PPARgamma inhibits hepatocellular carcinoma metastases in vitro and in mice.
PPARgamma inhibits hepatocellular carcinoma metastases in vitro and in mice.
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DOI：
10.1038/bjc.2012.130
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发表时间：
2012-04-24
影响因子：
8.8
通讯作者：
Yu, J.
中科院分区：
文献类型：
--
作者：
Shen, B.;Chu, E. S. H.;Zhao, G.;Man, K.;Wu, C-W;Cheng, J. T. Y.;Li, G.;Nie, Y.;Lo, C. M.;Teoh, N.;Farrell, G. C.;Sung, J. J. Y.;Yu, J.
关键词：
我们先前已经证明了过氧化物酶体增殖物激活受体(PPARγ)的激活抑制了肝癌的发生。我们旨在研究PPARγ对肝细胞癌转移潜能的影响，并探讨其可能的机制。用表达PPARγ的重组腺病毒(Ad-PPARγ)或Ad-LacZ感染人肝癌细胞(MHCC97L、BEL-7404)，并用PPARγ激动剂罗格列酮处理。通过创伤愈合实验、体外Matrigel侵袭模型和小鼠原位肝肿瘤转移模型观察γ对细胞迁移和侵袭活性的影响。与对照组(Ad-LacZ)相比，经AdPPARγ、罗格列酮或AdPPARγ联合罗格列酮处理的肝癌细胞(MHCC97L、BEL-7404)均有明显的PPARγ表达。这种诱导明显抑制了肝癌细胞的迁移。此外，感染Ad-PPARγ或罗格列酮处理的MHCC97L和BEL-7404细胞的侵袭力显著降低，最高可达60%。Ad-PPARγ与罗格列酮联合应用具有相加效应。罗格列酮激活PPARγ可显著降低原位肝细胞癌小鼠模型肺转移的发生率和严重程度。PPARγ在肝癌中作用的关键机制包括上调细胞黏附基因、E-钙粘素和SYK(脾酪氨酸激酶)、细胞外基质调节因子金属蛋白酶组织抑制物3、肿瘤抑制基因视网膜母细胞瘤1，以及下调前转移基因MMP9、MMP13、HPSE和肝细胞生长因子。芯片聚合酶链式反应显示PPARγ对TIMP3、MMP9、MMP13和HPSE有直接的转录调控作用。过氧化物酶体增殖物激活受体-γ在体内外对肝癌的侵袭和转移潜能具有抑制作用，是预防和治疗肝癌转移的靶点。
We have previously demonstrated that peroxisome proliferator-activated receptor (PPARγ) activation inhibits hepatocarcinogenesis. We aim to investigate the effect of PPARγ on hepatocellular carcinoma (HCC) metastatic potential and explore its underlying mechanisms. Human HCC cells (MHCC97L, BEL-7404) were infected with adenovirus-expressing PPARγ (Ad-PPARγ) or Ad-lacZ and treated with or without PPARγ agonist (rosiglitazone). The effects of PPARγ on cell migration and invasive activity were determined by wound healing assay and Matrigel invasive model in vitro, and in an orthotopic liver tumour metastatic model in mice. Pronounced expression of PPARγ was demonstrated in HCC cells (MHCC97L, BEL-7404) treated with Ad-PPARγ, rosiglitazone or Ad-PPARγ plus rosiglitazone, compared with control (Ad-LacZ). Such induction markedly suppressed HCC cell migration. Moreover, the invasiveness of MHCC97L and BEL-7404 cells infected with Ad-PPARγ, or treated with rosiglitazone was significantly diminished up to 60%. Combination of Ad-PPARγ and rosiglitazone showed an additive effect. Activation of PPARγ by rosiglitazone significantly reduced the incidence and severity of lung metastasis in an orthotopic HCC mouse model. Key mechanisms underlying the effect of PPARγ in HCC include upregulation of cell adhesion genes, E-cadherin and SYK (spleen tyrosine kinase), extracellular matrix regulator tissue inhibitors of metalloproteinase (TIMP) 3, tumour suppressor gene retinoblastoma 1, and downregulation of pro-metastatic genes MMP9 (matrix metallopeptidase 9), MMP13, HPSE (heparanase), and Hepatocyte growth factor (HGF). Direct transcriptional regulation of TIMP3, MMP9, MMP13, and HPSE by PPARγ was shown by ChIP-PCR. Peroxisome proliferator-activated receptor-gamma exerts an inhibitory effect on the invasive and metastatic potential of HCC in vitro and in vivo, and is thus, a target for the prevention and treatment of HCC metastases.
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影响因子：
3.3
作者：
Kondratiev, Svetlana;Gnepp, Douglas R.;Laver, Nora V.
通讯作者：
Laver, Nora V.
影响因子：
13.5
作者：
Ding, Wei;You, Hanning;Dang, Hien;LeBlanc, Francis;Galicia, Vivian;Lu, Shelly C.;Stiles, Bangyan;Rountree, C. Bart
通讯作者：
Rountree, C. Bart
影响因子：
11.2
作者：
Bailet, Olivier;Fenouille, Nina;Tartare-Deckert, Sophie
通讯作者：
Tartare-Deckert, Sophie
DOI：
10.1002/hed.20322
发表时间：
2006-03-01
影响因子：
2.9
作者：
Luukkaa, M;Vihinen, P;Grénman, R
通讯作者：
Grénman, R
影响因子：
29.4
作者：
Bosch, FX;Ribes, J;Cléries, R
通讯作者：
Cléries, R