title: Clustering nuclear receptors in liver regeneration identifies candidate modulators of hepatocyte proliferation and hepatocarcinoma.
abstract: OBJECTIVE
  Liver regeneration (LR) is a valuable model for studying mechanisms modulating hepatocyte proliferation. Nuclear receptors (NRs) are key players in the control of cellular functions, being ideal modulators of hepatic proliferation and carcinogenesis.
  
  
  RESULTS
  We used a previously validated RT-qPCR platform to profile modifications in the expression of all 49 members of the NR superfamily in mouse liver during LR. Twenty-nine NR transcripts were significantly modified in their expression during LR, including fatty acid (peroxisome proliferator-activated receptors, PPARs) and oxysterol (liver X receptors, Lxrs) sensors, circadian masters RevErbα and RevErbβ, glucocorticoid receptor (Gr) and constitutive androxane receptor (Car). In order to detect the NRs that better characterize proliferative status vs. proliferating liver, we used the novel Random Forest (RF) analysis to selected a trio of down-regulated NRs (thyroid receptor alpha, Trα; farsenoid X receptor beta, Fxrβ; Pparδ) as best discriminators of the proliferating status. To validate our approach, we further studied PPARδ role in modulating hepatic proliferation. We first confirmed the suppression of PPARδ both in LR and human hepatocellular carcinoma at protein level, and then demonstrated that PPARδ agonist GW501516 reduces the proliferative potential of hepatoma cells.
  
  
  CONCLUSIONS
  Our data suggest that NR transcriptome is modulated in proliferating liver and is a source of biomarkers and bona fide pharmacological targets for the management of liver disease affecting hepatocyte proliferation.
authors.affiliation: Fondazione Mario Negri Sud, Santa Maria Imbaro (Chieti), Chieti, Italy; Unit of General Pathology, Aging Research Center (Ce.S.I.), "Gabriele D'Annunzio" University and Foundation, Chieti, Italy; Interdisciplinary Department of Medicine, "Aldo Moro" University of Bari, Bari, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Vacca
authors.affiliation: National Cancer Institute, IRCCS Oncologico "Giovanni Paolo II", Bari, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: D'Amore
authors.affiliation: National Cancer Institute, IRCCS Oncologico "Giovanni Paolo II", Bari, Italy.
authors.forename: Giusi
authors.initials: G
authors.lastname: Graziano
authors.affiliation: Fondazione Mario Negri Sud, Santa Maria Imbaro (Chieti), Chieti, Italy.
authors.forename: Andria
authors.initials: A
authors.lastname: D'Orazio
authors.affiliation: National Cancer Institute, IRCCS Oncologico "Giovanni Paolo II", Bari, Italy.
authors.forename: Marica
authors.initials: M
authors.lastname: Cariello
authors.affiliation: Fondazione Mario Negri Sud, Santa Maria Imbaro (Chieti), Chieti, Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Massafra
authors.affiliation: Fondazione Mario Negri Sud, Santa Maria Imbaro (Chieti), Chieti, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Salvatore
authors.affiliation: Fondazione Mario Negri Sud, Santa Maria Imbaro (Chieti), Chieti, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Martelli
authors.affiliation: Fondazione Mario Negri Sud, Santa Maria Imbaro (Chieti), Chieti, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Murzilli
authors.affiliation: Fondazione Mario Negri Sud, Santa Maria Imbaro (Chieti), Chieti, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lo Sasso
authors.affiliation: Unit of General Pathology, Aging Research Center (Ce.S.I.), "Gabriele D'Annunzio" University and Foundation, Chieti, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Mariani-Costantini
authors.affiliation: Interdisciplinary Department of Medicine, "Aldo Moro" University of Bari, Bari, Italy; National Cancer Institute, IRCCS Oncologico "Giovanni Paolo II", Bari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Moschetta
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D008115:Liver Regeneration / Q000235:genetics*; D008297:Male; D051379:Mice; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear