Abstract

Previous reports from these authors found that activation of peroxisome proliferator-activated receptor gamma (PPAR?) suppressed hepatocellular carcinoma (HCC). This study sought to identify the molecular target of PPAR? and characterize its antitumor effect in HCC.Optimal PPAR? binding activity was obtained using the PPAR? agonist rosiglitazone (100 µM) as determined by enzyme-linked immunosorbent assay. Under PPAR? activation, 114 PPAR? downstream targets associated with cancer development were identified by oligonucleotide microarray and Gene Ontology analysis. Among them, Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 2 (CITED2) was the most prominent PPAR?-bound target, as determined by chromatin immunoprecipitation-polymerase chain reaction.CITED2 messenger RNA and protein was significantly down-regulated in primary HCCs compared with their adjacent nontumor tissues. PPAR? induced expression of CITED2 in HCC cell lines after adenovirus-PPAR? transduction. The biological function of CITED2 was evaluated by loss- and gain-of-function assays. CITED2 knockdown in the hepatocyte cell line LO2 and HCC cell line Hep3B significantly increased cell viability and clonogenicity, and promoted G1 -S phase transition in both cell lines. In contrast, ectopic expression of CITED2 in HepG2 and BEL7404 HCC cell lines significantly suppressed cell growth. The tumor suppressive effect of CITED2 was associated with up-regulation of cyclin-dependent kinase inhibitors p15(INK4B) , p21(Wat1/Cip1) , p27(Kip1) , antiproliferative regulator interferon alpha 1, proapoptotic mediators including tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), TNFRSF25, caspase-8, granzyme A, and the tumor suppressor gene maspin. CITED2 was also associated with the down-regulation of cell cycle regulator cyclin D1, oncogene telomerase reverse transcriptase, and proinvasion/metastasis gene matrix metallopeptidase 2.CITED2 is a direct effector of PPAR? for tumor suppression. Cancer 2013. © 2012 American Cancer Society.

View details for DOI 10.1002/cncr.27865

View details for Web of Science ID 000315696600016

View details for PubMedID 23212831