Hepatocellular carcinoma chemoprevention by targeting the angiotensin-converting enzyme and EGFR transactivation
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-07-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.159254 |
| _version_ | 1811334900689666048 |
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| author | Emilie Crouchet Shen Li Mozhdeh Sojoodi Simonetta Bandiera Naoto Fujiwara Hussein El Saghire Shijia Zhu Tongqi Qian Fahmida Akter Rasha Fabio Del Zompo Stephen C. Barrett Eugénie Schaeffer Marine A. Oudot Clara Ponsolles Sarah C. Durand Sarani Ghoshal Gunisha Arora Fabio Giannone Raymond T. Chung Nevena Slovic Nicolaas Van Renne Emanuele Felli Patrick Pessaux Joachim Lupberger Nathalie Pochet Catherine Schuster Kenneth K. Tanabe Yujin Hoshida Bryan C. Fuchs Thomas F. Baumert |
| author_facet | Emilie Crouchet Shen Li Mozhdeh Sojoodi Simonetta Bandiera Naoto Fujiwara Hussein El Saghire Shijia Zhu Tongqi Qian Fahmida Akter Rasha Fabio Del Zompo Stephen C. Barrett Eugénie Schaeffer Marine A. Oudot Clara Ponsolles Sarah C. Durand Sarani Ghoshal Gunisha Arora Fabio Giannone Raymond T. Chung Nevena Slovic Nicolaas Van Renne Emanuele Felli Patrick Pessaux Joachim Lupberger Nathalie Pochet Catherine Schuster Kenneth K. Tanabe Yujin Hoshida Bryan C. Fuchs Thomas F. Baumert |
| author_sort | Emilie Crouchet |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T17:16:03Z |
| format | Article |
| id | doaj.art-d091965ffda14d4aaba85c9d24b3a727 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-13T17:16:03Z |
| publishDate | 2022-07-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-d091965ffda14d4aaba85c9d24b3a7272022-12-22T02:38:08ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-07-01713Hepatocellular carcinoma chemoprevention by targeting the angiotensin-converting enzyme and EGFR transactivationEmilie CrouchetShen LiMozhdeh SojoodiSimonetta BandieraNaoto FujiwaraHussein El SaghireShijia ZhuTongqi QianFahmida Akter RashaFabio Del ZompoStephen C. BarrettEugénie SchaefferMarine A. OudotClara PonsollesSarah C. DurandSarani GhoshalGunisha AroraFabio GiannoneRaymond T. ChungNevena SlovicNicolaas Van RenneEmanuele FelliPatrick PessauxJoachim LupbergerNathalie PochetCatherine SchusterKenneth K. TanabeYujin HoshidaBryan C. FuchsThomas F. BaumertHepatocellular 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.https://doi.org/10.1172/jci.insight.159254Hepatology |
| spellingShingle | Emilie Crouchet Shen Li Mozhdeh Sojoodi Simonetta Bandiera Naoto Fujiwara Hussein El Saghire Shijia Zhu Tongqi Qian Fahmida Akter Rasha Fabio Del Zompo Stephen C. Barrett Eugénie Schaeffer Marine A. Oudot Clara Ponsolles Sarah C. Durand Sarani Ghoshal Gunisha Arora Fabio Giannone Raymond T. Chung Nevena Slovic Nicolaas Van Renne Emanuele Felli Patrick Pessaux Joachim Lupberger Nathalie Pochet Catherine Schuster Kenneth K. Tanabe Yujin Hoshida Bryan C. Fuchs Thomas F. Baumert Hepatocellular carcinoma chemoprevention by targeting the angiotensin-converting enzyme and EGFR transactivation JCI Insight Hepatology |
| title | Hepatocellular carcinoma chemoprevention by targeting the angiotensin-converting enzyme and EGFR transactivation |
| title_full | Hepatocellular carcinoma chemoprevention by targeting the angiotensin-converting enzyme and EGFR transactivation |
| title_fullStr | Hepatocellular carcinoma chemoprevention by targeting the angiotensin-converting enzyme and EGFR transactivation |
| title_full_unstemmed | Hepatocellular carcinoma chemoprevention by targeting the angiotensin-converting enzyme and EGFR transactivation |
| title_short | Hepatocellular carcinoma chemoprevention by targeting the angiotensin-converting enzyme and EGFR transactivation |
| title_sort | hepatocellular carcinoma chemoprevention by targeting the angiotensin converting enzyme and egfr transactivation |
| topic | Hepatology |
| url | https://doi.org/10.1172/jci.insight.159254 |
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