Cytosolic phospholipase A2alpha and peroxisome proliferator-activated receptor gamma signaling pathway counteracts transforming growth factor beta-mediated inhibition of primary and transformed hepatocyte growth.
Cytosolic phospholipase A2alpha and peroxisome proliferator-activated receptor gamma signaling pathway counteracts transforming growth factor beta-mediated inhibition of primary and transformed hepatocyte growth.
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DOI：
10.1002/hep.23703
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发表时间：
2010-08
期刊：
影响因子：
13.5
通讯作者：
Wu, Tong
中科院分区：
文献类型：
--
作者：
Han, Chang;Bowen, William C.;Li, Guiying;Demetris, Anthony J.;Michalopoulos, George K.;Wu, Tong
肝细胞癌通常在与慢性肝炎和肝硬化相关的肝细胞异常生长的情况下发生。转化生长因子-βs（Transforming growth factor-β s，TGF-βs）是一种多功能的细胞因子，在调节肝细胞生长、分化、迁移、细胞外基质生成、干细胞稳态和肝癌发生中起关键作用。然而，TGF-β影响肝细胞功能的机制仍不完全确定。我们在此报道，TGF-β通过同时激活Smad和磷酸化cPLA 2 α（一种释放花生四烯酸以产生生物活性类花生酸的限速关键酶）来调节原代和转化肝细胞的生长。在大鼠原代肝细胞、人肝癌细胞和新开发的cPLA 2 α转基因小鼠的肝细胞中检测TGF-β和cPLA 2 α信号通路之间的相互作用。我们的数据表明，cPLA 2 α激活PPAR-γ，从而抵消Smad 2/3介导的细胞生长抑制。因此，cPLA 2 α和PPAR-γ对TGF-β信号通路的调节可能是控制肝细胞生长和肝癌发生的重要机制。
Hepatocellular carcinoma often develops in the setting of abnormal hepatocyte growth associated with chronic hepatitis and liver cirrhosis. Transforming growth factor-βs (TGF-βs) are multifunctional cytokines pivotal in the regulation of hepatic cell growth, differentiation, migration, extracellular matrix production, stem cell homeostasis and hepatocarcinogenesis. However, the mechanisms by which TGF-βs influence hepatic cell functions remain incompletely defined. We report herein that TGF-β regulates the growth of primary and transformed hepatocytes through concurrent activation of Smad and phosphorylation of cPLA2α, a rate-limiting key enzyme that releases arachidonic acid for production of bioactive eicosanoids. The interplays between TGF-β and cPLA2α signaling pathways were examined in rat primary hepatocytes, human hepatocellular carcinoma cells and hepatocytes isolated from the newly developed cPLA2α transgenic mice. Our data show that cPLA2α activates PPAR-γ and thus counteracts Smad2/3-mediated inhibition of cell growth. Therefore, regulation of TGF-β signaling by cPLA2α and PPAR-γ may represent an important mechanism for control of hepatic cell growth and hepatocarcinogenesis.
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影响因子：
8
作者：
Lin, L.;Amin, R.;Gallicano, G. I.;Glasgow, E.;Jogunoori, W.;Jessup, J. M.;Zasloff, M.;Marshall, J. L.;Shetty, K.;Johnson, L.;Mishra, L.;He, A. R.
通讯作者：
He, A. R.
DOI：
10.1073/pnas.93.12.5877
发表时间：
1996-06-11
影响因子：
11.1
作者：
Bottinger, EP;Factor, VM;Sporn, MB
通讯作者：
Sporn, MB
影响因子：
8
作者：
Romero-Gallo, J;Sozmen, EG;Grady, WM
通讯作者：
Grady, WM
影响因子：
13.5
作者：
BEDOSSA, P;PELTIER, E;POYNARD, T
通讯作者：
POYNARD, T
影响因子：
8
作者：
Kanzler, S;Meyer, E;Blessing, M
通讯作者：
Blessing, M