同时降低 pSmad3C/p21^<WAF1> 的 TGF-β 依赖性肿瘤抑制活性。总之，随着肝脏疾病的进展，与HCV感染相关的慢性炎症使人肝脏TGF-β信号从肿瘤抑制转变为纤维形成，从而加速肝纤维化，增加肝细胞癌的风险。