Thiazolidinediones inhibit hepatocarcinogenesis in hepatitis B virus-transgenic mice by peroxisome proliferator-activated receptor γ-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 c (PPARc), 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 PPARc expression and activity. The effect of TZD oral administration for 26 weeks was tested on tumor formation in PPARc-expressing and PPARc-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 PPARc-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. PPARc deletion in hepatocytes of HBV-transgenic mice (Tg[HBV]CreKOc) did not modify hepatic carcinogenesis but increased the TZD antitumorigenic effect. Proteomic analysis identified nucleophosmin (NPM) as a TZD target in PPARc-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)

Increased Risk of Gastrointestinal Malignancy in Patients with Diabetes Mellitus and Correlations with Anti-Diabetes Drugs: A Nationwide Population-based Study in Taiwan

“…α-glucosidase inhibitors have been reported to exert prolonged antiviral effects against the hepatitis B virus, which is the major risk factor for hepatic cancer. Galli et al demonstrated that TZD may inhibit hepatocarcinogenesis (42). The peroxisome proliferator-activated receptor-γ (PPAR-γ) ligand has been reported to inhibit colon cancer cell proliferation in vitro (43); however, TZD did Table 3 not decrease the risk of colon cancer in our study.…”

CITED2 is a novel direct effector of peroxisome proliferator‐activated receptor γ in suppressing hepatocellular carcinoma cell growth

“…In this study, we identified the PPARc downstream targets relevant to carcinogenesis, by using oligonucleotide microarray and gene ontology analysis. Among the identified targets and consistent with the major function of PPARc in HCC suppression, [7][8][9] Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 2 (CITED2) was identified as a direct effector of PPARc in HCC cells by chromatin immunoprecipitation (ChIP)-polymerase chain reaction (PCR). With the observation that CITED2 is significantly downregulated in primary HCCs compared with paired adjacent normal tissues, we further demonstrated the tumor suppressive properties of CITED2 through gain-or loss-of-CITED2 function analyses, which are at least in part mediated by the suppression of cell proliferation and inhibition of cell cycle G 1 -to-S phase transition.…”

“…6 We and others previously showed that rosiglitazone, a thiazolidinedione-class drug, inhibited hepatocarcinogenesis in vitro and in vivo by inducing cell apoptosis and cell cycle arrest. [7][8][9] However, the PPARc regulatory network and its molecular targets in liver cancer remain largely unknown. In this study, we identified the PPARc downstream targets relevant to carcinogenesis, by using oligonucleotide microarray and gene ontology analysis.…”

Gamma‐Glutamylcysteine Ethyl Ester Protects against Cyclophosphamide‐Induced Liver Injury and Hematologic Alterations via Upregulation of PPARγ and Attenuation of Oxidative Stress, Inflammation, and Apoptosis

“…Together with other agonists, TZDs showed beneficial therapeutic effects in oxidative stress-related diseases [59, 60]. As an example, rosiglitazone induces the antioxidant enzyme heme oxygenase 1 (HO-1) in hepatocytes [61] and pioglitazone protects against CP-induced oxidative stress in rats [60]. In response to oxidative stress, activation of PPAR γ has been reported to directly modulate the expression of several antioxidant genes.…”