Thiazolidinediones Inhibit Hepatocarcinogenesis in Hepatitis B Virus Transgenic Mice by Peroxisome Proliferator-Activated Receptor γ-Independent Regulation of Nucleophosmin

被引：49

作者：

Galli, Andrea ^{[1
,2
]}

Ceni, Elisabetta ^{[1
,2
]}

Mello, Tommaso ^{[1
,2
]}

Polvani, Simone ^{[1
,4
]}

Tarocchi, Mirko ^{[1
,2
]}

Buccoliero, Francesca ^{[1
]}

Lisi, Francesca ^{[1
]}

Cioni, Laura ^{[1
]}

Ottanelli, Barbara ^{[1
]}

Foresta, Valeria ^{[1
]}

Mastrobuoni, Guido ^{[3
]}

Moneti, Gloriano ^{[3
]}

Pieraccini, Giuseppe ^{[3
]}

Surrenti, Calogero ^{[1
]}

Milani, Stefano ^{[1
,2
]}

机构：

[1] Univ Florence, Dept Clin Pathophysiol, Gastroenterol Unit, I-50139 Florence, Italy

[2] Univ Florence, Ctr Excellence Res Transfer & High Educ, DENOthe, I-50139 Florence, Italy

[3] Univ Florence, Mass Spectrometry Ctr, I-50139 Florence, Italy

[4] FiorGen Farmacogenom Fdn, Florence, Italy

来源：

HEPATOLOGY | 2010年 / 52卷 / 02期

关键词：

PPAR-GAMMA; ANTIDIABETIC THIAZOLIDINEDIONES; HEPATOCELLULAR-CARCINOMA; PROTEIN-KINASE; PANCREATIC-CANCER; UP-REGULATION; EXPRESSION; GROWTH; GENE; RESISTANCE;

D O I：

10.1002/hep.23669

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

100201 [内科学];

摘要：

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 (PPAR gamma), 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 PPAR gamma expression and activity. The effect of TZD oral administration for 26 weeks was tested on tumor formation in PPAR gamma-expressing and PPAR gamma-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 PPAR gamma-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. PPAR gamma deletion in hepatocytes of HBV-transgenic mice (Tg[HBV] CreKO gamma) did not modify hepatic carcinogenesis but increased the TZD antitumorigenic effect. Proteomic analysis identified nucleophosmin (NPM) as a TZD target in PPAR gamma-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;52:493-505)

引用

页码：493 / 505

页数：13

共 44 条

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