Clustering nuclear receptors in liver regeneration identifies candidate modulators of hepatocyte proliferation and hepatocarcinoma

Michele Vacca, Simona D'Amore, Giusi Graziano, Andria D'Orazio, Marica Cariello, Vittoria Massafra, Lorena Salvatore, Nicola Martelli, Stefania Murzilli, Giuseppe Lo Sasso, Renato Mariani-Costantini, Antonio Moschetta

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background & Aims: 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. Methods & 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 PPARd 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.

Original languageEnglish (US)
Article numbere104449
JournalPLoS One
Volume9
Issue number8
DOIs
StatePublished - Aug 12 2014

Fingerprint

liver regeneration
Liver Regeneration
Cytoplasmic and Nuclear Receptors
Liver
Modulators
hepatocytes
Cluster Analysis
Hepatocytes
receptors
Peroxisome Proliferator-Activated Receptors
liver
Hepatocellular Carcinoma
hepatoma
Glucocorticoid Receptors
Transcriptome
Liver Diseases
Thyroid Gland
Carcinogenesis
Discriminators
Fatty Acids

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Vacca, M., D'Amore, S., Graziano, G., D'Orazio, A., Cariello, M., Massafra, V., ... Moschetta, A. (2014). Clustering nuclear receptors in liver regeneration identifies candidate modulators of hepatocyte proliferation and hepatocarcinoma. PLoS One, 9(8), [e104449]. https://doi.org/10.1371/journal.pone.0104449

Clustering nuclear receptors in liver regeneration identifies candidate modulators of hepatocyte proliferation and hepatocarcinoma. / Vacca, Michele; D'Amore, Simona; Graziano, Giusi; D'Orazio, Andria; Cariello, Marica; Massafra, Vittoria; Salvatore, Lorena; Martelli, Nicola; Murzilli, Stefania; Lo Sasso, Giuseppe; Mariani-Costantini, Renato; Moschetta, Antonio.

In: PLoS One, Vol. 9, No. 8, e104449, 12.08.2014.

Research output: Contribution to journalArticle

Vacca, M, D'Amore, S, Graziano, G, D'Orazio, A, Cariello, M, Massafra, V, Salvatore, L, Martelli, N, Murzilli, S, Lo Sasso, G, Mariani-Costantini, R & Moschetta, A 2014, 'Clustering nuclear receptors in liver regeneration identifies candidate modulators of hepatocyte proliferation and hepatocarcinoma', PLoS One, vol. 9, no. 8, e104449. https://doi.org/10.1371/journal.pone.0104449
Vacca, Michele ; D'Amore, Simona ; Graziano, Giusi ; D'Orazio, Andria ; Cariello, Marica ; Massafra, Vittoria ; Salvatore, Lorena ; Martelli, Nicola ; Murzilli, Stefania ; Lo Sasso, Giuseppe ; Mariani-Costantini, Renato ; Moschetta, Antonio. / Clustering nuclear receptors in liver regeneration identifies candidate modulators of hepatocyte proliferation and hepatocarcinoma. In: PLoS One. 2014 ; Vol. 9, No. 8.
@article{f99f31ca945e4f91ba0593b9c601434a,
title = "Clustering nuclear receptors in liver regeneration identifies candidate modulators of hepatocyte proliferation and hepatocarcinoma",
abstract = "Background & Aims: 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. Methods & 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 PPARd 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.",
author = "Michele Vacca and Simona D'Amore and Giusi Graziano and Andria D'Orazio and Marica Cariello and Vittoria Massafra and Lorena Salvatore and Nicola Martelli and Stefania Murzilli and {Lo Sasso}, Giuseppe and Renato Mariani-Costantini and Antonio Moschetta",
year = "2014",
month = "8",
day = "12",
doi = "10.1371/journal.pone.0104449",
language = "English (US)",
volume = "9",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "8",

}

TY - JOUR

T1 - Clustering nuclear receptors in liver regeneration identifies candidate modulators of hepatocyte proliferation and hepatocarcinoma

AU - Vacca, Michele

AU - D'Amore, Simona

AU - Graziano, Giusi

AU - D'Orazio, Andria

AU - Cariello, Marica

AU - Massafra, Vittoria

AU - Salvatore, Lorena

AU - Martelli, Nicola

AU - Murzilli, Stefania

AU - Lo Sasso, Giuseppe

AU - Mariani-Costantini, Renato

AU - Moschetta, Antonio

PY - 2014/8/12

Y1 - 2014/8/12

N2 - Background & Aims: 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. Methods & 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 PPARd 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.

AB - Background & Aims: 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. Methods & 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 PPARd 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.

UR - http://www.scopus.com/inward/record.url?scp=84905851448&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84905851448&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0104449

DO - 10.1371/journal.pone.0104449

M3 - Article

VL - 9

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 8

M1 - e104449

ER -