title: Loss of Trim24 (Tif1alpha) gene function confers oncogenic activity to retinoic acid receptor alpha.
abstract: 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 Tif1alpha) 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.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Department of Functional Genomics, Centre National de la Recherche Scientifique UMR7104, Université Louis Pasteur, Collége de France, Illkirch, France.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Khetchoumian
authors.forename: Marius
authors.initials: M
authors.lastname: Teletin
authors.forename: Johan
authors.initials: J
authors.lastname: Tisserand
authors.forename: Manuel
authors.initials: M
authors.lastname: Mark
authors.forename: Benjamin
authors.initials: B
authors.lastname: Herquel
authors.forename: Mihaela
authors.initials: M
authors.lastname: Ignat
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
authors.forename: Florence
authors.initials: F
authors.lastname: Cammas
authors.forename: Thierry
authors.initials: T
authors.lastname: Lerouge
authors.forename: Christelle
authors.initials: C
authors.lastname: Thibault
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Régine
authors.initials: R
authors.lastname: Losson
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D049109:Cell Proliferation; D016147:Genes, Tumor Suppressor; D022781:Hepatocytes / Q000166:cytology; D008113:Liver Neoplasms / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D009687:Nuclear Proteins; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; C093517:transcriptional intermediary factor 1