Hepatitis B virus X protein inhibits p53-mediated upregulation of mitofusin-2 in hepatocellular carcinoma cells.
Hepatitis B virus X protein inhibits p53-mediated upregulation of mitofusin-2 in hepatocellular carcinoma cells.
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DOI：
10.1016/j.bbrc.2012.04.015
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发表时间：
2012-05
影响因子：
3.1
通讯作者：
Weilin Wang;Dongkai Zhou;Jian-feng Wei;Zehui Wu;Xiao-xiao Cheng;Qiang Sun;Haiyang Xie;Lin Zhou;Shusen Zheng
中科院分区：
文献类型：
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作者：
Weilin Wang;Dongkai Zhou;Jian-feng Wei;Zehui Wu;Xiao-xiao Cheng;Qiang Sun;Haiyang Xie;Lin Zhou;Shusen Zheng
乙肝病毒X(HBX)蛋白在肝细胞癌中具有重要作用。我们先前的研究表明，肝细胞癌中潜在的抑癌基因Mfn2是P53的一个新的直接靶点，它通过线粒体凋亡途径发挥凋亡作用。然而，HBx和Mfn2在肝细胞癌发生发展过程中的表达之间的关系尚不清楚。我们发现HBx对未经阿霉素处理的肝癌细胞Mfn2或P53的表达几乎没有直接影响。Western Blot和Real-Time-PCR结果显示，同时用阿霉素或与p53共转染HBx的肝癌细胞中，HBx可抑制Mfn2的表达。通过凝胶迁移率改变分析，我们证实HBx干扰了P53蛋白的结合事件和Mfn2启动子的P53结合位点-寡核苷酸。此外，荧光素酶活性检测显示，HBx载体在阿霉素诱导的HepG2细胞中，Mfn2启动子的活性没有增加。这些结果表明，HBx影响P53介导的Mfn2转录，为深入了解HBx对P53依赖的化疗药物(如用于治疗肝癌的阿霉素)的负面影响提供了线索。
The hepatitis B virus X (HBx) protein has many significant roles in hepatocellular carcinoma (HCC). Our previous research demonstrated that mitofusion-2 (Mfn2), a potential tumor suppressor gene in HCC, is a novel direct target of p53 that exerts apoptotic effects via the mitochondrial apoptotic pathway. However, the relationship between HBx and Mfn2 expression in the development of HCC is unknown. We found that HBx had little direct effect on the expression of Mfn2 or p53 in HCC cells not treated with doxorubicin. However, HBx inhibited the upregulation of Mfn2 in HBx-transfected HCC cells simultaneously treated with doxorubicin or cotransfected with p53 plasmid, as evidenced by Western Blot and real-time PCR. Through electrophoretic mobility shift analysis, we confirmed that HBx interfered with the binding event of the p53 protein and the p53 binding site-oligo of the Mfn2 promoter. Moreover, luciferase assays revealed that the activity of the Mfn2 promoter did not increase when transfected with HBx plasmid in doxorubicin-treated HepG2 cells. These results indicate that HBx impacts p53-mediated transcription of Mfn2, providing insight into the negative effect of HBx against p53-dependent chemotherapeutic agents, such as doxorubicin, used in the treatment of HCC.