Autotaxin expression and its connection with the TNF-alpha-NF-kappaB axis in human hepatocellular carcinoma.
Autotaxin expression and its connection with the TNF-alpha-NF-kappaB axis in human hepatocellular carcinoma.
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DOI：
10.1186/1476-4598-9-71
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发表时间：
2010-03-31
期刊：
影响因子：
37.3
通讯作者：
Maluccio MA
中科院分区：
文献类型：
--
作者：
Wu JM;Xu Y;Skill NJ;Sheng H;Zhao Z;Yu M;Saxena R;Maluccio MA
自分泌运动因子（ATX）是一种细胞外溶血磷脂酶D，其从溶血磷脂酰胆碱（LPC）产生溶血磷脂酸（LPA）。ATX和LPA都被证明与许多癌症有关。然而，ATX的功能作用和ATX在人肝细胞癌（HCC）中的表达调控仍然是难以捉摸的。在这项研究中，ATX的表达进行了评估，从38人肝癌和10个正常对照组的组织。ATX主要在组织切片内的肿瘤细胞中检测到，并且其在HCC中的过表达与炎症和肝硬化特异性相关。此外，在正常人肝细胞和肝癌细胞系中检查ATX表达。肝癌细胞Hep 3B和Huh 7的ATX表达强于肝母细胞瘤细胞HepG 2和正常肝细胞。促炎细胞因子肿瘤坏死因子α（TNF-α）选择性地促进Hep 3B和Huh 7细胞中ATX的表达和分泌，这导致溶血磷脂酶D活性相应增加。此外，我们还探讨了ATX在肝癌细胞中表达的调控机制，并确定了核因子-κ B（NF-κB）在基础和TNF-α诱导的ATX表达中的关键作用。进一步的研究表明，分泌的具有酶活性的ATX刺激Hep 3B细胞的侵袭。本报告首次强调了ATX参与人类HCC的临床和生物学证据。TNF-α/NF-κB轴与ATX-LPA信号通路的相互作用提示ATX可能在炎症相关的肝肿瘤发生中起重要作用。
Autotaxin (ATX) is an extracellular lysophospholipase D that generates lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). Both ATX and LPA have been shown to be involved in many cancers. However, the functional role of ATX and the regulation of ATX expression in human hepatocellular carcinoma (HCC) remain elusive. In this study, ATX expression was evaluated in tissues from 38 human HCC and 10 normal control subjects. ATX was detected mainly in tumor cells within tissue sections and its over-expression in HCC was specifically correlated with inflammation and liver cirrhosis. In addition, ATX expression was examined in normal human hepatocytes and liver cancer cell lines. Hepatoma Hep3B and Huh7 cells displayed stronger ATX expression than hepatoblastoma HepG2 cells and normal hepatocytes did. Proinflammtory cytokine tumor necrosis factor alpha (TNF-α) promoted ATX expression and secretion selectively in Hep3B and Huh7 cells, which led to a corresponding increase in lysophospholipase-D activity. Moreover, we explored the mechanism governing the expression of ATX in hepatoma cells and established a critical role of nuclear factor-kappa B (NF-κB) in basal and TNF-α induced ATX expression. Further study showed that secreted enzymatically active ATX stimulated Hep3B cell invasion. This report highlights for the first time the clinical and biological evidence for the involvement of ATX in human HCC. Our observation that links the TNF-α/NF-κB axis and the ATX-LPA signaling pathway suggests that ATX is likely playing an important role in inflammation related liver tumorigenesis.
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