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 Tif1α) 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.
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Acknowledgements
This letter is dedicated to the memory of Bertrand Le Douarin on the ninth anniversary of his premature death. He discovered and carried out the first molecular characterization of TIF1α. We thank M. Cerviño, X. Belin, J.-V. Fougerolle, L. Walsh and E. Alexandre for technical help. We also thank all the common facilities of the IGBMC and, in particular, C. Ebel and J. Barths for assistance in FACS analysis, D. Dembélé for help with statistical analyses, N. Ghyselinck for providing Rara mutant mice, C. Suzi and P. Reczek (Bristol-Myers Squibb) for the gift of BMS493, M. Oulad-Abdelghani for the gift of antibody to β-tubulin 1TUB1A2 and P. Kastner and P. Germain for helpful discussions. This work was supported by the French Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, and Agence Nationale de la Recherche, the Association pour la Recherche sur le Cancer (ARC) and the Collège de France. Special thanks to R.P. Vashakidze from Volzhsky Orgsynthese for the financial support of K.K. K.K. was also supported by the French Ministère de la Recherche et des Technologies, the Ligue Nationale contre le Cancer and the Armenian Foundation Boghos Noubar Pacha (Belgium). M.I. was supported by a Charcot fellowship from the French Ministère des Affaires étrangères.
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K.K. created and analyzed all knock-out mice. M.T. and M.I. performed the quantification and histopathological assessment of mouse tumor and proliferation phenotypes under supervision of M.M. J.T. carried out microarray, qRT-PCR and ChIP experiments. B.H. worked on the analysis of Trim24 on cell models under supervision of K.K. J.Z.-R. contributed to Trim24 expression analysis. T.L. and C.T. provided technical assistance with plasmid contruction and microarray work, respectively. P.C., F.C. and D.M. provided project supervision. R.L. provided the general concept, design of study, supervision and manuscript writing.
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Khetchoumian, K., Teletin, M., Tisserand, J. et al. Loss of Trim24 (Tif1α) gene function confers oncogenic activity to retinoic acid receptor alpha. Nat Genet 39, 1500–1506 (2007). https://doi.org/10.1038/ng.2007.15
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DOI: https://doi.org/10.1038/ng.2007.15
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