Interferon-alpha-induced hepatitis C virus clearance restores p53 tumor suppressor more than direct-acting antivirals.
Interferon-alpha-induced hepatitis C virus clearance restores p53 tumor suppressor more than direct-acting antivirals.
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DOI：
10.1002/hep4.1025
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发表时间：
2017-05
影响因子：
5.1
通讯作者：
Dash S
中科院分区：
文献类型：
--
作者：
Aydin Y;Chatterjee A;Chandra PK;Chava S;Chen W;Tandon A;Dash A;Chedid M;Moehlen MW;Regenstein F;Balart LA;Cohen A;Lu H;Wu T;Dash S
直接作用抗病毒药物（DAA）清除丙型肝炎病毒（HCV）并不能消除晚期肝硬化患者发生肝细胞癌（HCC）的风险，其机制尚不清楚。许多病毒和细菌感染降解p53，有利于细胞存活，以适应内质网（ER）应激反应。在这项研究中，我们检查了干扰素α或DAA清除HCV是否使ER应激正常化并恢复细胞培养中p53肿瘤抑制因子的表达。我们发现，HCV感染诱导慢性内质网应激和未折叠的蛋白质反应在未转化的原代人肝细胞。未折叠蛋白反应在感染的原代人肝细胞和Huh-7.5细胞中诱导分子伴侣介导的自噬（CMA），导致p53降解并诱导小鼠双微体2（Mdm 2）表达。通过小分子（nutlin-3）抑制p53/Mdm 2相互作用或沉默Mdm 2并不能挽救p53降解，表明HCV感染诱导p53降解不依赖于Mdm 2途径。有趣的是，我们发现HCV感染以溶酶体依赖性机制降解p53，因为溶酶体相关膜蛋白2A沉默恢复了p53降解。我们的研究结果表明，基于干扰素-α的抗病毒治疗诱导的HCV清除使ER应激反应正常化并恢复p53，而DAA的HCV清除两者都没有。我们发现，HCV感染的肝硬化中p53的表达降低与ER应激和CMA反应相关的伴侣蛋白的表达有关。结论：HCV诱导的ER应激和CMA促进晚期肝硬化中p53降解。通过DAA清除HCV并不能恢复p53，这为为什么DAA的病毒治疗不能消除晚期肝病患者的HCC风险提供了一个潜在的解释。我们认为，解决ER应激反应是降低病毒治愈后肝硬化患者肝癌风险的另一种方法。（Hepatology Communications 2017;1：256 - 269）
The mechanism why hepatitis C virus (HCV) clearance by direct‐acting antivirals (DAAs) does not eliminate the risk of hepatocellular carcinoma (HCC) among patients with advanced cirrhosis is unclear. Many viral and bacterial infections degrade p53 in favor of cell survival to adapt an endoplasmic reticulum (ER)‐stress response. In this study, we examined whether HCV clearance by interferon‐alpha or DAAs normalizes the ER stress and restores the expression of p53 tumor suppressor in cell culture. We found that HCV infection induces chronic ER stress and unfolded protein response in untransformed primary human hepatocytes. The unfolded protein response induces chaperone‐mediated autophagy (CMA) in infected primary human hepatocytes and Huh‐7.5 cells that results in degradation of p53 and induced expression of mouse double minute 2 (Mdm2). Inhibition of p53/Mdm2 interactions by small molecule (nutlin‐3) or silencing Mdm2 did not rescue the p53 degradation, indicating that HCV infection induces degradation of p53 independent of the Mdm2 pathway. Interestingly, we found that HCV infection degrades p53 in a lysosome‐dependent mechanism because lysosome‐associated membrane protein 2A silencing restored p53 degradation. Our results show that HCV clearance induced by interferon‐alpha‐based antiviral therapies normalizes the ER‐stress response and restores p53, whereas HCV clearance by DAAs does neither. We show that decreased expression of p53 in HCV‐infected cirrhotic liver is associated with expression of chaperones associated with ER stress and the CMA response. Conclusion: HCV‐induced ER stress and CMA promote p53 degradation in advanced liver cirrhosis. HCV clearance by DAAs does not restore p53, which provides a potential explanation for why a viral cure by DAAs does not eliminate the HCC risk among patients with advanced liver disease. We propose that resolving the ER‐stress response is an alternative approach to reducing HCC risk among patients with cirrhosis after viral cure. (Hepatology Communications 2017;1:256‐269)
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