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Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation

Human hepatocellular carcinomas (HCCs), which arise on a background of chronic liver damage and inflammation, express c-Fos, a component of the AP-1 transcription factor. Using mouse models, we show that hepatocyte-specific deletion of c-Fos protects against diethylnitrosamine (DEN)-induced HCCs, wh...

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Autores principales: Bakiri, Latifa, Hamacher, Rainer, Graña, Osvaldo, Guío-Carrión, Ana, Campos-Olivas, Ramón, Martinez, Lola, Dienes, Hans P., Thomsen, Martin K., Hasenfuss, Sebastian C., Wagner, Erwin F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413325/
https://www.ncbi.nlm.nih.gov/pubmed/28356389
http://dx.doi.org/10.1084/jem.20160935
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author Bakiri, Latifa
Hamacher, Rainer
Graña, Osvaldo
Guío-Carrión, Ana
Campos-Olivas, Ramón
Martinez, Lola
Dienes, Hans P.
Thomsen, Martin K.
Hasenfuss, Sebastian C.
Wagner, Erwin F.
author_facet Bakiri, Latifa
Hamacher, Rainer
Graña, Osvaldo
Guío-Carrión, Ana
Campos-Olivas, Ramón
Martinez, Lola
Dienes, Hans P.
Thomsen, Martin K.
Hasenfuss, Sebastian C.
Wagner, Erwin F.
author_sort Bakiri, Latifa
collection PubMed
description Human hepatocellular carcinomas (HCCs), which arise on a background of chronic liver damage and inflammation, express c-Fos, a component of the AP-1 transcription factor. Using mouse models, we show that hepatocyte-specific deletion of c-Fos protects against diethylnitrosamine (DEN)-induced HCCs, whereas liver-specific c-Fos expression leads to reversible premalignant hepatocyte transformation and enhanced DEN-carcinogenesis. c-Fos–expressing livers display necrotic foci, immune cell infiltration, and altered hepatocyte morphology. Furthermore, increased proliferation, dedifferentiation, activation of the DNA damage response, and gene signatures of aggressive HCCs are observed. Mechanistically, c-Fos decreases expression and activity of the nuclear receptor LXRα, leading to increased hepatic cholesterol and accumulation of toxic oxysterols and bile acids. The phenotypic consequences of c-Fos expression are partially ameliorated by the anti-inflammatory drug sulindac and largely prevented by statin treatment. An inverse correlation between c-FOS and the LXRα pathway was also observed in human HCC cell lines and datasets. These findings provide a novel link between chronic inflammation and metabolic pathways important in liver cancer.
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spelling pubmed-54133252017-11-01 Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation Bakiri, Latifa Hamacher, Rainer Graña, Osvaldo Guío-Carrión, Ana Campos-Olivas, Ramón Martinez, Lola Dienes, Hans P. Thomsen, Martin K. Hasenfuss, Sebastian C. Wagner, Erwin F. J Exp Med Research Articles Human hepatocellular carcinomas (HCCs), which arise on a background of chronic liver damage and inflammation, express c-Fos, a component of the AP-1 transcription factor. Using mouse models, we show that hepatocyte-specific deletion of c-Fos protects against diethylnitrosamine (DEN)-induced HCCs, whereas liver-specific c-Fos expression leads to reversible premalignant hepatocyte transformation and enhanced DEN-carcinogenesis. c-Fos–expressing livers display necrotic foci, immune cell infiltration, and altered hepatocyte morphology. Furthermore, increased proliferation, dedifferentiation, activation of the DNA damage response, and gene signatures of aggressive HCCs are observed. Mechanistically, c-Fos decreases expression and activity of the nuclear receptor LXRα, leading to increased hepatic cholesterol and accumulation of toxic oxysterols and bile acids. The phenotypic consequences of c-Fos expression are partially ameliorated by the anti-inflammatory drug sulindac and largely prevented by statin treatment. An inverse correlation between c-FOS and the LXRα pathway was also observed in human HCC cell lines and datasets. These findings provide a novel link between chronic inflammation and metabolic pathways important in liver cancer. The Rockefeller University Press 2017-05-01 /pmc/articles/PMC5413325/ /pubmed/28356389 http://dx.doi.org/10.1084/jem.20160935 Text en © 2017 Bakiri et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Bakiri, Latifa
Hamacher, Rainer
Graña, Osvaldo
Guío-Carrión, Ana
Campos-Olivas, Ramón
Martinez, Lola
Dienes, Hans P.
Thomsen, Martin K.
Hasenfuss, Sebastian C.
Wagner, Erwin F.
Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation
title Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation
title_full Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation
title_fullStr Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation
title_full_unstemmed Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation
title_short Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation
title_sort liver carcinogenesis by fos-dependent inflammation and cholesterol dysregulation
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413325/
https://www.ncbi.nlm.nih.gov/pubmed/28356389
http://dx.doi.org/10.1084/jem.20160935
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