Overexpression of Jab1 in hepatocellular carcinoma and its inhibition by peroxisome proliferator-activated receptorγ ligands in vitro and in vivo
Overexpression of Jab1 in hepatocellular carcinoma and its inhibition by peroxisome proliferator-activated receptorγ ligands in vitro and in vivo
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DOI：
10.1158/1078-0432.ccr-07-5040
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发表时间：
2008-07-01
影响因子：
11.5
通讯作者：
Hung, Wen-Chun
中科院分区：
文献类型：
--
作者：
Hsu, Ming-Chuan;Huang, Chao-Cheng;Hung, Wen-Chun
Jun激活结构域结合蛋白1（Jun activation domain-binding protein 1，Jab 1）是COP 9信号体的第五个亚基，具有致癌活性。我们研究了Jab 1在肝细胞癌（HCC）组织和细胞系中的表达，并测试了过氧化物酶体增殖物激活受体γ（PPAR γ）配体对Jab 1 expression.Experimental Design的影响：Jab 1在HCC组织和细胞系中的表达进行了研究，通过实时逆转录-PCR，免疫组化染色和Western印迹。启动子活性和染色质免疫沉淀分析进行，以解决Jab 1启动子的抑制PPAR γ配体。使用RNA干扰来阐明PPAR γ配体诱导的Jab 1抑制。结果：在肝癌组织中，Jab 1主要分布于细胞核和细胞浆中，有37%（37/99）的肝癌组织中Jab 1过表达，Jab 1的表达与性别、丙型肝炎病毒感染有关，而与B型肝炎病毒感染呈负相关。此外，Jab 1在HCC细胞系中过表达。PPAR γ配体曲格列酮和罗格列酮下调HCC细胞中Jab 1的表达，曲格列酮通过抑制Sp1和Tcf 4介导的转录直接抑制Jab 1启动子活性。这种抑制是通过两个PPAR γ依赖性和非依赖性机制介导的。Jab 1的异位表达抵消了曲格列酮诱导的生长抑制。动物实验证实，瘤内或腹腔注射曲格列酮减弱肝癌的生长和减少Jab 1在肿瘤tissues.Conclusions表达：我们的研究结果表明，Jab 1是过度表达在肝癌和PPAR γ配体可能会抑制Jab 1抑制肝癌细胞的增殖。
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 gamma (PPAR gamma) 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 gamma ligands. RNA interference was used to clarify PPAR gamma ligand-induced inhibition of Jab1. Anticancer and Jab1-suppressing activity of PPAR gamma 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 gamma 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 gamma-dependent and PPAR gamma-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 gamma ligands may suppress Jab1 to inhibit the proliferation of HCC cells.