Persistence of HCV-induced epigenetic reprogramming drives liver cancer risk following viral cure. Homo sapiens

Chronic hepatitis C virus (HCV) infection is a major cause of hepatocellular carcinoma (HCC). Despite effective antiviral therapies, the risk to develop HCC is not eliminated following viral cure. Here, we show that chronic infection induces genome-wide changes in histone modifications and corresponding transcript/protein expression that persist following treatment-induced sustained virological response (SVR). Integrative pathway analyses of patient liver tissues combined with perturbation studies in a humanized mouse model demonstrate that the virus-induced epigenetic reprogramming drives hepatocarcinogenesis.

慢性丙型肝炎病毒（HCV）感染是肝细胞癌（HCC）的主要致病因素。尽管现有有效的抗病毒治疗手段可实现病毒清除，但患者在达到病毒治愈后，罹患肝细胞癌的风险仍未消除。本研究发现，慢性HCV感染会诱导全基因组范围内的组蛋白修饰及对应转录本、蛋白表达发生改变，且这类改变在治疗诱导的持续病毒学应答（SVR）后仍持续存在。通过对患者肝组织开展整合通路分析，并结合人源化小鼠模型中的功能扰动实验，本研究证实病毒诱导的表观遗传重编程可驱动肝细胞癌变。