ArticleThe Journal of biological chemistry2022
Human constitutive androstane receptor represses liver cancer development and hepatoma cell proliferation by inhibiting erythropoietin signaling.
Article in The Journal of biological chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 27 citations in OpenAlex.
- Erythropoietin in Tumor Immunity: Mechanistic Evidence, Clinical Cautions, and Translational Opportunities.Cancers · 2026Review
- Integrated Transcriptomic Analyses Identify Four Prognosis-Associated Genes in Hepatocellular Carcinoma.International journal of molecular sciences · 2026Article
- Integrative Bioinformatic Characterization of the HDAC6-Driven Cytoskeleton-Wnt Signaling Interface in Hepatocellular Carcinoma: Implications for Immune Modulation and Therapeutic Targeting.International journal of molecular sciences · 2026Article
- Mechanistic insights into CAR-mediated repression of the HNF4α-FABP1 axis and inhibition of HepG2 cell proliferation.Pharmacological research · 2026Article
- United multi-omics and machine learning refine regulatory T cell-defined hepatocellular carcinoma subtypes.iScience · 2026Article
- CAR: Discovery and development by the pharmacogenetics laboratory at NIEHS, NIH.Pharmacological research · 2025Review
- A Comparative Analysis of the Roles of von Willebrand Factor and ADAMTS13 in Hepatocellular Carcinoma: A Bioinformatics and Microarray-Based Study.Current issues in molecular biology · 2025Article
- Constitutive androstane receptor (CAR) functions as a tumor suppressor via regulating stemness in liver cancer.Scientific reports · 2024Article
- Computational analyses to reveal the key determinants of the high malignancy level of cholangiocarcinoma.Journal of translational internal medicine · 2024Article
- Constitutive androstane receptor: A tumor suppressor and a biomarker for favorable prognosis of liver diseases.Genes & diseases · 2024Article
- Construction of m7G RNA modification-related prognostic model and prediction of immune therapy response in hepatocellular carcinoma.Translational cancer research · 2024Article
- An integrated investigation of sulfotransferases (SULTs) in hepatocellular carcinoma and identification of the role of SULT2A1 on stemness.Apoptosis : an international journal on programmed cell death · 2024Article
- Bile acids, gut microbiota, and therapeutic insights in hepatocellular carcinoma.Cancer biology & medicine · 2023Review
- Characterization of stem cell subtypes and prognostic signature in hepatocellular carcinoma.Journal of cancer research and clinical oncology · 2023Article
- Article
- Regulation of Nuclear Receptors PXR and CAR by Small Molecules and Signal Crosstalk: Roles in Drug Metabolism and Beyond.Drug metabolism and disposition: the biological fate of chemicals · 2023Review
- Xenobiotic Receptors, a Journey of Rewards.Drug metabolism and disposition: the biological fate of chemicals · 2023Review
- Molecular subtypes and scoring tools related to Foxo signaling pathway for assessing hepatocellular carcinoma prognosis and treatment responsiveness.Frontiers in pharmacology · 2023Article
- SLC-0111, an inhibitor of carbonic anhydrase IX, attenuates hepatoblastoma cell viability and migration.Frontiers in oncology · 2023Article
- Prognostic model for hepatocellular carcinoma based on anoikis-related genes: immune landscape analysis and prediction of drug sensitivity.Frontiers in medicine · 2023Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
The constitutive androstane receptor (CAR) is a nuclear receptor that plays a crucial role in regulating xenobiotic metabolism and detoxification, energy homeostasis, and cell proliferation by modulating the transcription of numerous target genes. CAR activation has been established as the mode of action by which phenobarbital-like nongenotoxic carcinogens promote liver tumor formation in rodents. This paradigm, however, appears to be unrelated to the function of human CAR (hCAR) in hepatocellular carcinoma (HCC), which remains poorly understood. Here, we show that hCAR expression is significantly lower in HCC than that in adjacent nontumor tissues and, importantly, reduced hCAR expression is associated with a worse HCC prognosis. We also show overexpression of hCAR in human hepatoma cells (HepG2 and Hep3B) profoundly suppressed cell proliferation, cell cycle progression, soft-agar colony formation, and the growth of xenografts in nude mice. RNA-Seq analysis revealed that the expression of erythropoietin (EPO), a pleiotropic growth factor, was markedly repressed by hCAR in hepatoma cells. Addition of recombinant EPO in HepG2 cells partially rescued hCAR-suppressed cell viability. Mechanistically, we showed that overexpressing hCAR repressed mitogenic EPO-EPO receptor signaling through dephosphorylation of signal transducer and activator of transcription 3, AKT, and extracellular signal-regulated kinase 1/2. Furthermore, we found that hCAR downregulates EPO expression by repressing the expression and activity of hepatocyte nuclear factor 4 alpha, a key transcription factor regulating EPO expression. Collectively, our results suggest that hCAR plays a tumor suppressive role in HCC development, which differs from that of rodent CAR and offers insight into the hCAR-hepatocyte nuclear factor 4 alpha-EPO axis in human liver tumorigenesis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.