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Peroxiredoxin 2 is a driver of hepatocarcinogenesis in metabolic liver disease

ABSTRACT: Chronic liver disease and hepatocellular carcinoma are a global health burden, causing approximately two million deaths globally per year. Treatment options for advanced liver disease are limited and strategy to prevent hepatocellular carcinoma (HCC) development are lacking. Peroxiredoxin 2 (PRDX2) PRDX2 is a soluble cellular enzyme that detoxify peroxides generated during oxidative stress. This protein is involved in the control of various physiological process including cell growth and differentiation by regulating numerous signaling pathways. PRDX2 was also reported to promote tumor growth including colorectal and breast cancers. Since its role in liver disease progression and HCC development is unknown, we therefore further explored the role of PRDX2. This study aims to understand the mechanistic events of Prdx2 KO on the cell circuits driving metabolic liver disease progression and HCC development. We induced a liver-specific Prdx2 KO in a Cas9 transgenic mouse model for NASH and HCC. Prdx2 gene was specifically targeted in hepatocytes by combining a Cre-dependent expression of the Cas9 endonuclease in the liver and the hepatic delivery of specific single guide (sg) RNA to hepatocytes using Adeno-associated virus 8 (AAV8) as vector. Chronic liver disease and HCC were thereafter induced by a single dose of diethylnitrosamine (DEN), followed by a 6-month choline-deficient L-amino acid-defined high-fat diet (CDAHFD). At the time of sacrifice, animals were anesthetized, weighted and a terminal blood collection was performed by cardiac puncture. Total RNA from mice liver were obtained using Tri Reagent (MRC) and Direct-zol RNA Miniprep kit (Zymo Research).

ORGANISM(S): Mus musculus

PROVIDER: GSE199320 | GEO | 2025/08/01

REPOSITORIES: GEO

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Project description:Mouse models of hepatocellular carcinoma (HCC) simulate specific subgroups of human HCC. We investigated hepatocarcinogenesis in Mdr2-KO mice, a model of inflammation-associated HCC, using gene expression profiling and immunohistochemical analyses. Gene expression profiling demonstrated that although Mdr2-KO mice differ from other published murine HCC models, they share several important deregulated pathways and many coordinately differentially expressed genes with human HCC datasets. Analysis of genome positions of differentially expressed genes in liver tumors revealed a prolonged region of down-regulated genes on murine chromosome 8 in three of the six analyzed tumor samples. This region is syntenic to human chromosomal regions that are frequently deleted in human HCC and harbor multiple tumor suppressor genes. Real-time RT-PCR analysis of 16 tumor samples confirmed down-regulation of several tumor suppressors in most tumors. We demonstrate that in the aged Mdr2-KO mice, cyclin D1 nuclear level is increased in dysplastic hepatocytes that do not form nodules; however, it is decreased in dysplastic nodules and in liver tumors. We found that this decrease is mostly at the protein, rather than the mRNA level. These findings raise the question on the role of cyclin D1 at early stages of hepatocarcinogenesis in the Mdr2-KO HCC model. Furthermore, we show that most liver tumors in Mdr2-KO mice were characterized by the absence of b-catenin activation. In conclusion, the Mdr2-KO mouse may serve as a model for b-catenin-negative subgroup of human HCCs characterized by low nuclear cyclin D1 levels in tumor cells and by down-regulation of multiple tumor suppressor genes. Experiment Overall Design: The liver RNA samples from six Mdr2-KO tumors, six non-tumorous liver tissues (four matched and two unmatched), as well as from three control heterozygous mice at 16 months of age were subjected to gene expression profiling using the genome scale Affymetrix Mouse Genome 430 2.0 Array.

Project description:Chronic liver inflammation precedes the majority of hepatocellular carcinomas (HCC). Here, we explore the connection between chronic inflammation and DNA methylation in the liver at the late precancerous stages of HCC development in Mdr2/Abcb4-knockout (Mdr2-KO) mice, a model of inflammation-mediated HCC. Using methylated DNA immunoprecipitation (MeDIP) followed by hybridization with Agilent CpG Islands (CGIs) microarrays we found specific CGIs in 76 genes which were hypermethylated in the Mdr2-KO liver compared to age-matched controls. Methylation of thirty among these genes was highly specific to the studied HCC model. We revealed that in most tested cases, the observed hypermethylation resulted from an age-dependent decrease of methylation of the specific CGIs in control livers with no decrease in mutant mice. Chronic inflammation did not change global levels of DNA methylation in Mdr2-KO liver, but caused a 2-fold decrease of the global 5-hydroxymethylcytosine level in mutants compared to controls. This decrease could result from a less efficient age-dependent demethylation of specific CpG sites in the liver of Mdr2-KO mutants, as described above. Expression of some tested hypermethylated genes was increased in Mdr2-KO livers compared to controls (28%), others were either similarly expressed (44%), or not expressed in the liver (28%). Liver cell fractionation revealed, that the relative hypermethylation of specific CGIs in Mdr2-KO compared to control livers affected either hepatocyte, or non-hepatocyte, or both fractions. There was only episodic correlation between changes of gene methylation and expression in cell fractions. Conclusion: Chronic liver inflammation causes hypermethylation of specific CGIs, which may affect both hepatocytes and non-hepatocyte liver cells. These changes may serve as markers of an increased regenerative activity and of a precancerous microenvironment in the chronically inflamed liver. Two-condition experiment, Mdr2-KO vs Mdr2-/+ liver tissue from 12m-old male FVB strain mice. Biological replicates: 3 control replicates, 3 knockout replicates.

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Peroxiredoxin 2 is a driver of hepatocarcinogenesis in metabolic liver disease

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