DDX3, a DEAD box RNA helicase, is deregulated in hepatitis virus-associated hepatocellular carcinoma and is involved in cell growth control
DDX3, a DEAD box RNA helicase, is deregulated in hepatitis virus-associated hepatocellular carcinoma and is involved in cell growth control
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DOI：
10.1038/sj.onc.1209239
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发表时间：
2006-03-01
期刊：
影响因子：
8
通讯作者：
Lee, YHW
中科院分区：
文献类型：
--
作者：
Chang, PC;Chi, CW;Lee, YHW
肝细胞癌（HCC）是世界范围内癌症死亡的主要原因之一，与肝炎病毒感染高度相关。我们以前的报告表明，一个死亡盒RNA解旋酶，DDX 3，是针对和丙型肝炎病毒（HCV）的核心蛋白，这暗示DDX 3参与HCV相关的肝癌的发展。在这项研究中，DDX 3在肝癌发生中的潜在作用是通过检查其在手术切除的人HCC标本中的表达来研究的。在这里，我们报告的差异失调DDX 3表达肝炎病毒相关的肝癌。在B型肝炎病毒（HBV）阳性的HCC中发现DDX 3表达显著下调，而在HCV阳性的HCC中没有发现。DDX 3的表达受性别的差异调节，而且，有一种趋势，即肝癌中DDX 3表达的下调在男性中比在女性中更频繁。在未转化的小鼠成纤维细胞系NIH-3 T3中，用小干扰RNA（siRNA）基因敲低DDX 3，导致过早进入S期并增强细胞生长。这种增强的细胞周期进程与DDX 3敲低细胞中细胞周期蛋白D1的上调和p21（WAF 1）的下调有关。此外，DDX 3表达的组成性减少增加了NIH-3 T3细胞对血清耗竭诱导的凋亡的抵抗力，并增强了ras诱导的锚定非依赖性生长，表明DDX 3参与细胞生长控制。这些研究结果与以前的研究表明，DDX 3的失调，与细胞生长调节功能的DEAD盒RNA解旋酶，参与HBV和HCV相关的发病机制。
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide and is highly correlated with hepatitis virus infection. Our previous report shows that a DEAD box RNA helicase, DDX3, is targeted and regulated by hepatitis C virus (HCV) core protein, which implicates the involvement of DDX3 in HCV-related HCC development. In this study, the potential role of DDX3 in hepatocarcinogenesis is investigated by examining its expression in surgically excised human HCC specimens. Here we report the differential deregulation of DDX3 expression in hepatitis virus-associated HCC. A significant downregulation of DDX3 expression is found in HCCs from hepatitis B virus (HBV)-positive patients, but not from HCV-positive ones, compared to the corresponding nontumor tissues. The expression of DDX3 is differentially regulated by the gender and, moreover, there is a tendency that the downregulation of DDX3 expression in HCCs is more frequent in males than in females. Genetic knockdown of DDX3 with small interfering RNAs (siRNA) in a nontransformed mouse fibroblast cell line, NIH-3T3, results in a premature entry to S phase and an enhancement of cell growth. This enhanced cell cycle progression is linked to the upregulation of cyclin D1 and the downregulation of p21(WAF1) in the DDX3 knockdown cells. In addition, constitutive reduction of DDX3 expression increases the resistance of NIH-3T3 cells to serum depletion-induced apoptosis and enhances the ras-induced anchorage-independent growth, indicating the involvement of DDX3 in cell growth control. These findings together with the previous study suggest that the deregulation of DDX3, a DEAD box RNA helicase with cell growth-regulatory functions, is involved in HBV- and HCV-associated pathogenesis.