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Human constitutive androstane receptor represses liver cancer development and hepatoma cell proliferation by inhibiting erythropoietin signaling
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 a...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9052153/ https://www.ncbi.nlm.nih.gov/pubmed/35367211 http://dx.doi.org/10.1016/j.jbc.2022.101885 |
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author | Li, Zhihui Kwon, So Mee Li, Daochuan Li, Linhao Peng, Xiwei Zhang, Junran Sueyoshi, Tatsuya Raufman, Jean-Pierre Negishi, Masahiko Wang, Xin Wei Wang, Hongbing |
author_facet | Li, Zhihui Kwon, So Mee Li, Daochuan Li, Linhao Peng, Xiwei Zhang, Junran Sueyoshi, Tatsuya Raufman, Jean-Pierre Negishi, Masahiko Wang, Xin Wei Wang, Hongbing |
author_sort | Li, Zhihui |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9052153 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-90521532022-05-03 Human constitutive androstane receptor represses liver cancer development and hepatoma cell proliferation by inhibiting erythropoietin signaling Li, Zhihui Kwon, So Mee Li, Daochuan Li, Linhao Peng, Xiwei Zhang, Junran Sueyoshi, Tatsuya Raufman, Jean-Pierre Negishi, Masahiko Wang, Xin Wei Wang, Hongbing J Biol Chem Research Article 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. American Society for Biochemistry and Molecular Biology 2022-03-30 /pmc/articles/PMC9052153/ /pubmed/35367211 http://dx.doi.org/10.1016/j.jbc.2022.101885 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Article Li, Zhihui Kwon, So Mee Li, Daochuan Li, Linhao Peng, Xiwei Zhang, Junran Sueyoshi, Tatsuya Raufman, Jean-Pierre Negishi, Masahiko Wang, Xin Wei Wang, Hongbing Human constitutive androstane receptor represses liver cancer development and hepatoma cell proliferation by inhibiting erythropoietin signaling |
title | Human constitutive androstane receptor represses liver cancer development and hepatoma cell proliferation by inhibiting erythropoietin signaling |
title_full | Human constitutive androstane receptor represses liver cancer development and hepatoma cell proliferation by inhibiting erythropoietin signaling |
title_fullStr | Human constitutive androstane receptor represses liver cancer development and hepatoma cell proliferation by inhibiting erythropoietin signaling |
title_full_unstemmed | Human constitutive androstane receptor represses liver cancer development and hepatoma cell proliferation by inhibiting erythropoietin signaling |
title_short | Human constitutive androstane receptor represses liver cancer development and hepatoma cell proliferation by inhibiting erythropoietin signaling |
title_sort | human constitutive androstane receptor represses liver cancer development and hepatoma cell proliferation by inhibiting erythropoietin signaling |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9052153/ https://www.ncbi.nlm.nih.gov/pubmed/35367211 http://dx.doi.org/10.1016/j.jbc.2022.101885 |
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