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

• Published in: Journal of hepatology 2011-11, Vol.55 (5), p.1069-1078
• Main Authors: Leoni, Vera P, Ledda-Columbano, Giovanna M, Pibiri, Monica, Saliba, Christian, Perra, Andrea, Kowalik, Marta A, Grober, Oli M.V, Ravo, Maria, Weisz, Alessandro, Locker, Joseph, Ghiso, Elena, Giordano, Silvia, Columbano, Amedeo
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Cycle Checkpoints - genetics; Cell Proliferation - drug effects; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - genetics; Diethylnitrosamine; Female; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression; Gene Silencing; Genes, jun; Hepatocellular carcinoma; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - pathology; Liver hyperplasia; Liver Neoplasms, Experimental - chemically induced; Liver Neoplasms, Experimental - genetics; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Mice; Mice, Knockout; Nuclear receptors; Pyridines - pharmacology; Receptors, Cytoplasmic and Nuclear - metabolism; Triiodothyronine - pharmacology; Tumors
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2011.02.016

Background & Aims 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. Methods The effect of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) on hepatocyte proliferation was determined in c-jun conditional knockout ( c-junΔli ) or in mouse liver where c-jun has been silenced. To study the role of c-jun in HCC development, c-junΔli and WT mice were given diethylnitrosamine (DENA) followed by repeated injections of TCPOBOP. Results Hepatocyte proliferation induced by TCPOBOP was associated with a stronger proliferative response and earlier S phase entry in c-junΔli 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-junΔli 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. Conclusions (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.