Hepatitis C virus NS5A drives a PTEN-PI3K/Akt feedback loop to support cell survival
Hepatitis C virus NS5A drives a PTEN-PI3K/Akt feedback loop to support cell survival
复制标题
丙型肝炎病毒 NS5A 驱动 PTEN-PI3K/Akt 反馈环路以支持细胞存活
DOI：
10.1111/liv.12733
复制
发表时间：
2015-06-01
影响因子：
6.7
通讯作者：
Gong, Guozhong
中科院分区：
文献类型：
--
作者：
Cheng, Du;Zhang, Leiliang;Gong, Guozhong
背景与目的在丙型肝炎病毒（HCV）感染的HCC患者中，磷酸酶和紧张素同源物（PTEN）水平的降低与HCC的发病机制和预后不良有关。控制PTEN减少的分子过程和肝细胞PTEN功能障碍的结果尚不清楚。方法采用实时荧光定量PCR和免疫印迹法检测血清蛋白和mRNA水平。报告基因法测定PTEN启动子活性。使用sirna或药物抑制剂干扰信号通路。结果HCV通过降低PTEN启动子活性、mRNA转录和蛋白水平，在转录水平下调PTEN的表达。我们进一步发现NS5A蛋白是HCV蛋白中PTEN减少的关键决定因素。ns5a介导的PTEN下调是通过活性氧（ROS）依赖的核因子- κ B （NF-B）和非活性氧依赖的磷酸肌醇-3激酶（PI3K）途径的共同作用发生的。此外，NS5A对细胞凋亡具有保护作用。此外，我们发现下调PTEN可减轻其对PI3K-Akt通路的抑制作用，并触发Akt的累积激活。这个PTEN-PI3K/Akt反馈网络介导了NS5A引起的细胞凋亡的抑制。这些数据表明HCV NS5A通过ros依赖性和非依赖性途径共同下调PTEN的表达，进而驱动PTEN- pi3k /Akt反馈回路支持细胞存活。我们的研究结果提供了新的见解，表明NS5A参与了hcv相关的肝癌发生。
Background & AimsDecreased levels of phosphatase and tensin homologue (PTEN) are associated with hepatocellular carcinoma (HCC) pathogenesis and poor prognosis in hepatitis C virus (HCV)-infected HCC patients. The molecular processes governing the reduction in PTEN and outcome of PTEN dysfunction in hepatocytes are poorly understood.MethodsThe levels of proteins and mRNA were assessed by real time PCR and immunoblot. PTEN promoter activity was measured by reporter assay. Signalling pathways were perturbed using siRNAs or pharmacological inhibitors.ResultsHere, we report that HCV down-regulates PTEN expression at the transcriptional level by decreasing its promoter activity, mRNA transcription, and protein levels. We further identify NS5A protein as a key determinant of PTEN reduction among HCV proteins. NS5A-mediated down-regulation of PTEN occurs through a cooperation of reactive oxygen species (ROS)-dependent Nuclear Factor- kappa B (NF-B) and ROS-independent phosphoinositol-3-kinase (PI3K) pathways. Moreover, NS5A protects cells against apoptosis. In addition, we found that down-regulation of PTEN relieves its inhibitory effect on PI3K-Akt pathway and triggers cumulative activation of Akt. This PTEN-PI3K/Akt feedback network mediates the suppression of cell apoptosis caused by NS5A.ConclusionsThese data demonstrate that HCV NS5A down-regulates PTEN expression through a cooperation of ROS-dependent and -independent pathways that subsequently drives a PTEN-PI3K/Akt feedback loop to support cell survival. Our findings provide new insights suggesting that NS5A contributes to HCV-related hepatocarcinogenesis.