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J Hepatol. 2011 Nov;55(5):1069-78. doi: 10.1016/j.jhep.2011.02.016. Epub 2011 Feb 25.

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

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1
Department of Toxicology, University of Cagliari, Italy.

Abstract

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-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.

RESULTS:

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.

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.

PMID:
21354444
DOI:
10.1016/j.jhep.2011.02.016
[Indexed for MEDLINE]
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