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Overexpression of Jab1 in Hepatocellular Carcinoma and Its Inhibition by Peroxisome Proliferator-Activated Receptor Ligands In vitro and In vivo

Authors' Affiliations: ¹ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University; ² Department of Pathology, and ³ Division of Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center; ⁴ Institute of Biomedical Sciences, National Sun Yat-Sen University; ⁵ Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan, Taiwan; and ⁶ National Sun Yat-Sen University-Kaohsiung Medical University Joint Research Center, Taiwan, People's Republic of China

Requests for reprints: Wen-Chun Hung, Institute of Biomedical Sciences, National Sun Yat-Sen University, No. 70, Lien-Hai Road, Kaohsiung 804, Taiwan, People's Republic of China. Phone: 886-7-5252000, ext. 5817; Fax: 886-7-2259573; E-mail: hung1228{at}ms10.hinet.net.

Purpose: Jun activation domain-binding protein 1 (Jab1) is the fifth subunit of the COP9 signalosome and exhibits oncogenic activity. We investigated Jab1 expression in hepatocellular carcinoma (HCC) tissues and cell lines and tested the effect of peroxisome proliferator-activated receptor (PPAR) ligands on Jab1 expression.

Experimental Design: Jab1 expression in HCC tissues and cell lines was studied by real-time reverse transcription-PCR, immunohistochemical staining, and Western blotting. Promoter activity and chromatin immunoprecipitation assays were done to address the inhibition of Jab1 promoter by PPAR ligands. RNA interference was used to clarify PPAR ligand-induced inhibition of Jab1. Anticancer and Jab1-suppressing activity of PPAR ligands was tested in nude mice.

Results: Jab1 was detected in the nucleus and cytoplasm of HCC tissues and 37% (37 of 99) of tissues exhibited Jab1 overexpression. Jab1 expression correlated with sex and hepatitis C virus infection, whereas it was negatively associated with hepatitis B virus infection. Additionally, Jab1 was overexpressed in HCC cell lines. PPAR ligands troglitazone and rosiglitazone down-regulated Jab1 expression in HCC cells, and troglitazone directly suppressed Jab1 promoter activity by inhibiting Sp1- and Tcf4-mediated transcription. This suppression was mediated via both PPAR-dependent and PPAR-independent mechanisms. Ectopic expression of Jab1 counteracted troglitazone-induced growth inhibition. Animal studies verified that intratumor or i.p. injection of troglitazone attenuated HCC growth and reduced Jab1 expression in tumor tissues.

Conclusions: Our results indicate that Jab1 is overexpressed in HCC and PPAR ligands may suppress Jab1 to inhibit the proliferation of HCC cells.