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

https://www.ncbi.nlm.nih.gov/pubmed/35801591

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.