title: Thiazolidinediones inhibit hepatocarcinogenesis in hepatitis B virus-transgenic mice by peroxisome proliferator-activated receptor gamma-independent regulation of nucleophosmin.
abstract: Antidiabetic thiazolidinediones (TZD) have in vitro antiproliferative effect in epithelial cancers, including hepatocellular carcinoma (HCC). The effective anticancer properties and the underlying molecular mechanisms of these drugs in vivo remain unclear. In addition, the primary biological target of TZD, the ligand-dependent transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma), is up-regulated in HCC and seems to provide tumor-promoting responses. The aim of our study was to evaluate whether chronic administration of TZD may affect hepatic carcinogenesis in vivo in relation to PPARgamma expression and activity. The effect of TZD oral administration for 26 weeks was tested on tumor formation in PPARgamma-expressing and PPARgamma-deficient mouse models of hepatic carcinogenesis. Proteomic analysis was performed in freshly isolated hepatocytes by differential in gel electrophoresis and mass spectrometry analysis. Identified TZD targets were confirmed in cultured PPARgamma-deficient hepatocytes. TZD administration in hepatitis B virus (HBV)-transgenic mice (TgN[Alb1HBV]44Bri) reduced tumor incidence in the liver, inhibiting hepatocyte proliferation and increasing apoptosis. PPARgamma deletion in hepatocytes of HBV-transgenic mice (Tg[HBV]CreKOgamma) did not modify hepatic carcinogenesis but increased the TZD antitumorigenic effect. Proteomic analysis identified nucleophosmin (NPM) as a TZD target in PPARgamma-deficient hepatocytes. TZD inhibited NPM expression at protein and messenger RNA levels and decreased NPM promoter activity. TZD inhibition of NPM was associated with the induction of p53 phosphorylation and p21 expression.
  
  
  CONCLUSIONS
  These findings suggest that chronic administration of TZD has anticancer activity in the liver via inhibition of NPM expression and indicate that these drugs might be useful for HCC chemoprevention and treatment.
authors.affiliation: Gastroenterology Unit, Department of Clinical Pathophysiology, University of Florence, Florence, Italy. a.galli@dfc.unifi.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Galli
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ceni
authors.forename: Tommaso
authors.initials: T
authors.lastname: Mello
authors.forename: Simone
authors.initials: S
authors.lastname: Polvani
authors.forename: Mirko
authors.initials: M
authors.lastname: Tarocchi
authors.forename: Francesca
authors.initials: F
authors.lastname: Buccoliero
authors.forename: Francesca
authors.initials: F
authors.lastname: Lisi
authors.forename: Laura
authors.initials: L
authors.lastname: Cioni
authors.forename: Barbara
authors.initials: B
authors.lastname: Ottanelli
authors.forename: Valeria
authors.initials: V
authors.lastname: Foresta
authors.forename: Guido
authors.initials: G
authors.lastname: Mastrobuoni
authors.forename: Gloriano
authors.initials: G
authors.lastname: Moneti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pieraccini
authors.forename: Calogero
authors.initials: C
authors.lastname: Surrenti
authors.forename: Stefano
authors.initials: S
authors.lastname: Milani
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000517:prevention & control* / Q000821:virology*; D006515:Hepatitis B virus; D022781:Hepatocytes; D008113:Liver Neoplasms / Q000517:prevention & control* / Q000821:virology*; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000517:prevention & control / Q000821:virology; D009687:Nuclear Proteins / Q000502:physiology*; D000090243:Nucleophosmin; D047495:PPAR gamma / Q000502:physiology*; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: D009687:Nuclear Proteins; D047495:PPAR gamma; D045162:Thiazolidinediones; D000090243:Nucleophosmin