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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1069-1078
Number of pages10
JournalJournal of Hepatology
Volume55
Issue number5
DOIs
Publication statusPublished - Nov 2011

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Cytoplasmic and Nuclear Receptors
Hepatocytes
Ligands
Diethylnitrosamine
Hepatocellular Carcinoma
Liver
Thyroid Hormone Receptors
Hepatectomy
S Phase
Hyperplasia
1,4-bis(2-(3,5-dichloropyridyloxy))benzene
Regeneration
Cell Death
Injections
Therapeutics
Growth
Neoplasms

Keywords

  • Cell cycle
  • Hepatocellular carcinoma
  • Liver hyperplasia
  • Nuclear receptors

ASJC Scopus subject areas

  • Hepatology

Cite this

Leoni, V. P., Ledda-Columbano, G. M., Pibiri, M., Saliba, C., Perra, A., Kowalik, M. A., ... Columbano, A. (2011). Expression of c-jun is not mandatory for mouse hepatocyte proliferation induced by two nuclear receptor ligands: TCPOBOP and T3. Journal of Hepatology, 55(5), 1069-1078. https://doi.org/10.1016/j.jhep.2011.02.016

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

In: Journal of Hepatology, Vol. 55, No. 5, 11.2011, p. 1069-1078.

Research output: Contribution to journalArticle

Leoni, VP, Ledda-Columbano, GM, Pibiri, M, Saliba, C, Perra, A, Kowalik, MA, Grober, OMV, Ravo, M, Weisz, A, Locker, J, Ghiso, E, Giordano, S & Columbano, A 2011, 'Expression of c-jun is not mandatory for mouse hepatocyte proliferation induced by two nuclear receptor ligands: TCPOBOP and T3', Journal of Hepatology, vol. 55, no. 5, pp. 1069-1078. https://doi.org/10.1016/j.jhep.2011.02.016
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. / Expression of c-jun is not mandatory for mouse hepatocyte proliferation induced by two nuclear receptor ligands : TCPOBOP and T3. In: Journal of Hepatology. 2011 ; Vol. 55, No. 5. pp. 1069-1078.
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T2 - TCPOBOP and T3

AU - Leoni, Vera P.

AU - Ledda-Columbano, Giovanna M.

AU - Pibiri, Monica

AU - Saliba, Christian

AU - Perra, Andrea

AU - Kowalik, Marta A.

AU - Grober, Oli M V

AU - Ravo, Maria

AU - Weisz, Alessandro

AU - Locker, Joseph

AU - Ghiso, Elena

AU - Giordano, Silvia

AU - Columbano, Amedeo

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N2 - 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.

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