Regulation of hepatitis B virus replication by the phosphatidylinositol 3-kinase-Akt signal transduction pathway
Regulation of hepatitis B virus replication by the phosphatidylinositol 3-kinase-Akt signal transduction pathway
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DOI：
10.1128/jvi.00541-07
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发表时间：
2007-09-01
影响因子：
5.4
通讯作者：
Guo, Ju-Tao
中科院分区：
文献类型：
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作者：
Guo, Haitao;Zhou, Tianlun;Guo, Ju-Tao
磷脂酰肌醇3-激酶(PI3K)-蛋白激酶B(Akt)信号通路是主要的致癌途径之一，在包括肝细胞癌在内的多种人类肿瘤中被激活。它也可以被丙型肝炎病毒(丙型肝炎病毒)非结构蛋白5A(NS5A)激活。在目前的研究中，我们开始确定这一途径对乙肝病毒复制的调节作用。我们的结果表明，结构性活性Akt1的表达深刻地抑制了HBVRNA的转录，从而降低了HepG2细胞中的HBVDNA复制。这种对乙肝病毒基因转录的抑制显然是通过激活mTOR介导的，因为mTOR抑制剂雷帕霉素可以消除mTOR的激活。此外，用PI3K、Akt和mTOR抑制剂处理表达乙肝病毒的HepG2.2.15细胞，可增加3.5kb和2.4kb病毒RNA的转录和HBVDNA的复制。这一观察结果表明，该通路在HepG2细胞中的基础水平激活调节了乙肝病毒的复制。与以往报道的丙型肝炎病毒NS5A蛋白可以与PI3K的P85亚基结合并激活PI3K-Akt信号转导通路的结果一致，我们的结果表明该蛋白的表达可以抑制HBVRNA的转录，减少HBVDNA的复制。综上所述，我们的结果表明，PI3K-Akt通路在肝肿瘤发生过程中的激活可能至少部分地负责消除肿瘤细胞中的乙肝病毒复制，也可能为观察到的丙型肝炎病毒合并感染抑制乙肝病毒复制提供了一个解释。
The phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway is one of the major oncogenic pathways and is activated in many types of human cancers, including hepatocellular carcinoma. It can also be activated by the hepatitis C virus (HCV) nonstructurall 5A (NS5A) protein. In the present study, we set out to determine the regulatory effects of this pathway on the replication of hepatitis B virus (HBV). Our results demonstrate that the expression of a constitutively active Akt1 profoundly inhibited HBV RNA transcription and consequently reduced HBV DNA replication in HepG2 cells. This suppression of HBV gene transcription was apparently mediated by the activation of mTOR, as it was abolished by the mTOR inhibitor rapamycin. Moreover, treatment of HBV-expressing HepG2.2.15 cells with inhibitors of PI3K, Akt, and mTOR increased the transcription of 3.5-kb and 2.4-kb viral RNA as well as the replication of HBV DNA. This observation implies that the basal level activation of this pathway in HepG2 cells regulated HBV replication. Consistent with previous reports showing that the HCV NS5A protein could bind to the p85 subunit of PI3K and activate the PI3K-Akt signal transduction pathway, our results showed that expression of this protein could inhibit HBV RNA transcription and reduce HBV DNA replication in HepG2 cells. Taken together, our results suggest that the activation of the PI3K-Akt pathway during liver oncogenesis may be at least partially responsible for the elimination of HBV replication from tumor cells and may also provide an explanation for the observed suppression of HBV replication by HCV coinfection.