Interleukin-1β/Iinterleukin-1 Receptor-Associated Kinase 1 Inflammatory Signaling Contributes to Persistent Gankyrin Activation During Hepatocarcinogenesis
Interleukin-1β/Iinterleukin-1 Receptor-Associated Kinase 1 Inflammatory Signaling Contributes to Persistent Gankyrin Activation During Hepatocarcinogenesis
复制标题
Interleukin-1β/Interleukin-1 受体相关激酶 1 炎症信号传导有助于肝癌发生过程中持续的 Gankyrin 激活
DOI：
10.1002/hep.27551
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发表时间：
2015-02-01
期刊：
影响因子：
13.5
通讯作者：
Wang, Hongyang
中科院分区：
文献类型：
--
作者：
Su, Bo;Luo, Tao;Wang, Hongyang
肝细胞癌（HCC）是炎症相关癌症的原型。癌蛋白Gankyrin在HCC中主要增加，在HCC的发展和转移中起关键作用。然而，Gankyrin在HCC中上调的确切机制仍不清楚。开发了Gankyrin荧光素酶报告子以从促炎细胞因子列表中筛选Gankyrin的潜在调节剂，并且发现白细胞介素（IL）-1作为其激活剂之一。在临床癌前病变和恶性肝病样本中，观察到IL-1/白细胞介素-1受体相关激酶1（IRAK-1）信号增强伴Gankyrin增加。Gankyrin和磷酸化IRAK-1的低表达是HCC的有利预后标志物。在二乙基亚硝胺（DEN）大鼠肝癌模型中观察到类似的相关性。来自Gankyrin报告活性、实时聚合酶链反应或免疫印迹的结果进一步证实了IL-1/IRAK-1炎症信号传导对Gankyrin的上调。构建了一系列截短的Gankyrin报告基因，通过电泳迁移率变动分析（EMSA）和染色质免疫沉淀（ChIP）分析Gankyrin启动子的特性。Gankyrin的核心启动子含有核因子Y（NF-Y）家族成员的结合位点，其可以募集组蛋白乙酰转移酶共激活因子E1 A结合蛋白p300（p300）或CREB结合蛋白（CBP）来促进Gankyrin的转录。相反，NF-Y、p300或CBP的敲低抑制Gankyrin表达。IL-1刺激引起IRAK-1、c-Jun N-末端激酶（JNK）和p300的顺序磷酸化，并增强p300/CBP/NF-Y复合物向Gankyrin启动子的募集。磷酸化JNK的抑制损害IL-1/IRAK-1信号传导介导的Gankyrin的上调。结论：IL-1/IRAK-1信号通路通过JNK和NF-Y/p300/CBP复合物促进Gankyrin表达的发现为炎症促进肝癌的发生提供了新的视角。（肝病学2015;61：585-597）
Hepatocellular carcinoma (HCC) is a prototype of inflammation-associated cancer. Oncoprotein Gankyrin, which mostly increases in HCC, plays a critical role in HCC development and metastasis. However, the exact mechanism of Gankyrin up-regulation in HCC remains unclear. A Gankyrin luciferase reporter was developed to screen a potential regulator for Gankyrin from a list of proinflammatory cytokines, and interleukin (IL)-1 was found as one of its activators. In clinical premalignant and malignant liver disease samples, enhanced IL-1/interleukin-1 receptor-associated kinase 1 (IRAK-1) signaling accompanied by increased Gankyrin was observed. Lower expression of Gankyrin and phospho-IRAK-1 are favorable prognostic markers for HCC. A similar correlation was observed in the diethylnitrosamine (DEN) model of rat hepatocarcinogenesis. The results from Gankyrin reporter activity, real-time polymerase chain reaction, or immunoblotting further confirmed the up-regulation of Gankyrin by IL-1/IRAK-1 inflammatory signaling. Moreover, a series of Gankyrin's truncated reporters were constructed, and electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) were performed to analyze the properties of Gankyrin promoter. Mechanistically, the core promoter of Gankyrin contains the binding site of nuclear factor Y (NF-Y) family members, which can recruit histone acetyltransferase coactivator E1A-binding protein p300 (p300) or CREB-binding protein (CBP) to promote Gankyrin transcription. Conversely, knockdown of NF-Y, p300, or CBP inhibits Gankyrin expression. IL-1 stimulation causes sequential phosphorylation of IRAK-1, c-Jun N-terminal kinase (JNK), and p300 and enhances recruitment of the p300/CBP/NF-Y complex to Gankyrin promoter. Inhibition of phospho-JNK impairs IL-1/IRAK-1 signaling-mediated up-regulation of Gankyrin. Conclusion: The finding of IL-1/IRAK-1 signaling promoting Gankyrin expression through JNK and NF-Y/p300/CBP complex provides a fresh view on inflammation-enhanced hepatocarcinogenesis. (Hepatology 2015;61:585-597)