Hepatitis B virus upregulates cellular inhibitor of apoptosis protein 2 expression via the PI3K/AKT/NF-κB signaling pathway in liver cancer
Hepatitis B virus upregulates cellular inhibitor of apoptosis protein 2 expression via the PI3K/AKT/NF-κB signaling pathway in liver cancer
复制标题
DOI：
10.3892/ol.2020.11267
复制
发表时间：
2020-03-01
期刊：
影响因子：
2.9
通讯作者：
Chen, Longhua
中科院分区：
文献类型：
--
作者：
Lian, Jianping;Zou, Yuanhua;Chen, Longhua
抗凋亡基因的激活被认为是导致B型肝炎病毒（HBV）感染诱导的肝癌的因素之一。细胞凋亡抑制蛋白2（cIAP 2）是IAP家族的成员，在各种类型的癌症中上调，并作为潜在的治疗靶点。然而，据我们所知，cIAP 2在HBV诱导的肝癌中的重要性尚未研究。在本研究中，cIAP 2在肝细胞中的表达响应HBV感染和相关的机制进行了研究。临床肝组织标本Western blot分析显示，cIAP 2在HBV阳性的非癌组织中的表达高于HBV阴性的非癌组织，在HBV阳性的肝癌组织中表达进一步增强。对两种肝细胞系进行的逆转录定量PCR和蛋白质印迹实验也证实，HBV感染后，cIAP 2表达在mRNA和蛋白质水平上均增加。启动子分析表明，HBV能以感染剂量依赖的方式激活cIAP 2启动子，这种激活作用涉及cIAP 2启动子上的NF-κ B结合位点。进一步的分析表明，HBV通过PI 3 K/AKT信号通路增强NF-κ B磷酸化和核转位，导致cIAP 2启动子的结合和激活。目前的数据表明，HBV感染通过激活PI 3 K/AKT/NF-κ B信号通路，通过促进NF-κ B与cIAP 2启动子的结合，诱导肝脏中cIAP 2的表达，这可能导致癌变。本研究的发现为理解HBV诱导的肝癌提供了更多的信息，也为治疗或诊断这种疾病提供了潜在的靶点。
Activation of antiapoptotic genes has been indicated as one of the factors that contributes to hepatitis B virus (HBV) infection-induced liver cancer. The cellular inhibitor of apoptosis protein 2 (cIAP2), a member of the IAP family, is upregulated in various types of cancer and serves as a potential treatment target. However, to the best of our knowledge, the importance of cIAP2 in HBV-induced liver cancer has not been investigated. In the present study, cIAP2 expression in liver cells in response to HBV infection and the underlying mechanism involved was investigated. Western blot analysis of clinical liver samples showed that higher cIAP2 expression was detected in HBV-positive non-cancerous tissue compared with that in HBV-negative non-cancerous tissue, and the expression was further increased in HBV-positive liver cancer tissue. Reverse transcription-quantitative PCR and western blot experiments performed on two liver cell lines also confirmed that cIAP2 expression was increased upon HBV infection at both the mRNA and protein levels. Promoter analysis revealed that HBV could activate cIAP2 promoter in an infection dose-dependent manner, and this activation involved a NF-kappa B-binding site in the cIAP2 promoter. Further analysis demonstrated that HBV enhanced NF-kappa B phosphorylation and nuclear translocation via the PI3K/AKT signaling pathway, leading to the binding and activation of cIAP2 promoter. The present data demonstrates that HBV-infection induces cIAP2 expression in the liver by activation of the PI3K/AKT/NF-kappa B signaling pathway through promoting the binding of NF-kappa B to cIAP2 promoter, which may lead to carcinogenesis. The findings from the present study provide more information for understanding HBV-induced liver cancer and also offer a potential target for treatment or diagnosis of this disease.