Thiazolidinediones inhibit hepatocarcinogenesis in hepatitis B virus–transgenic mice by peroxisome proliferator‐activated receptor γ–independent regulation of nucleophosmin†

Aug 5, 2010Hepatology (Baltimore, Md.)

Thiazolidinediones reduce liver cancer development in hepatitis B mice through a pathway not involving PPAR-gamma by controlling nucleophosmin

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Abstract

Chronic administration of thiazolidinediones (TZD) for 26 weeks reduced liver tumor incidence in specific mouse models.

TZD treatment inhibited hepatocyte proliferation and increased apoptosis in hepatitis B virus-transgenic mice.
The deletion of the PPARgamma gene in hepatocytes did not affect liver cancer development but enhanced the antitumor effect of TZD.
Proteomic analysis identified nucleophosmin (NPM) as a target of TZD in PPARgamma-deficient hepatocytes.
TZD treatment led to reduced NPM expression at both protein and messenger RNA levels.
Inhibition of NPM by TZD was linked to increased phosphorylation of p53 and expression of p21.

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UNLABELLED: 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.

CONCLUSION: 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.

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Thiazolidinediones inhibit hepatocarcinogenesis in hepatitis B virus–transgenic mice by peroxisome proliferator‐activated receptor γ–independent regulation of nucleophosmin†

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