Letter abstract
Nature Genetics 39, 1500 - 1506 (2007)
Published online: 18 November 2007 | doi:10.1038/ng.2007.15
Loss of Trim24 (Tif1
) gene function confers oncogenic activity to retinoic acid receptor alpha
Konstantin Khetchoumian1,3, Marius Teletin1, Johan Tisserand1, Manuel Mark1, Benjamin Herquel1, Mihaela Ignat1,3, Jessica Zucman-Rossi2, Florence Cammas1, Thierry Lerouge1, Christelle Thibault1, Daniel Metzger1, Pierre Chambon1 & Régine Losson1
Hepatocellular carcinoma (HCC) is a major cause of death worldwide. Here, we provide evidence that the ligand-dependent nuclear receptor co-regulator Trim24 (also known as Tif1
) functions in mice as a liver-specific tumor suppressor. In Trim24-null mice, hepatocytes fail to execute proper cell cycle withdrawal during the neonatal-to-adult transition and continue to cycle in adult livers, becoming prone to a continuum of cellular alterations that progress toward metastatic HCC. Using pharmacological approaches, we show that inhibition of retinoic acid signaling markedly reduces hepatocyte proliferation in Trim24-/- mice. We further show that deletion of a single retinoic acid receptor alpha (Rara) allele in a Trim24-null background suppresses HCC development and restores wild-type expression of retinoic acid–responsive genes in the liver, thus demonstrating that in this genetic background Rara expresses an oncogenic activity correlating with a dysregulation of the retinoic acid signaling pathway. Our results not only provide genetic evidence that Trim24 and Rara co-regulate hepatocarcinogenesis in an antagonistic manner but also suggest that aberrant activation of Rara is deleterious to liver homeostasis.
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Functional Genomics, Centre National de la Recherche Scientifique (CNRS) UMR7104, Institut National de la Santé et de la Recherche Médicale (INSERM) U596, Université Louis Pasteur (ULP), Collége de France, BP 10142, F-67404 Illkirch-Cedex, France.
- INSERM U674 Institut Universitaire d'Hématologie, Centre d'étude du polymorphisme humain (CEPH), F-75010 Paris, France.
- Present addresses: Laboratoire de Génétique Moléculaire, Institut de recherches cliniques, Montréal Québec, Canada H2W 1R7 (K.K.) and INSERM U701 Institut de Recherches contre les Cancers de l'Appareil Digestif (IRCAD), F-67000 Strasbourg, France (M.I.).
Correspondence to: Régine Losson1 e-mail: losson@igbmc.u-strasbg.fr
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