Hepatocellular carcinoma chemoprevention by targeting the angiotensin-converting enzyme and EGFR transactivation
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
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
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Research Article Hepatology

Hepatocellular carcinoma chemoprevention by targeting the angiotensin-converting enzyme and EGFR transactivation

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.

Authors

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

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Figure 2

In vivo validation of captopril for HCC chemoprevention in a DEN fibrosis/HCC rat model.

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In vivo validation of captopril for HCC chemoprevention in a DEN fibrosi...
(A–D) Captopril alleviates fibrosis progression and prevents HCC development in vivo. Male Wistar DEN-treated rats received vehicle control or captopril for 10 weeks (vehicle, n = 10; captopril, n = 10). (A) Representative morphometric analysis of liver slices at the time of sacrifice are shown. Picrosirius red staining was used to quantify collagen cross bridging. Proliferating cell nuclear antigen (PCNA) staining was used to quantify cell proliferation. Original magnification, ×100. (B) Assessment of the RAS component in vivo. ACE expression was assessed by qPCR and Ang II serum levels by ELISA. (C) Collagen proportional area (CPA) expressed in percentage of liver tissue and measurement of the fibrosis markers by qPCR. (D) The body weight, the liver/body weight ratio, and the number of total tumors was plotted for each animal. (E and F) Measurement of albumin and total bilirubin, serum transaminases (alanine aminotransferase [ALT], aspartate aminotransferase, [AST], alkaline phosphatase [ALP], and γ-glutamyl transferase [γGT]) are shown. (G) Captopril decreases liver inflammation in vivo. Measurement by qPCR of the macrophage marker Cd68 and proinflammatory/fibrotic cytokines. For B–G, boxes represent the 75th and 25th percentiles, the whiskers represent the most extreme data points, and the horizontal bar represents the median. #P < 0.05, ##P < 0.01, and ###P < 0.001, vehicle vs. PBS. *P < 0.05, captopril vs. vehicle. Kruskal-Wallis test followed by Dunn’s multiple comparisons test was used to compare the 3 groups (B, C, E–G); unpaired t test was used to compare 2 groups (D). (H) Captopril reverses the PLS in vivo. PLS induction was determined by GSEA using PBS animals as reference. Simplified heatmaps show PLS global status and PLS poor- and good-prognosis gene expression. RQ, relative quantification.