title: Expression of c-jun is not mandatory for mouse hepatocyte proliferation induced by two nuclear receptor ligands: TCPOBOP and T3.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Toxicology, University of Cagliari, Italy.
authors.forename: Vera P
authors.initials: VP
authors.lastname: Leoni
authors.forename: Giovanna M
authors.initials: GM
authors.lastname: Ledda-Columbano
authors.forename: Monica
authors.initials: M
authors.lastname: Pibiri
authors.forename: Christian
authors.initials: C
authors.lastname: Saliba
authors.forename: Andrea
authors.initials: A
authors.lastname: Perra
authors.forename: Marta A
authors.initials: MA
authors.lastname: Kowalik
authors.forename: Oli M V
authors.initials: OM
authors.lastname: Grober
authors.forename: Maria
authors.initials: M
authors.lastname: Ravo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Weisz
authors.forename: Joseph
authors.initials: J
authors.lastname: Locker
authors.forename: Elena
authors.initials: E
authors.lastname: Ghiso
authors.forename: Silvia
authors.initials: S
authors.lastname: Giordano
authors.forename: Amedeo
authors.initials: A
authors.lastname: Columbano
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D000090702:Constitutive Androstane Receptor; D004052:Diethylnitrosamine; D005260:Female; D015870:Gene Expression; D020868:Gene Silencing; D016758:Genes, jun; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D011725:Pyridines / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D014284:Triiodothyronine / Q000494:pharmacology*
chemical_list: D000090702:Constitutive Androstane Receptor; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D014284:Triiodothyronine; D004052:Diethylnitrosamine; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene