Evaluation of nuclear factor-κB, urokinase-type plasminogen activator, and HBx and their clinicopathological significance in hepatocellular carcinoma
Evaluation of nuclear factor-κB, urokinase-type plasminogen activator, and HBx and their clinicopathological significance in hepatocellular carcinoma
复制标题
DOI：
10.1158/1078-0432.ccr-03-0574
复制
发表时间：
2004-06-15
影响因子：
11.5
通讯作者：
Ng, IOL
中科院分区：
文献类型：
--
作者：
Chan, CF;Yau, TO;Ng, IOL
目的：核因子kappaB（NF-kappaB）信号通路是人类疾病和癌症的重要调节通路。其下游靶基因之一是尿激酶纤溶酶原激活剂（uPA），参与癌症侵袭和转移。本研究的目的是评估人肝细胞癌 (HCC) 中 NF-kappaB 激活、uPA 上调和乙型肝炎病毒 X 蛋白 (HBx) 表达，并评估其临床病理学意义。 实验设计：我们评估了 32 例人类 HCC 中 NF-kappaB 激活、uPA 表达和 HBx 的存在。通过与临床病理学特征的相关性来评估它们的临床病理学意义。还在体外分析了 HBx 介导的异常 NF-kappaB 信号通路和 uPA 上调。结果：我们发现在 HCC 中经常观察到 NF-kappaB 激活和 uPA 上调（分别为 56% 和 59%），特别是在 HBx 阳性 HCC 中。 NF-κB 激活和 uPA 过表达彼此密切相关 (P < 0.0001)。此外，NF-κB 的激活和 uPA 的上调均与静脉侵袭、直接肝脏侵袭和肿瘤包膜缺失等更具侵袭性的肿瘤行为显着相关。在体外，HBx 转染 HepG2 细胞，通过核因子 kappaB 激酶 β (IKKbeta) 抑制剂诱导 NF-kappaB 激活。 HBx 还与 IKKbeta 协同上调 uPA 并增强细胞侵袭。结论：数据表明 NF-kappaB 失调和 uPA 过度表达可能导致 HCC 中更具侵袭性的肿瘤行为。此外，我们的数据表明 IKKbeta 在 HBx 激活的 NF-kappaB 信号通路中发挥着关键作用。
Purpose: Nuclear factor kappaB (NF-kappaB) signaling pathway is an important regulating pathway in human diseases and cancers. One of its downstream target genes is urokinase plasminogen activator (uPA), which is involved in cancer invasion and metastasis. The purpose of this study was to evaluate NF-kappaB activation, uPA up-regulation, and hepatitis B viral X protein (HBx) expression in human hepatocellular carcinoma (HCC) and to assess their clinicopathological significance.Experimental Design: We evaluated NF-kappaB activation, expression of uPA, and presence of HBx in 32 human HCCs. Their clinicopathological significance was assessed by correlation with the clinicopathological features. Aberrant NF-kappaB signaling pathway and uPA up-regulation mediated by HBx were also analyzed in vitro.Results: We found that NF-kappaB activation and uPA up-regulation were frequently (56% and 59%, respectively) observed in HCCs, and particularly in HBx-positive HCCs. NF-kappaB activation and uPA overexpression were closely associated with one another (P < 0.0001). Furthermore, both activation of NF-kappaB and up-regulation of uPA were significantly associated with a more aggressive tumor behavior in terms of venous invasion, direct liver invasion, and absence of tumor encapsulation. In vitro, NF-kappaB activation was induced by HBx transfection in HepG2 cells through inhibitor of nuclear factor-kappaB kinase beta (IKKbeta). HBx also up-regulated uPA and enhanced cell invasion synergistically with IKKbeta.Conclusions: The data indicate that NF-kappaB dysregulation and uPA overexpression may lead to a more aggressive tumor behavior in HCC. In addition, our data suggest that IKKbeta plays a critical role in the HBx-activated NF-kappaB signaling pathway.