Thiazolidinediones inhibit hepatocarcinogenesis in hepatitis B virus-transgenic mice by peroxisome proliferator-activated receptor gamma-independent regulation of nucleophosmin

[Guest guest]

Hepatology. 2010 Aug;52(2):493-505.

Thiazolidinediones inhibit hepatocarcinogenesis in hepatitis B virus-transgenic

mice by peroxisome proliferator-activated receptor gamma-independent regulation

of nucleophosmin.

Galli A, Ceni E, Mello T, Polvani S, Tarocchi M, Buccoliero F, Lisi F, Cioni L,

Ottanelli B, Foresta V, Mastrobuoni G, Moneti G, Pieraccini G, Surrenti C,

Milani S.

Gastroenterology Unit, Department of Clinical Pathophysiology, Florence, Italy.

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. 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. HEPATOLOGY 2010.

PMID: 20683949

[Guest guest]

Hepatology. 2010 Aug;52(2):493-505.

Thiazolidinediones inhibit hepatocarcinogenesis in hepatitis B virus-transgenic

mice by peroxisome proliferator-activated receptor gamma-independent regulation

of nucleophosmin.

Galli A, Ceni E, Mello T, Polvani S, Tarocchi M, Buccoliero F, Lisi F, Cioni L,

Ottanelli B, Foresta V, Mastrobuoni G, Moneti G, Pieraccini G, Surrenti C,

Milani S.

Gastroenterology Unit, Department of Clinical Pathophysiology, Florence, Italy.

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. 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. HEPATOLOGY 2010.

PMID: 20683949