Wilms' tumor 1 gene modulates Fas-related death signals and anti-apoptotic functions in hepatocellular carcinoma.
Wilms' tumor 1 gene modulates Fas-related death signals and anti-apoptotic functions in hepatocellular carcinoma.
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Wilms 肿瘤 1 基因调节肝细胞癌中 Fas 相关的死亡信号和抗凋亡功能。
DOI：
10.1007/s00535-012-0708-7
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发表时间：
2013
期刊：
影响因子：
6.3
通讯作者：
Onji M.
中科院分区：
文献类型：
--
作者：
Uesugi K;Hiasa Y;Tokumoto Y;Mashiba T;Koizumi Y;Hirooka M;Abe M;Matsuura B;Onji M.
BackgroundThe Wilms' tumor 1（WT 1）基因在肝细胞癌（HCC）中过表达并上调肿瘤生长和致癌潜能，但其具体机制尚待阐明。MethodsWe鉴定了WT 1基因在体外对人肝癌细胞系的调控中所涉及的宿主基因，并进一步鉴定了与细胞凋亡相关的基因。此外，我们评估了40个肝癌和58个非肝癌的人肝样本收集在surgence.ResultsAnalysis的影响，小干扰RNA介导的敲低WT 1细胞凋亡的膜联蛋白V标记分析，和调制的caspase-3，-8和-9的活性，WT 1的基因的改变表明，WT 1具有抗凋亡的作用。我们鉴定了三个受WT 1调节的凋亡相关基因：细胞FLICE抑制蛋白（cFLIP）基因上调，Fas相关死亡结构域（FADD）和核因子κ B（NF-κB）下调。有趣的是，FADD或NF-κB的敲低导致WT 1的上调，并且cFLIP的表达与WT 1的表达平行变化。我们进一步评估了WT 1介导的HCC和非HCC人类肝脏样本中的基因改变。结论WT 1可调节cFLIP、FADD和NF-κB的表达，在肝癌中具有抗凋亡作用。WT 1的这种作用机制可能与HCC的肿瘤生长和致癌潜力有关。
BackgroundThe Wilms’ tumor 1 (WT1) gene is known to be overexpressed in hepatocellular carcinoma (HCC) and to upregulate tumor growth and oncogenic potential, although the detailed mechanisms remain to be elucidated.MethodsWe identified host genes involved in WT1 gene modulation of human liver cancer cell lines in vitro, and further characterized genes related to apoptosis. Moreover, we evaluated the alteration of genes by WT1 in 40 HCC and 58 non-HCC human liver samples collected at resection.ResultsAnalysis of the effect of small interfering RNAs-mediated knock-down of WT1 on apoptosis using an annexin V labeling assay, and on modulation of the activity of caspases-3, -8 and -9, indicated that WT1 has an anti-apoptotic role. We identified three apoptosis-related genes that were modulated by WT1; the cellular FLICE-inhibitory proteins (cFLIP) gene was upregulated, and Fas-associated death domain (FADD) and nuclear factor kappa B (NF-κB) were downregulated. Interestingly, knock-down of FADD or NF-κB resulted in the upregulation of WT1, and the expression of cFLIP changed in parallel with WT1 expression. We further evaluated WT1-mediated alteration of genes in HCC and non-HCC human liver samples. Both HCC and non-HCC tissues that expressed relatively high levels of WT1 showed cFLIP overexpression.ConclusionsWT1 modulates cFLIP, FADD and NF-κB, and has an anti-apoptotic role in HCC. This mechanism of action of WT1 could be related to the tumor growth and oncogenic potential of HCC.