1. Pregnane X receptor (PXR) deficiency promotes hepatocarcinogenesis via induction of Akr1c18 expression and prostaglandin F 2α (PGF 2α ) levels.
- Author
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Shi T, Fan QY, Liu SB, and Zhang SY
- Subjects
- Animals, Humans, Male, Mice, Carcinogenesis metabolism, Carcinogenesis genetics, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular chemically induced, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular pathology, Diethylnitrosamine toxicity, Gene Expression Regulation, Neoplastic, Liver Neoplasms metabolism, Liver Neoplasms chemically induced, Liver Neoplasms genetics, Liver Neoplasms pathology, Liver Neoplasms, Experimental metabolism, Liver Neoplasms, Experimental chemically induced, Liver Neoplasms, Experimental genetics, Liver Neoplasms, Experimental pathology, Mice, Inbred C57BL, Mice, Knockout, Dinoprost metabolism, Dinoprost biosynthesis, Pregnane X Receptor metabolism, Pregnane X Receptor genetics
- Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, plays a critical role in the metabolism of endogenous and exogenous substances in the liver. Here, we investigate whether PXR plays a role in pathogenesis of HCC. We show that liver tumors were developed in diethylnitrosamine (DEN)-treated in PXR knockout (KO) mice. Hepatic levels of prostaglandin F
2α (PGF2α ) and aldo-keto reductase family 1 member C18 (Akr1c18), a prostaglandin synthase of catalyzing reduction of PGH2 to PGF2α , were significantly elevated in DEN-treated PXR KO mice. Hepatic mRNA levels of alpha fetoprotein (AFP), cyclin D1 (Ccnd1), fibroblast growth factor 21 (FGF21), and inflammatory cytokine interleukin 6 (IL-6) were significantly increased in DEN-treated PXR KO mice. Other members of Akr1c family, liver metabolizing enzymes including Cyp1a2, Cyp2b10 and Cyp3a11, and bile acid synthesis enzyme Cyp7a1 mRNA levels were significantly decreased in DEN-treated PXR KO mice. Our findings revealed that PXR deficiency promoted DEN-induced HCC in mice via induction of Akr1c18 expression and PGF2α levels and the increased PGF2α levels synthetized by Akr1c18 enhanced hepatocytes proliferation and induced inflammatory cytokine production, which accelerated liver tumor development after DEN treatment, suggesting that PXR deficiency may create a microenvironment that is more prone to DEN-induced liver tumors and targeting PXR and Akr1c18 to reduce PGF2α biosynthesis may be a potential and novel therapeutic strategy for HCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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