Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture.
Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture.
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PERK-NRF2致癌信号的激活促进了持续感染的HCV培养物中MDM2介导的RB降解。
DOI：
10.1038/s41598-017-10087-6
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发表时间：
2017-08-23
影响因子：
4.6
通讯作者：
Dash S
中科院分区：
文献类型：
--
作者：
Aydin Y;Chedid M;Chava S;Danielle Williams D;Liu S;Hagedorn CH;Sumitran-Holgersson S;Reiss K;Moroz K;Lu H;Balart LA;Dash S
丙型肝炎病毒(丙型肝炎病毒)慢性感染导致如此高的肝细胞癌发病率的机制尚不清楚。我们发现内质网(ER)应激的Perk轴在100%的丙型肝炎病毒感染的肝细胞中诱发了显著的Nrf2核转位。Nrf2在慢性感染培养物中的持续核转位可诱导MDM2介导的视网膜母细胞瘤蛋白(Rb)降解。沉默PERK和Nrf2可恢复MDM2介导的Rb降解，提示PERK/Nrf2轴的持续激活在慢性感染的丙型肝炎病毒培养模型中产生致癌应激。内质网应激和PERK抑制剂可阻止Nrf2的激活和核转位，提示PERK轴参与了慢性丙型肝炎病毒感染过程中Nrf2信号的持续激活。此外，我们发现，基于干扰素-α的抗病毒药物诱导的丙型肝炎病毒清除可以使ER应激反应正常化，并阻止Nrf2的核转位，而联合使用DAAs对丙型肝炎病毒清除两者都没有影响。总之，我们在这里报道了一种新的机制，即在慢性丙型肝炎病毒感染期间，ER应激的PERK轴的持续激活如何激活致癌的Nrf2信号，从而通过诱导MDM2介导的Rb降解来促进肝细胞的存活和肿瘤的发生。
The mechanism of how chronic hepatitis C virus (HCV) infection leads to such a high rate of hepatocellular carcinoma (HCC) is unknown. We found that the PERK axis of endoplasmic reticulum (ER) stress elicited prominent nuclear translocation of Nrf2 in 100% of HCV infected hepatocytes. The sustained nuclear translocation of Nrf2 in chronically infected culture induces Mdm2-mediated retinoblastoma protein (Rb) degradation. Silencing PERK and Nrf2 restored Mdm2-mediated Rb degradation, suggesting that sustained activation of PERK/Nrf2 axis creates oncogenic stress in chronically infected HCV culture model. The activation of Nrf2 and its nuclear translocation were prevented by ER-stress and PERK inhibitors, suggesting that PERK axis is involved in the sustained activation of Nrf2 signaling during chronic HCV infection. Furthermore, we show that HCV clearance induced by interferon-α based antiviral normalized the ER-stress response and prevented nuclear translocation of Nrf2, whereas HCV clearance by DAAs combination does neither. In conclusion, we report here a novel mechanism for how sustained activation of PERK axis of ER-stress during chronic HCV infection activates oncogenic Nrf2 signaling that promotes hepatocyte survival and oncogenesis by inducing Mdm2-mediated Rb degradation.
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影响因子：
4.8
作者：
Carvajal-Yepes, Monica;Himmelsbach, Kiyoshi;Hildt, Eberhard
通讯作者：
Hildt, Eberhard
影响因子：
6
作者：
Chandra, Partha K.;Bao, Lili;Dash, Srikanta
通讯作者：
Dash, Srikanta
影响因子：
25.7
作者：
Conti, Fabio;Buonfiglioli, Federica;Brillanti, Stefano
通讯作者：
Brillanti, Stefano
DOI：
10.1073/pnas.171311298
发表时间：
2001-08-14
影响因子：
11.1
作者：
Gong, GZ;Waris, G;Siddiqui, A
通讯作者：
Siddiqui, A
影响因子：
5.2
作者：
Chan SW
通讯作者：
Chan SW