Targeting peroxiredoxin 2 prevents hepatocarcinogenesis in metabolic liver disease models
Emilie Crouchet, Eugénie Schaeffer, Marine A. Oudot, Julien Moehlin, Cloé Gadenne, Frank Jühling, Hussein El Saghire, Naoto Fujiwara, Shijia Zhu, Fahmida Akter Rasha, Sarah C. Durand, Anouk Charlot, Clara Ponsolles, Romain Martin, Nicolas Brignon, Fabio Del Zompo, Laura Meiss-Heydmann, Marie Parnot, Nourdine Hamdane, Danijela Heide, Jenny Hetzer, Mathias Heikenwälder, Emanuele Felli, Patrick Pessaux, Nathalie Pochet, Joffrey Zoll, Brian Cunniff, Yujin Hoshida, Laurent Mailly, Thomas F. Baumert, Catherine Schuster
Emilie Crouchet, Eugénie Schaeffer, Marine A. Oudot, Julien Moehlin, Cloé Gadenne, Frank Jühling, Hussein El Saghire, Naoto Fujiwara, Shijia Zhu, Fahmida Akter Rasha, Sarah C. Durand, Anouk Charlot, Clara Ponsolles, Romain Martin, Nicolas Brignon, Fabio Del Zompo, Laura Meiss-Heydmann, Marie Parnot, Nourdine Hamdane, Danijela Heide, Jenny Hetzer, Mathias Heikenwälder, Emanuele Felli, Patrick Pessaux, Nathalie Pochet, Joffrey Zoll, Brian Cunniff, Yujin Hoshida, Laurent Mailly, Thomas F. Baumert, Catherine Schuster
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Research Article Hepatology Oncology

Targeting peroxiredoxin 2 prevents hepatocarcinogenesis in metabolic liver disease models

Abstract

Treatment options for advanced liver disease and hepatocellular carcinoma (HCC) are limited, and strategies to prevent HCC development are lacking. Aiming to discover therapeutic targets, we combined genome-wide transcriptomic analysis of liver tissues from patients with advanced liver disease and HCC and a cell-based system predicting liver disease progression and HCC risk. Computational analysis predicted peroxiredoxin 2 (PRDX2) as a candidate gene mediating hepatocarcinogenesis and HCC risk. Analysis of tissues from patients with HCC confirmed a perturbed expression of PRDX2 in cancer. In vivo perturbation studies in mouse models for hepatocarcinogenesis driven by metabolic dysfunction–associated steatohepatitis showed that specific Prdx2 KO in hepatocytes improved metabolic liver functions, restored AMPK activity, and prevented HCC development by suppressing oncogenic signaling. Perturbation studies in HCC cell lines, a cell line–derived xenograft mouse model, and patient-derived HCC spheroids revealed that PRDX2 also mediates cancer initiation, cancer cell proliferation, and survival through its antioxidant activity. Targeting PRDX2 may therefore be a strategy to prevent HCC development in metabolic liver disease.

Authors

Emilie Crouchet, Eugénie Schaeffer, Marine A. Oudot, Julien Moehlin, Cloé Gadenne, Frank Jühling, Hussein El Saghire, Naoto Fujiwara, Shijia Zhu, Fahmida Akter Rasha, Sarah C. Durand, Anouk Charlot, Clara Ponsolles, Romain Martin, Nicolas Brignon, Fabio Del Zompo, Laura Meiss-Heydmann, Marie Parnot, Nourdine Hamdane, Danijela Heide, Jenny Hetzer, Mathias Heikenwälder, Emanuele Felli, Patrick Pessaux, Nathalie Pochet, Joffrey Zoll, Brian Cunniff, Yujin Hoshida, Laurent Mailly, Thomas F. Baumert, Catherine Schuster

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Figure 2

Prdx2 KO improves liver steatosis and prevents HCC development in a MASH/HCC mouse model.

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Prdx2 KO improves liver steatosis and prevents HCC development in a MAS...
(A) AlbCre-Cas9 mice were injected with AAV8 vectors coding for a control or a Prdx2-specific sgRNA. Liver disease was induced by single-dose DEN injection and CDA-HFD (chow diet n = 6, sgCtrl n = 18, sgPrdx2 n = 16). (B) IHC analysis of PRDX2 expression in mouse liver tissues validating Prdx2 KO in hepatocytes. Positive islets in KO animals correspond to nontransduced areas. Scale bars: 250 μm (×10) and 100 μm (×20). (C and D) Prdx2 KO prevents HCC development in vivo. (C) Representative morphometric analysis, H&E coloration, and IHC analyses of mouse livers. Scale bar: 250 μm. (D) Body weight, liver weight and liver-to-body weight ratios, the number of surface tumor nodules, and quantification of the MCM-2 cell proliferation marker are reported. (E) Prdx2 KO improves liver function. Analysis of liver function by measurement of albumin, aspartate, and alanine aminotransferases (ASAT, ALAT), alkaline phosphatase (ALP), and total bilirubin. (F) Prdx2 KO does not modulate liver fibrosis. Fibrosis levels were evaluated through quantification of collagen proportionate area (CPA) of Sirius red staining performed in C, hydroxyproline quantification, and by fibrotic gene expression (qRT-PCRs). (G) Prdx2 KO improves liver steatosis. Lipid accumulation and lipid droplet size were evaluated through quantification of Oil Red O staining performed in C. Serum lipid profile analysis of cholesterol (total, HDL, and LDL) and triglycerides are shown. The graphs show mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 (Kruskal-Wallis test followed by Dunn’s multiple-comparison test).