Expression of c-jun is not mandatory for mouse hepatocyte proliferation induced by two nuclear receptor ligands: TCPOBOP and T3.

Journal of hepatology 2011 Nov

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Mice lacking c-jun in the liver display impaired regeneration after partial hepatectomy (PH), and were reported to be more resistant to chemically-induced hepatocellular carcinoma (HCC). We investigated the role of c-jun in normal and preneoplastic hepatocyte proliferation induced by ligands of nuclear receptors, which cause liver hyperplasia in the absence of cell loss/death. The effect of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) on hepatocyte proliferation was determined in c-jun conditional knockout (c-jun(Δli)) or in mouse liver where c-jun has been silenced. To study the role of c-jun in HCC development, c-jun(Δli) and WT mice were given diethylnitrosamine (DENA) followed by repeated injections of TCPOBOP. Hepatocyte proliferation induced by TCPOBOP was associated with a stronger proliferative response and earlier S phase entry in c-jun(Δli) mice, compared to WT animals. Moreover, silencing of c-jun in the liver of CD-1 mice caused increased hepatocyte proliferation. A stronger hepatocyte proliferative response of c-jun(Δli) mice was observed also following treatment with a ligand of thyroid hormone receptor. Finally, loss of c-jun did not inhibit the development of HCC induced by DENA and promoted by TCPOBOP. (i) c-jun may, under certain conditions, negatively regulate proliferation of normal hepatocytes, (ii) c-jun is not an absolute requirement for DENA/TCPOBOP-induced HCC formation, suggesting that the therapeutic potential of c-jun/JNK inhibition in liver tumors might be impaired by an increased stimulation of cell growth due to blockade of the c-jun pathway. Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Citation

Vera P Leoni, Giovanna M Ledda-Columbano, Monica Pibiri, Christian Saliba, Andrea Perra, Marta A Kowalik, Oli M V Grober, Maria Ravo, Alessandro Weisz, Joseph Locker, Elena Ghiso, Silvia Giordano, Amedeo Columbano. Expression of c-jun is not mandatory for mouse hepatocyte proliferation induced by two nuclear receptor ligands: TCPOBOP and T3. Journal of hepatology. 2011 Nov;55(5):1069-78