Does the hepatitis B antigen HBx promote the appearance of liver cancer stem cells?
Does the hepatitis B antigen HBx promote the appearance of liver cancer stem cells?
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DOI：
10.1158/0008-5472.can-10-3951
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发表时间：
2011-05-15
期刊：
影响因子：
11.2
通讯作者：
Feitelson MA
中科院分区：
文献类型：
--
作者：
Arzumanyan A;Friedman T;Ng IO;Clayton MM;Lian Z;Feitelson MA
乙型肝炎病毒（HBV）是慢性肝病（CLD）和肝细胞癌（HCC）的主要病原体。 HBV 编码的 X 抗原、HBx 以及与干细胞自我更新有关的途径有助于导致 HCC，但尚不清楚 HBx 表达是否会促进“干细胞性”。因此，实验旨在检验 HBx 通过促进癌症干细胞 (CSC) 特有的特性来触发恶性转化的假设。为了检验这一假设，用 HBx 稳定转导 HepG2 细胞，然后分析“干性”的表型和分子特征。还通过对 HBV 感染患者的肝脏和肿瘤组织切片进行免疫组织化学染色来评估 HBx 和“干性”相关标记物之间的关系。结果表明，Oct-4、Nanog、Klf4、β-catenin 和 EpCAM 在体外和体内均被 HBx 激活。在感染患者的人类 HCC 细胞的细胞核中检测到 EpCAM。 HBx 通过激活 β-连环蛋白和 miR-181 的表观遗传上调来促进“干性”，这两者都针对 EpCAM。 HBx 表达也与 E-钙粘蛋白水平降低相关。此外，HBx 刺激细胞迁移、在软琼脂中生长以及球体形成。这项工作首次提出HBV促进HCC发病机制中的“干性”。 HBx 相关的多个“干性”标记表达上调支持了以下假设：HBx 至少部分通过促进作为 CSC 特征的基因表达的变化来促进肝癌发生。
Hepatitis B virus (HBV) is a major etiologic agent of chronic liver disease (CLD) and hepatocellular carcinoma (HCC). HBV encoded X antigen, HBx, and pathways implicated in the self-renewal of stem cells contribute to HCC, but it is not clear whether HBx expression promotes “stemness.” Thus, experiments were designed to test the hypothesis that HBx triggers malignant transformation by promoting properties that are characteristic of cancer stem cells (CSCs). To test this hypothesis, HepG2 cells were stably transduced with HBx and then assayed for phenotypic and molecular characteristics of “stemness.” The relationship between HBx and “stemness”-associated markers was also evaluated by immunohistochemical staining of liver and tumor tissue sections from HBV infected patients. The results showed that Oct-4, Nanog, Klf4, β-catenin and EpCAM were activated by HBx in vitro and in vivo. EpCAM was detected in the nuclei of human HCC cells from infected patients. HBx promotes “stemness” by activating β-catenin and epigenetic up-regulation of miR-181, both of which target EpCAM. HBx expression was also associated with depressed levels of E-cadherin. Moreover, HBx stimulated cell migration, growth in soft agar, and spheroid formation. This work is the first to propose that HBV promotes “stemness” in the pathogenesis of HCC. HBx associated up-regulated expression of multiple “stemness” markers support the hypothesis that HBx contributes to hepatocarcinogenesis, at least in part, by promoting changes in gene expression that are characteristics of CSCs.