Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/8391
Título
Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation
Autor(es)
Bakiri, Latifa CNIO | Hamacher, Rainer | Graña Castro, Osvaldo CNIO | Guío-Carrión, Ana | Campos Olivas, Ramon CNIO | Martinez, Lola CNIO | Dienes, Hans P | Thomsen, Martin K | Hasenfuss, Sebastian C | Wagner, Erwin F
Fecha de publicación
2017-05-01
Cita
J Exp Med. 2017;214(5):1387-1409.
Idioma
Inglés
Tipo de documento
journal article
Resumen
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.
MESH
Animals | Carcinoma, Hepatocellular | Cell Transformation, Neoplastic | Cholesterol | Diethylnitrosamine | Disease Models, Animal | Drosophila Proteins | Liver | Liver Neoplasms | Mice | Proto-Oncogene Proteins c-fos | Repressor Proteins
Descripción
233294
Versión en línea
DOI
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