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Abstract Details
Hepatocellular carcinoma chemoprevention by targeting the angiotensin-converting enzyme and EGFR transactivation
1Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, Strasbourg, France.
2Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
3Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
4Service de chirurgie viscérale et digestive, Pôle hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
5Institut hospitalo-universitaire (IHU), Institute for Minimally Invasive Hybrid Image-Guided Surgery, Université de Strasbourg, Strasbourg, France.
6Liver Center and Gastrointestinal Division, Massachusetts General Hospital.
7Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA.
8Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
9Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.
Abstract
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.