Aspartyl-(asparaginyl)-β-hydroxylase regulates hepatocellular carcinoma invasiveness
Aspartyl-(asparaginyl)-β-hydroxylase regulates hepatocellular carcinoma invasiveness
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DOI：
10.1016/j.jhep.2006.01.038
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发表时间：
2006-05-01
影响因子：
25.7
通讯作者：
Wands, JR
中科院分区：
文献类型：
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作者：
de la Monte, SM;Tamaki, S;Wands, JR
背景/目标：我们测量了乙酰天冬酰胺基-β-羟化酶（AAH）基因在人肝细胞癌和周围的未参与的肝脏在mRNA和蛋白质水平的表达，并检查了这种enzyme.Methods的调节和功能：由于肝癌的生长是通过胰岛素受体底物，1型（IRS-1）的信号转导介导的，我们检查，如果AAH是胰岛素和IGF-1在肝癌细胞调控的下游基因。此外，在转基因（Tg）小鼠模型（其中人（h）IRS-1基因在肝脏中过表达）和体外模型（其中C末端截短显性阴性hIRS-1 cDNA（hIRS-Delta C）在FOCUS HCC细胞中过表达）中检查了IRS-1对AAH的调节。结果：胰岛素和IGF-1刺激可增加FOCUS和Hep-G2细胞中AAH mRNA和蛋白的表达及运动能力。这些作用是通过Erk MAPK和PI 3激酶-Akt途径介导的。hIRS-1的过表达导致Tg小鼠肝脏中高水平的AAH，而hIRS-Δ C的过表达降低了FOCUS细胞中AAH的表达、运动性和侵袭性。最后，AAH的过表达显着增加运动和侵袭HepG 2细胞，而siRNA抑制AAH的表达显着降低FOCUS cells.Conclusions的定向运动：结果表明，增强AAH基因的活性是一个共同的特点，人肝癌和生长因子信号通过IRS-1调节AAH的表达，并增加运动和肝癌细胞的侵袭。因此，AAH可能是体内调节肿瘤生长的重要靶点。(c)2006年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background/Aims: We measured aspartyl (asparaginyl)-beta-hydroxylase (AAH) gene expression in human hepatocelluar carcinoma and surrounding uninvolved liver at both the mRNA and protein level and examined the regulation and function of this enzyme.Methods: Since growth of HCC is mediated by signaling through the insulin-receptor substrate, type 1 (IRS-1), we examined-if AAH is a downstream gene regulated by insulin and IGF-1 in HCC cells. In addition, IRS-1 regulation of AAH was examined in a transgenic (Tg) mouse model in which the human (h) IRS-1 gene was over-expressed in the liver, and an in vitro model in which a C-terminus truncated dominant-negative hIRS-1 cDNA (hIRS-Delta C) was over-expressed in FOCUS HCC cells. The direct effects of AAH on motility and invasiveness were examined in AAH-transfected HepG2 cells.Results: Insulin and IGF-1 stimulation increased AAH mRNA and protein expression and motility in FOCUS and Hep-G2 cells. These effects were mediated by signaling through the Erk MAPK and PI3 kinase-Akt pathways. Overexpression of hIRS-1 resulted in high levels of AAH in Tg mouse livers, while over-expression of hIRS-Delta C reduced AAH expression, motility, and invasiveness in FOCUS cells. Finally, over-expression of AAH significantly increased motility and invasiveness in HepG2 cells, whereas siRNA inhibition of AAH expression significantly reduced directional motility in FOCUS cells.Conclusions: The results suggest that enhanced AAH gene activity is a common feature of human HCC and growth factor signaling through IRS-1 regulates AAH expression and increases motility and invasion of HCC cells. Therefore, AAH may represent an important target for regulating tumor growth in vivo. (c) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.