Cisplatin Enhances Hepatitis B Virus Replication and PGC-1α Expression through Endoplasmic Reticulum Stress.
Cisplatin Enhances Hepatitis B Virus Replication and PGC-1α Expression through Endoplasmic Reticulum Stress.
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顺铂通过内质网应激增强乙型肝炎病毒复制和 PGC-1 α 表达
DOI：
10.1038/s41598-018-21847-3
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发表时间：
2018-02-22
影响因子：
4.6
通讯作者：
Huang A
中科院分区：
文献类型：
--
作者：
Li X;Pan E;Zhu J;Xu L;Chen X;Li J;Liang L;Hu Y;Xia J;Chen J;Chen W;Hu J;Wang K;Tang N;Huang A
慢性乙肝感染仍然是一个严重的全球公共卫生问题。据报道，在接受抗癌治疗、免疫抑制治疗或器官和组织移植的患者中，乙肝病毒(乙肝病毒)的重新激活是常见的。然而，与化疗药物相关的乙肝病毒重新激活的确切机制仍不清楚。在此，我们报道了PGC-1α在顺铂诱导的乙肝病毒转录和复制中起核心作用。首先，顺铂治疗上调了乙肝病毒复制细胞和乙肝病毒转基因小鼠模型中pGC-1α和肝细胞核因子4α(hnf-4α)的表达水平。PGC-1α与hNf-4α共激活，hNf-4与乙肝病毒基因组的核心启动子和增强子II区域相互作用，从而促进乙肝病毒的产生。相反，肝癌细胞中的pGC-1α和hnf-4α被RNA干扰抑制，逆转了顺铂对乙肝病毒的激活。此外，pGC-1α上调依赖于顺铂介导的内质网(ER)应激。我们进一步观察到，在顺铂处理的细胞中，cAMP反应元件结合蛋白的募集对于pGC-1α的转录激活起着至关重要的作用。最后，药物抑制内质网应激损伤顺铂诱导的pGC-1α表达上调和乙肝病毒的产生。这些发现揭示了新的分子机制，表明内质网应激-前列腺素C_1α信号通路在顺铂诱导的乙肝病毒再激活中起着关键作用。
Chronic hepatitis B infection remains a serious public health issue worldwide. Hepatitis B virus (HBV) reactivation is commonly reported in patients receiving anticancer therapy, immunosuppressive therapy, or organ and tissue transplantation. However, the precise mechanisms underlying chemotherapeutic agent-related HBV reactivation remain unclear. Here, we report that peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) plays a central role in cisplatin-induced HBV transcription and replication. First, cisplatin treatment upregulated the expression levels of PGC-1α and hepatocyte nuclear factor 4 alpha (HNF-4α) in both HBV-replicating cells and an HBV-transgenic mouse model. PGC-1α coactivates with HNF-4α, which interacts with a core promoter and enhancer II region of HBV genome, thereby promoting HBV production. In contrast, knockdown of PGC-1α and HNF-4α by RNA interference in hepatoma cells reversed HBV activation in response to cisplatin. Additionally, PGC-1α upregulation depended on cisplatin-mediated endoplasmic reticulum (ER) stress. We further observed that the recruitment of cyclic AMP-responsive element-binding protein plays a crucial role for PGC-1α transcriptional activation in cisplatin-treated cells. Finally, pharmacologic inhibition of ER stress impaired PGC-1α upregulation and HBV production induced by cisplatin treatment. These findings demonstrate novel molecular mechanisms indicating that ER stress-PGC1α signaling pathway plays a critical role in cisplatin-evoked HBV reactivation.
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影响因子：
3.7
作者：
Churin Y;Roderfeld M;Stiefel J;Würger T;Schröder D;Matono T;Mollenkopf HJ;Montalbano R;Pompaiah M;Reifenberg K;Zahner D;Ocker M;Gerlich W;Glebe D;Roeb E
通讯作者：
Roeb E
影响因子：
13.5
作者：
Jang, JW;Choi, JY;Lee, YS
通讯作者：
Lee, YS
影响因子：
7.1
作者：
Fernandez-Marcos, Pablo J.;Auwerx, Johan
通讯作者：
Auwerx, Johan
影响因子：
6.3
作者：
Hayashi, Kazuhiko;Ishigami, Masatoshi;Hirooka, Yoshiki
通讯作者：
Hirooka, Yoshiki
影响因子：
25.7
作者：
Peiffer, Kai-Henrik;Akhras, Sami;Hildt, Eberhard
通讯作者：
Hildt, Eberhard