IRE1-XBP1 signaling pathway regulates IL-6 expression and promotes progression of hepatocellular carcinoma
IRE1-XBP1 signaling pathway regulates IL-6 expression and promotes progression of hepatocellular carcinoma
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DOI：
10.3892/ol.2018.9176
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发表时间：
2018-10-01
期刊：
影响因子：
2.9
通讯作者：
Zheng, Yi
中科院分区：
文献类型：
--
作者：
Fang, Peipei;Xiang, Luxia;Zheng, Yi
在内质网应激激活的三种未折叠蛋白反应途径中，肌醇要求酶1 (IRE1)- x- box结合蛋白1 （XBP1）信号是最保守的。这些途径涉及多种类型的癌症，包括肝细胞癌（HCC）。然而，IRE1-XBP1信号在HCC发展中的作用尚不清楚。本研究采用逆转录-定量聚合酶链反应分析XBP1和白细胞介素(IL)-6在人体组织和细胞中的表达水平。利用ChIP和荧光素酶报告基因检测来研究XBP1s与IL-6启动子DNA之间的相互作用。研究发现IRE1-XBP1信号通过调节肝脏IL-6表达促进HCC细胞增殖。观察到XBP1剪接水平与肝脏IL-6含量在人HCC组织中升高，且两者呈正相关（r(2)=0.5846， P=0.004）。IRE1或XBP1s的异位表达增加了LO2和Hep3B细胞中IL-6的水平。此外，IRE1的药理抑制通过阻断XBP1s的产生，降低了IL-6的表达和分泌水平，XBP1s直接结合IL-6启动子并激活其表达。进一步研究表明，由XBP1s驱动的IL-6在细胞外分泌，以自分泌/旁分泌的方式激活信号转导因子和转录激活因子3 （STAT3）信号，调节Hep3B细胞的增殖。托珠单抗阻断IL-6-STAT3信号通路可减弱IRE1-XBP1信号通路促进Hep3B细胞增殖的作用。综上所述，本研究揭示IRE1-XBP1信号通过调节IL-6-STAT3信号通路的激活促进HCC的癌变。
Of the three unfolded protein response pathways, which are activated by endoplasmic reticulum stress, inositol-requiring enzyme 1 (IRE1)-X-box-binding protein 1 (XBP1) signaling is the most conserved. These pathways are implicated in a variety of types of cancer, including hepatocellular carcinoma (HCC). However, the role of IRE1-XBP1 signaling in the development of HCC remains unclear. In the current study, reverse transcription-quantiative polymerase chain reaction was used to analyze the expression levels of XBP1 and interleukin (IL)-6 in human tissues and cells. ChIP and luciferase reporter assays were utilized to investigate the interaction between XBP1s and IL-6 promoter DNA. It was revelaed that IRE1-XBP1 signaling promotes the proliferation of HCC cells via regulating hepatic IL-6 expression. It was observed that the splicing levels of XBP1 and hepatic IL-6 content were increased and positively correlated with each other in human HCC tissues (r(2)=0.5846, P=0.004). Ectopic expression of IRE1 or XBP1s increased IL-6 levels in LO2 and Hep3B cells. In addition, pharmacological inhibition of IRE1 reduced the levels of IL-6 expression and secretion through blocking the generation of XBP1s, which bound directly to the IL-6 promoter and activated its expression. Further investigation demonstrated that IL-6 driven by XBP1s was secreted outside of cells and activated signal transducer and activator of transcription 3 (STAT3) signaling in an autocrine/paracrine manner, to regulate the proliferation of Hep3B cells. Blockage of IL-6-STAT3 signaling with tocilizumab attenuated the effect of IRE1-XBP1 signaling in promoting Hep3B cell proliferation. In conclusion, the present study revealed that IRE1-XBP1 signaling promotes carcinogenesis of HCC by regulating the activation of the IL-6-STAT3 signaling pathway.