Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan.
Hepatol Res. 2013 Dec;43(12):1327-42. doi: 10.1111/hepr.12082. Epub 2013 Mar 4.
Insight into hepatic fibrogenesis and carcinogenesis (fibro-carcinogenesis) caused by hepatitis C virus (HCV) infection has come from recent analyses of transforming growth factor (TGF)-β signaling. TGF-β type I receptor and pro-inflammatory cytokine-activated kinases differentially phosphorylate Smad2 and Smad3 to create C-terminally (C), linker (L) or dually (L/C) phosphorylated (p) isoforms. This study aimed to elucidate how HCV infection affected hepatic fibro-carcinogenesis, particularly via phospho-Smad signaling.
We first studied phospho-Smad2/3 positivity of 100 patients in different stages of HCV-related chronic liver disease. To examine changes in phospho-Smad2/3 after HCV clearance, we analyzed 32 paired liver biopsy samples obtained before and after sustained virological response (SVR), dividing patients into two groups: 20 patients not developing hepatocellular carcinoma (HCC) after attaining SVR (non-HCC group), and 12 patients who developed HCC despite SVR (HCC group).
Hepatocytic tumor-suppressive pSmad3C signaling shifted to carcinogenic pSmad3L and fibrogenic pSmad2L/C signaling as liver diseases progressed. In the non-HCC group, 13 patients (65%) displayed fibrotic regression and inflammation reduction after SVR. Interestingly, SVR restored cytostatic pSmad3C signaling in hepatocytes, while eliminating prior carcinogenic pSmad3L and fibrogenic pSmad2L/C signaling. In the HCC group, seven patients (58%) displayed unchanged or even progressed fibrosis despite smoothened inflammatory activity, reflecting persistently high numbers of hepatocytes with pSmad3L- and pSmad2L/C-signaling and low pSmad3C-signaling.
HCV clearance limits fibrosis and reduces HCC incidence by switching inflammation-dependent phospho-Smad signaling from fibro-carcinogenesis to tumor suppression. However, progression to HCC would occur in severely fibrotic livers if an inflammation-independent fibro-carcinogenic process has already begun before HCV clearance.
对丙型肝炎病毒（HCV）感染引起的肝纤维化和癌变（肝纤维-癌变）的深入了解来自于对转化生长因子（TGF）-β信号的最新分析。TGF-βI 型受体和促炎细胞因子激活的激酶使 Smad2 和 Smad3 的 C 端（C）、连接区（L）或双位（L/C）磷酸化（p）异构体不同磷酸化。本研究旨在阐明 HCV 感染如何影响肝纤维-癌变，特别是通过磷酸化 Smad 信号。
我们首先研究了 100 例不同阶段 HCV 相关慢性肝病患者的磷酸化 Smad2/3 阳性率。为了研究 HCV 清除后磷酸化 Smad2/3 的变化，我们分析了 32 例获得持续病毒学应答（SVR）前后的配对肝活检样本，将患者分为两组：20 例获得 SVR 后未发生肝细胞癌（HCC）的患者（非 HCC 组）和 12 例尽管获得 SVR 仍发生 HCC 的患者（HCC 组）。
随着肝病的进展，肝细胞肿瘤抑制性 pSmad3C 信号向致癌性 pSmad3L 和纤维形成性 pSmad2L/C 信号转变。在非 HCC 组中，13 例（65%）患者在获得 SVR 后显示出纤维化消退和炎症减少。有趣的是，SVR 在恢复肝细胞的细胞抑制性 pSmad3C 信号的同时，消除了先前的致癌性 pSmad3L 和纤维形成性 pSmad2L/C 信号。在 HCC 组中，尽管炎症活性平滑化，7 例（58%）患者的纤维化仍无变化或甚至进展，这反映了仍有大量具有 pSmad3L 和 pSmad2L/C 信号的肝细胞和低 pSmad3C 信号。
HCV 清除通过将炎症依赖性磷酸化 Smad 信号从肝纤维-癌变转变为肿瘤抑制，限制纤维化并降低 HCC 的发生率。然而，如果在 HCV 清除之前已经开始了一种炎症非依赖性的纤维-癌变过程，则纤维化严重的肝脏仍会进展为 HCC。
