Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, Strasbourg, France.
Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
JCI Insight. 2022 Jul 8;7(13):e159254. doi: 10.1172/jci.insight.159254.
Hepatocellular carcinoma (HCC) is a leading cause of death among cirrhotic patients, for which chemopreventive strategies are lacking. Recently, we developed a simple human cell-based system modeling a clinical prognostic liver signature (PLS) predicting liver disease progression and HCC risk. In a previous study, we applied our cell-based system for drug discovery and identified captopril, an approved angiotensin converting enzyme (ACE) inhibitor, as a candidate compound for HCC chemoprevention. Here, we explored ACE as a therapeutic target for HCC chemoprevention. Captopril reduced liver fibrosis and effectively prevented liver disease progression toward HCC development in a diethylnitrosamine (DEN) rat cirrhosis model and a diet-based rat model for nonalcoholic steatohepatitis-induced (NASH-induced) hepatocarcinogenesis. RNA-Seq analysis of cirrhotic rat liver tissues uncovered that captopril suppressed the expression of pathways mediating fibrogenesis, inflammation, and carcinogenesis, including epidermal growth factor receptor (EGFR) signaling. Mechanistic data in liver disease models uncovered a cross-activation of the EGFR pathway by angiotensin. Corroborating the clinical translatability of the approach, captopril significantly reversed the HCC high-risk status of the PLS in liver tissues of patients with advanced fibrosis. Captopril effectively prevents fibrotic liver disease progression toward HCC development in preclinical models and is a generic and safe candidate drug for HCC chemoprevention.
肝细胞癌（HCC）是肝硬化患者死亡的主要原因，但目前缺乏有效的化学预防策略。最近，我们开发了一种简单的基于人类细胞的系统，该系统模拟了一种临床预后肝脏标志物（PLS），可预测肝病进展和 HCC 风险。在之前的研究中，我们应用我们的细胞系统进行药物发现，并确定了卡托普利（一种已批准的血管紧张素转换酶（ACE）抑制剂）是 HCC 化学预防的候选化合物。在这里，我们探讨了 ACE 作为 HCC 化学预防的治疗靶点。卡托普利可减少肝纤维化，并可有效预防二乙基亚硝胺（DEN）大鼠肝硬化模型和非酒精性脂肪性肝炎诱导的（NASH 诱导的）肝癌发生的饮食诱导大鼠模型中的肝病进展向 HCC 发展。对肝硬化大鼠肝组织的 RNA-Seq 分析表明，卡托普利可抑制介导纤维化、炎症和癌变的途径的表达，包括表皮生长因子受体（EGFR）信号通路。在肝病模型中的机制数据表明，血管紧张素可使 EGFR 通路发生交叉激活。卡托普利可显著逆转 PLS 在晚期纤维化患者肝组织中的 HCC 高危状态，这证实了该方法的临床转化能力。卡托普利可有效预防纤维化肝病向 HCC 发展，是一种用于 HCC 化学预防的通用且安全的候选药物。
