Division of Gastroenterology, Duke University, Durham, NC 27710, USA.
Lab Invest. 2010 Dec;90(12):1690-703. doi: 10.1038/labinvest.2010.147. Epub 2010 Aug 9.
Hedgehog (Hh) pathway activation promotes many processes that occur during fibrogenic liver repair. Whether the Hh pathway modulates the outcomes of virally mediated liver injury has never been examined. Gene-profiling studies of human hepatocellular carcinomas (HCCs) demonstrate Hh pathway activation in HCCs related to chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). Because most HCCs develop in cirrhotic livers, we hypothesized that Hh pathway activation occurs during fibrogenic repair of liver damage due to chronic viral hepatitis, and that Hh-responsive cells mediate disease progression and hepatocarciongenesis in chronic viral hepatitis. Immunohistochemistry and qRT-PCR analysis were used to analyze Hh pathway activation and identify Hh-responsive cell types in liver biopsies from 45 patients with chronic HBV or HCV. Hh signaling was then manipulated in cultured liver cells to directly assess the impact of Hh activity in relevant cell types. We found increased hepatic expression of Hh ligands in all patients with chronic viral hepatitis, and demonstrated that infection with HCV stimulated cultured hepatocytes to produce Hh ligands. The major cell populations that expanded during cirrhosis and HCC (ie, liver myofibroblasts, activated endothelial cells, and progenitors expressing markers of tumor stem/initiating cells) were Hh responsive, and higher levels of Hh pathway activity associated with cirrhosis and HCC. Inhibiting pathway activity in Hh-responsive target cells reduced fibrogenesis, angiogenesis, and growth. In conclusion, HBV/HCV infection increases hepatocyte production of Hh ligands and expands the types of Hh-responsive cells that promote liver fibrosis and cancer.
Hedgehog (Hh) 信号通路的激活促进了肝纤维化修复过程中发生的许多过程。Hh 信号通路是否调节病毒介导的肝损伤的结果尚未被研究过。对人类肝细胞癌 (HCC) 的基因谱研究表明，与乙型肝炎病毒 (HBV) 或丙型肝炎病毒 (HCV) 慢性感染相关的 HCC 存在 Hh 信号通路的激活。由于大多数 HCC 发生在肝硬化的肝脏中，我们假设 Hh 信号通路的激活发生在慢性病毒性肝炎导致的肝损伤的纤维化修复过程中，并且 Hh 反应性细胞介导慢性病毒性肝炎中的疾病进展和肝癌发生。我们使用免疫组织化学和 qRT-PCR 分析来分析肝脏活检组织中 45 例慢性 HBV 或 HCV 患者的 Hh 信号通路激活情况，并鉴定 Hh 反应性细胞类型。然后在培养的肝细胞中操纵 Hh 信号，以直接评估相关细胞类型中 Hh 活性的影响。我们发现所有慢性病毒性肝炎患者的肝内 Hh 配体表达增加，并证明 HCV 感染刺激培养的肝细胞产生 Hh 配体。在肝硬化和 HCC 期间扩增的主要细胞群体（即肝肌成纤维细胞、活化的内皮细胞和表达肿瘤干细胞/起始细胞标志物的祖细胞）对 Hh 有反应性，并且 Hh 信号通路活性与肝硬化和 HCC 相关。抑制 Hh 反应性靶细胞中的通路活性可减少纤维化、血管生成和生长。总之，HBV/HCV 感染增加了肝细胞产生 Hh 配体的能力，并扩大了促进肝纤维化和癌症的 Hh 反应性细胞的类型。
