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.

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

GHISO, ELENA;GIORDANO, Silvia;
2011

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.
55
5
1069
1078
http://www.sciencedirect.com/science/article/pii/S0168827811001991
Nuclear receptors; Hepatocellular carcinoma; Cell cycle; Liver hyperplasia
Leoni VP;Ledda-Columbano GM;Pibiri M;Saliba C;Perra A;Kowalik MA;Grober OM;Ravo M;Weisz A;Locker J;Ghiso E;Giordano S;Columbano A
File in questo prodotto:
File Dimensione Formato  
2011_Expression of c-jun is not mandatory for mouse hepatocyte proliferation induced by two nuclear receptor ligands.TCPOBOP and T3.pdf

Accesso riservato

Tipo di file: PDF EDITORIALE
Dimensione 2.28 MB
Formato Adobe PDF
2.28 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
2011_Expression of c-jun is not mandatory for mouse hepatocyte proliferation induced by two nuclear receptor ligands.TCPOBOP and T3_APERTO.pdf

Accesso aperto con embargo fino al 01/11/2012

Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 7.73 MB
Formato Adobe PDF
7.73 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/113530
Citazioni
  • ???jsp.display-item.citation.pmc??? 4
  • Scopus 8
  • ???jsp.display-item.citation.isi??? 7
social impact