Hepatocellular carcinoma chemoprevention by targeting the angiotensin-converting enzyme and EGFR transactivation.
Fiche publication
Date publication
juillet 2022
Journal
JCI insight
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BAUMERT Thomas, Dr LUPBERGER Joachim, Pr PESSAUX Patrick, Dr CROUCHET Emilie
Tous les auteurs :
Crouchet E, Li S, Sojoodi M, Bandiera S, Fujiwara N, El Saghire H, Zhu S, Qian T, Rasha FA, Del Zompo F, Barrett SC, Schaeffer E, Oudot MA, Ponsolles C, Durand SC, Ghoshal S, Arora G, Giannone F, Chung RT, Slovic N, Van Renne N, Felli E, Pessaux P, Lupberger J, Pochet N, Schuster C, Tanabe KK, Hoshida Y, Fuchs BC, Baumert TF
Lien Pubmed
Résumé
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.
Mots clés
Fibrosis, Hepatology, Liver cancer
Référence
JCI Insight. 2022 07 8;7(13):