Gene expression profile of hepatocellular carcinoma in low-dose, repeated diethylnitrosamine (DEN)-treated rat treated with erlotinib

Hepatocellular carcinoma (HCC) is the sixth most common solid tumor worldwide and the third leading cause of cancer-related death. Given the lack of successful treatment options, chemoprevention in high-risk patients has been proposed as an alternative strategy. Mounting evidence supports a role for epidermal growth factor (EGF) during chronic liver disease and hepatocellular transformation. We address the hypothesis that blocking the EGF-EGF receptor (EGFR) pathway may be an effective strategy for inhibiting fibrogenesis and hepatocarcinogenesis. A rat model of diethylnitrosamine (DEN)-induced cirrhosis was used to examine the effects of erlotinib on underlying chronic liver disease and HCC formation. The DEN-induced rat model closely resembles disease progression in humans both pathologically and molecularly. Erlotinib significantly prevented the development of HCC tumor nodules in a dose-dependent fashion. Further, erlotinib inhibited the activation of hepatic stellate cells and prevented fibrogenesis. Erlotinib also reduced hepatotoxicity and improved liver function. Finally, a gene expression signature predictive of poor survival in human cirrhosis patients was reversed in response to erlotinib. Our data demonstrate for the first time that EGFR inhibition prevents liver fibrogenesis. Further, our results suggest that erlotinib is a potentially effective HCC chemoprevention strategy through inhibition of cirrhosis progression which can be monitored at the molecular level.肝细胞癌（Hepatocellular carcinoma, HCC）是全球第六大常见实体瘤，亦是癌症相关死亡的第三大诱因。鉴于当前缺乏有效的治疗手段，高危人群的化学预防已被提出作为替代策略。越来越多的研究证据表明，表皮生长因子（Epidermal Growth Factor, EGF）在慢性肝病及肝细胞转化过程中发挥着关键作用。本研究针对"阻断EGF-表皮生长因子受体（EGF Receptor, EGFR）通路或可有效抑制肝纤维化与肝细胞癌变"这一假说展开验证。本研究采用二乙基亚硝胺（Diethylnitrosamine, DEN）诱导的肝硬化大鼠模型，探究厄洛替尼（Erlotinib）对慢性肝病进展及HCC形成的干预效果。该DEN诱导的大鼠模型在病理特征与分子层面均与人类肝病进程高度相似。实验结果显示，厄洛替尼可通过剂量依赖性方式显著抑制HCC肿瘤结节的生成。此外，厄洛替尼能够抑制肝星状细胞（hepatic stellate cells）的活化，阻断肝纤维化进程；同时减轻肝毒性，改善肝功能。尤为重要的是，在人类肝硬化患者中与不良预后相关的基因表达特征，可因厄洛替尼的干预得到逆转。本研究首次证实，EGFR抑制可阻断肝纤维化进程。此外，本研究结果表明，厄洛替尼或可通过抑制肝硬化进展成为一种潜在有效的HCC化学预防手段，且其作用机制可在分子层面进行监测。