The peroxisome proliferator-activating receptor γ (PPARγ) is a member of the nuclear receptor superfamily of transcription factors. The role of PPARγ in the onset and treatment of cancer has been the focus of recent attention. PPARγ agonists inhibit the proliferative activity of neoplastic cells, suppress the growth of human tumor xenografts in nude mice,2, 3 and reduce the frequency of spontaneous and carcinogen-induced preneoplastic and neoplastic lesions in animals,2-5 which is indicative of the tumor suppressor effects of PPARγ.2 These observations have prompted phase II

clinical trials using PPARγ agonists as novel therapy for patients with liposarcoma, colon, breast, and prostate cancer.5, 6 Our group and others have previously demonstrated the antitumorigenic effects of PPARγ agonists Protein Tyrosine Kinase inhibitor in several liver cancer cell lines.7, 8 PPARγ agonist stimulation induced cell cycle arrest and apoptosis and inhibited

the growth of liver cancer cells.9-12 Thus, these findings support the hypothesis that PPARγ may act as a potent tumor suppressor in hepatocarcinogenesis. Of note, the antitumor effects of PPARγ agonists may be mediated via PPARγ-dependent and PPARγ-independent pathways,2, 13 but the role of PPARγ find more itself in hepatocarcinogenesis is still unclear. To elucidate the role of PPARγ in its therapeutic efficacy against HCC, diethylnitrosamine (DEN) was used to induce primary liver cancer in PPARγ wild-type (PPARγ+/+) and PPARγ heterozygous-deficient (PPARγ+/−) mice, followed by treatment with the PPARγ agonist rosiglitazone. We also examined the functional significance of endogenous PPARγ overexpression in human HCC cells using an adenovirus-PPARγ construct. ACOX, acyl-coenzymeA oxidases; Ad-PPARγ, adenovirus-expressing PPARγ; APAF, apoptotic protease activating factor; cDNA, complementary DNA; ChIP, chromatin immunoprecipitation; DEN, diethylnitrosamine; FACS,

fluorescence-activated cell sorting; Fn, fibronectin; GDF15, growth Vildagliptin differentiation factor 15; HCC, hepatocellular carcinoma; MOI, multiplicity of infection; PARP, nuclear enzyme poly(ADP-ribose) polymerase; PCNA, proliferating cell nuclear antigen; PCR, polymerase chain reaction; PI, propidium iodide; PPARγ, peroxisome proliferator-activated receptor gamma; PTEN, phosphatase and tensin homolog; TBXA2R, thromboxane A2 receptor; TNF, tumor necrosis factor; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; WT, wild-type. All homozygous PPARγ knockout animals were embryonically lethal due to placental dysfunction. We therefore used PPARγ heterozygous-deficient mice (PPARγ+/−) in this study. PPARγ-deficient (PPARγ+/−) mice were kindly supplied by Professor Frank J. Gonzalez (Center for Cancer Research, National Cancer Institute, Bethesda, MD). The generation of the transgenic mice was described previously.