HBx mutations promote hepatoma cell migration through the Wnt/β-catenin signaling pathway.
HBx mutations promote hepatoma cell migration through the Wnt/β-catenin signaling pathway.
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HBx突变通过Wnt/-catenin信号通路促进肝癌细胞迁移
DOI：
10.1111/cas.13014
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发表时间：
2016-10
期刊：
影响因子：
5.7
通讯作者：
Tang N
中科院分区：
文献类型：
--
作者：
Chen Z;Tang J;Cai X;Huang Y;Gao Q;Liang L;Tian L;Yang Y;Zheng Y;Hu Y;Tang N
HBx突变（T1753 V、A1762 T、G1764 A和T1768 A）常见于B型肝炎病毒（HBV）相关肝细胞癌（HCC）。Wnt/β-catenin信号通路的异常激活参与HCC的发展。然而，尚未在肝癌细胞或HBV相关HCC样本中研究HBx突变体对Wnt/β-连环蛋白信号通路的激活。在这项研究中，我们检测了HBx突变体对HCC细胞迁移和增殖的影响，并评估了HBx转染的HCC细胞和HBV相关HCC组织中Wnt/β-catenin信号的激活。我们发现HBx突变体（T、A、TA和Combo）促进肝癌细胞的迁移和增殖。HBx Combo突变体增强了TOP‐luc活性，并增加了β-连环蛋白的核转位。此外，HBx Combo突变体通过糖原合成酶激酶-3 β的失活来增加并稳定β-连环蛋白水平，从而导致下游靶基因（例如c-Myc、CTGF和WISP 2）上调。在具有HBx TA和Combo突变的HCC组织中发现Wnt/β-catenin活化增强。β-连环蛋白的敲低有效地消除了由HBx TA和Combo突变体刺激的细胞迁移和增殖。我们的研究结果表明，HBx突变体，特别是Combo突变体，允许Wnt信号通路的组成性激活，并可能在HBV相关肝癌发生中发挥关键作用。
HBx mutations (T1753V, A1762T, G1764A, and T1768A) are frequently observed in hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC). Aberrant activation of the Wnt/β‐catenin signaling pathway is involved in the development of HCC. However, activation of the Wnt/β‐catenin signaling pathway by HBx mutants has not been studied in hepatoma cells or HBV‐associated HCC samples. In this study, we examined the effects of HBx mutants on the migration and proliferation of HCC cells and evaluated the activation of Wnt/β‐catenin signaling in HBx‐transfected HCC cells and HBV‐related HCC tissues. We found that HBx mutants (T, A, TA, and Combo) promoted the migration and proliferation of hepatoma cells. The HBx Combo mutant potentiated TOP‐luc activity and increased nuclear translocation of β‐catenin. Moreover, the HBx Combo mutant increased and stabilized β‐catenin levels through inactivation of glycogen synthase kinase‐3β, resulting in upregulation of downstream target genes such as c‐Myc,CTGF, and WISP2. Enhanced activation of Wnt/β‐catenin was found in HCC tissues with HBx TA and Combo mutations. Knockdown of β‐catenin effectively abrogated cell migration and proliferation stimulated by the HBx TA and Combo mutants. Our results indicate that HBx mutants, especially the Combo mutant, allow constitutive activation of the Wnt signaling pathway and may play a pivotal role in HBV‐associated hepatocarcinogenesis.
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影响因子：
4.5
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
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发表时间：
2013-05-22
期刊：
Viruses
影响因子：
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作者：
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通讯作者：
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影响因子：
56.9
作者：
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Kinzler, KW