Hepatitis B virus core promoter mutations contribute to hepatocarcinogenesis by deregulating SKP2 and its target, p21.
Hepatitis B virus core promoter mutations contribute to hepatocarcinogenesis by deregulating SKP2 and its target, p21.
复制标题
DOI：
10.1053/j.gastro.2011.06.048
复制
发表时间：
2011-10
期刊：
影响因子：
29.4
通讯作者：
Lok AS
中科院分区：
文献类型：
--
作者：
Huang Y;Tong S;Tai AW;Hussain M;Lok AS
临床研究表明乙型肝炎病毒（HBV）核心启动子（CP）突变与肝细胞癌（HCC）风险增加有关。CP区域与HBV x （HBx）基因重叠，该基因与肝癌的发生有关。细胞周期蛋白激酶抑制剂p21WAF1/CIP1是细胞周期进程和增殖的重要调节因子。我们确定了由CP突变引起的HBx突变是否解除了p21和这些过程的调控。我们构建了一系列与A1762T/G1764A （TA）、T1753A、T1768A或它们的组合（combo）对应的CP区域发生变化的HBx突变体，并在内源性启动子的控制下，在原代人肝细胞（PHH）和HepG2细胞中与野生型HBx一起表达。然后，我们分析了CP突变对p21表达和降解的影响，以及对细胞周期进程和增殖的影响。组合突变体降低了PHH和HepG2细胞中p21的水平，增加了cyclin E的表达。组合突变体加速了HepG2细胞中p21的降解，而单或双CP突变的HBx则没有。组合突变体增加了PHH和Huh7细胞中s期激酶相关蛋白2 （SKP2）的表达。SKP2的沉默消除了CP突变对p21表达的影响。p21的表达动力学与细胞周期分布的变化相关。组合突变体加速细胞周期进程；p21过表达恢复G1阻滞。具有CP突变组合的HBx突变上调SKP2，进而通过泛素介导的蛋白酶体降解下调p21。CP突变可能通过这一途径增加HCC的风险。
Clinical studies have associated hepatitis B virus (HBV) core promoter (CP) mutations with an increased risk of hepatocellular carcinoma (HCC). The CP region overlaps with the HBV × (HBx) gene, which has been implicated in hepatocarcinogenesis. The cyclin kinase inhibitor p21WAF1/CIP1 is an important regulator of cell cycle progression and proliferation. We determined whether HBx mutants that result from mutations in the CP deregulate p21 and these processes. We constructed a series of HBx mutants with changes in the CP region that correspond to A1762T/G1764A (TA), T1753A, T1768A, or a combination of these (combo) and expressed them, along with wild-type HBx under control of its endogenous promoter, in primary human hepatocytes (PHH) and HepG2 cells. We then analyzed the effects of CP mutations on expression and degradation of p21 and the effects on cell cycle progression and proliferation. The combo mutant decreased levels of p21 and increased cyclin E expression in PHH and HepG2 cells. The combo mutant, but not HBx with single or double CP mutations, accelerated p21 degradation in HepG2 cells. The combo mutant increased expression of S-phase kinase-associated protein 2 (SKP2) in PHH and Huh7 cells. Silencing of SKP2 abrogated the effects of CP mutations on p21 expression. The kinetics of p21 expression correlated with changes in cell cycle distribution. The combo mutant accelerated cell cycle progression; p21 overexpression restored G1 arrest. HBx mutants with changes that correspond to a combination of CP mutations upregulate SKP2, which then down-regulates p21 via ubiquitin-mediated proteasomal degradation. CP mutations might increase the risk for HCC via this pathway.
登录
查看更多内容
影响因子：
120.7
作者：
Chen, CJ;Yang, HI;Iloeje, UH
通讯作者：
Iloeje, UH
影响因子：
13.5
作者：
Chu, CJ;Keeffe, EB;Lok, ASF
通讯作者：
Lok, ASF
影响因子：
37.3
作者：
Charette N;De Saeger C;Lannoy V;Horsmans Y;Leclercq I;Stärkel P
通讯作者：
Stärkel P
影响因子：
4.8
作者：
Krude, T
通讯作者：
Krude, T
影响因子：
5.4
作者：
Buckwold, VE;Xu, ZC;Ou, JH
通讯作者：
Ou, JH