Subcellular Mislocalization of Mutant Hepatitis B X Proteins Contributes to Modulation of STAT/SOCS Signaling in Hepatocellular Carcinoma
Subcellular Mislocalization of Mutant Hepatitis B X Proteins Contributes to Modulation of STAT/SOCS Signaling in Hepatocellular Carcinoma
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DOI：
10.1159/000209672
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发表时间：
2008-01-01
期刊：
影响因子：
4.6
通讯作者：
Torresi, Joseph
中科院分区：
文献类型：
--
作者：
Bock, C. Thomas;Toan, Nguyen L.;Torresi, Joseph
目的：乙型肝炎病毒X（HBx）蛋白在肝细胞癌（HCC）的发病机制中发挥重要作用。 HBx 导致肝癌的一种潜在机制可能涉及细胞内分布以及通过上调 STAT3 连续调节增殖性重要 STAT/SOCS 信号传导。方法：对 153 名越南 HBV 感染患者（其中 48 名 HCC 患者）进行分析。通过测序确定 HBx 序列并亚克隆用于功能实验。通过免疫荧光测定确定 HBx 突变体的细胞内定位。使用蛋白质印迹和 PCR 分析研究了 HBx 突变体对 JAK/STAT/SOCS 信号传导的影响。结果：在 4/48 例 HCC 患者中，观察到截短的 HBx 以及全长突变的 HBx 蛋白。 HBx 突变蛋白的表达表现出非典型的核和核周定位。确定 HBx 突变体对 STAT/SOCS 信号传导影响的功能实验表明，与野生型 (wt)-HBx 相比，STAT3 激活的上调显着增加 (p > 0.001)。 STAT1 不被 wt-HBx 或 HBx 突变体激活。有趣的是，wt-HBx 和 HBx 突变体不激活 SOCS1 和 SOCS3 表达。结论：我们的结果表明，HBx 突变体的非典型核/核周定位可能是导致 STAT3 激活增强、STAT1 抑制和 SOCS1/SOCS3 表达沉默的原因。这一观察结果表明 HBx 突变体在肝癌发生中发挥积极作用，涉及 STAT/SOCS 信号传导失调。版权所有 (C) 2009 S. Karger AG，巴塞尔
Objective: The hepatitis B virus X (HBx) protein plays an important role in the pathogenesis of hepatocellular carcinoma (HCC). One potential mechanism by which HBx can cause liver cancer may involve intracellular distribution and consecutively modulation of the proliferative important STAT/SOCS signaling with upregulation of STAT3. Methods: 153 Vietnamese HBV-infected patients, including 48 patients with HCC, were analyzed. HBx sequences were determined by sequencing and subcloned for functional experiments. Intracellular localization of HBx mutants was determined by immunofluorescence assays. The impact of HBx mutants on JAK/STAT/SOCS signaling was investigated using Western blot and PCR analyses. Results: In 4/48 HCC patients, truncated HBx together with full-length mutated HBx proteins were observed. Expression of HBx mutant proteins demonstrated an atypical nuclear and perinuclear localization. Functional experiments to determine the effect of HBx mutants on STAT/SOCS signaling demonstrated a significantly increased upregulation of STAT3 activation (p > 0.001) in comparison to wild-type (wt)-HBx. STAT1 was not activated either by wt-HBx or HBx mutants. Interestingly, SOCS1 and SOCS3 expression was not activated by wt-HBx and HBx mutants. Conclusions: Our results suggest that atypical nuclear/perinuclear localization of HBx mutants might be responsible for an enhanced activation of STAT3, inhibition of STAT1 and silencing of SOCS1/SOCS3 expression. This observation points to an active role of HBx mutants in hepatocarcinogenesis that involves dysregulation of STAT/SOCS signaling. Copyright (C) 2009 S. Karger AG, Basel