Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor β signaling, promoting cirrhosis and hepatocellular carcinoma
Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor β signaling, promoting cirrhosis and hepatocellular carcinoma
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DOI：
10.1002/hep.21672
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发表时间：
2007-07-01
期刊：
影响因子：
13.5
通讯作者：
Seki, Toshihito
中科院分区：
文献类型：
--
作者：
Matsuzaki, Koichi;Murata, Miki;Seki, Toshihito
许多丙型肝炎病毒（HCV）感染引起的慢性肝炎患者会发生肝纤维化，并具有肝细胞癌（HCC）的高风险，但这一过程的机制尚不清楚。相反，转化生长因子β（TGF-β）不仅激活TGF-β I型受体（T β RI），还激活c-Jun N-末端激酶（JNK），后者将介体Smad 3转化为两种独特的磷酸化亚型：C-末端磷酸化Smad 3（pSmad 3C）和接头磷酸化Smad 3（pSmad 3L）。尽管T β RI/pSmad 3C途径通过上调p21（WAF 1）转录来抑制上皮细胞生长，但JNK/pSmad 3L介导的信号传导部分地通过上调纤溶酶原激活物抑制剂1（派-1）来促进细胞外基质沉积。我们研究了100例慢性HCV感染患者的慢性肝炎、肝硬化或HCC活检标本中结构域特异性SmaA 3磷酸化，并将Smad 3磷酸化与临床病程相关。随着HCV感染的肝脏从慢性肝炎到肝硬化到HCC的进展，肝细胞pSmad 3L/派-1随着纤维化阶段和坏死性炎症分级而增加，而pSmad 3C/p21（WAF 1）下降。在14例肝细胞pSmad 3L强阳性的慢性丙型肝炎患者中，8例在12年内发展为HCC; 12例pSmad 3L弱阳性患者中仅1例发展为HCC。我们进一步在体外寻找分子机制。由促炎细胞因子白细胞介素-1 β激活的JNK刺激pSmad 3L/派-1通路促进肝细胞侵袭，同时通过pSmad 3C/p21（WAF 1）通路降低TGF-β依赖性肿瘤抑制活性。结论：这些结果表明，与HCV感染相关的慢性炎症将肝细胞TGF-β信号从肿瘤抑制转移到纤维化，加速肝纤维化并增加HCC的风险。
Many patients with chronic hepatitis caused by hepatitis C virus (HCV) infection develop liver fibrosis with high risk for hepatocellular carcinoma (HCC), but the mechanism underling this process is unclear. Conversely, transforming growth factor beta (TGF-beta) activates not only TGF-beta type I receptor (T beta RI) but also c-Jun N-terminal kinase (JNK), which convert the mediator Smad3 into two distinctive phosphoisoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). Whereas the T beta RI/pSmad3C pathway suppresses epithelial cell growth by upregulating p21(WAF1) transcription, JNK/pSmad3L-mediated signaling promotes extracellular matrix deposition, partly, by upregulating plasminogen activator inhibitor 1 (PAI-1). We studied the domain-specific SmaA3 phosphorylation in biopsy specimens representing chronic hepatitis, cirrhosis, or HCC from 100 patients chronically infected with HCV, and correlated Smad3 phosphorylation with clinical course. As HCV-infected livers progressed from chronic hepatitis through cirrhosis to HCC, hepatocytic pSmad3L/PAI-1 increased with fibrotic stage and necroinflammatory grade, and pSmad3C/p21(WAF1) decreased. Of 14 patients with chronic hepatitis C with strong hepatocytic pSmad3L positivity, 8 developed HCC within 12 years; only 1 of 12 showing little pSmad3L positivity developed HCC. We further sought molecular mechanisms in vitro. JNK activation by the pro-inflammatory cytokine interleukin-1 beta stimulated the pSmad3L/PAI-1 pathway in facilitating hepatocytic invasion, in the meantime reducing TGF-beta-dependent tumor-suppressive activity by the pSmad3C/p21(WAF1) pathway. Conclusion: These results indicate that chronic inflammation associated with HCV infection shifts hepatocytic TGF-beta signaling from tumor-suppression to fibrogenesis, accelerating liver fibrosis and increasing risk for HCC.