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 5

Prdx2 KD in hepatocytes prevents HCC development in a preclinical mouse model for MASH/HCC.

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Prdx2 KD in hepatocytes prevents HCC development in a preclinical mouse...
(A) C57BL/6 WT mice were injected with DEN (single dose) and fed with CDA-HFD for 12 weeks before injection of GalNac siRNAs targeting Prdx2 expression or nontargeting control (weekly injection for 12 weeks). n = 8 for each group. (B and C) Prdx2 KO prevents HCC development in vivo. (B) Representative morphometric analysis, H&E, Sirius red, and Oil Red O coloration and TUNEL assay of mouse livers are shown. Scale bar: 250 μm. Prdx2 KD was assessed by IHC analysis. Scale bar: 50 μm. As the mice were euthanized 1 week after the last siRNA GalNac injection, the level of expression of PRDX2 re-increased in the livers. (C) Body weight, liver weight, and liver-to-body weight ratios and the number of surface tumor nodules are reported. Fibrosis levels were evaluated through quantification of collagen proportionate area (CPA) of Sirius red staining performed in B and hydroxyproline quantification. Lipid accumulation was evaluated through quantification of Oil Red O staining performed in B. Levels of apoptosis were evaluated by TUNEL assay (B) and quantification of positive cells. (D) Prdx2 KO decreases the number of nodules in mouse livers. Representative images of H&E coloration are shown. Arrows indicate tumor nodules. Scale bars: 5 mm. (E) Analysis of liver function by measurement of albumin, alanine aminotransferases (ALAT), and alkaline phosphatase (ALP). (F) Effect of Prdx2 KD on liver inflammation. Expression levels of C-C motif chemokine ligand 2 (Ccl2), IL-6 (Il6), and TNF-α (Tnfa) were assessed by qRT-PCR in mouse livers. In box-and-whisker plots, boxes represent the 75th and 25th percentiles, the whiskers represent the most extreme data points within IQR × 1.5, and the horizontal bar represents the median. The circles indicate observation for each sample. *P < 0.05, **P < 0.01 (Mann-Whitney U test).