IRE1α-XBP1信号通路调节IL-6表达并促进肝细胞癌的进展。,Oncology Letters

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IRE1α-XBP1信号通路调节IL-6表达并促进肝细胞癌的进展。
Oncology Letters ( IF 2.5 ) Pub Date : 2018-09-15 , DOI: 10.3892/ol.2018.9176
Peipei Fang ₁ , Luxia Xiang ₁ , Shanshan Huang ₁ , Lingxiang Jin ₁ , Guangyao Zhou ₁ , Lu Zhuge ₁ , Jie Li ₁ , Hengwei Fan ₂ , Lingli Zhou ₃ , Chenwei Pan ₁ , Yi Zheng _{1,

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Affiliation

在由内质网应激激活的三个未折叠的蛋白应答途径中，最需要保守的是需要肌醇的酶1α（IRE1α）-X-box-binding protein 1（XBP1）信号。这些途径与多种类型的癌症有关，包括肝细胞癌（HCC）。但是，IRE1α-XBP1信号在肝癌发生中的作用尚不清楚。在当前的研究中，逆转录-定量聚合酶链反应被用于分析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和萤光素酶报告基因检测XBP1与IL-6启动子DNA之间的相互作用。令人鼓舞的是，IRE1α-XBP1信号传导通过调节肝IL-6表达促进HCC细胞的增殖。观察到在人HCC组织中，XBP1和肝IL-6含量的剪接水平增加并且彼此正相关（r2 = 0.5846，P = 0.004）。IRE1α或XBP1s的异位表达增加了LO2和Hep3B细胞的IL-6水平。此外，IRE1α的药理学抑制作用通过阻断XBP1的产生来降低IL-6表达和分泌水平，XBP1s直接与IL-6启动子结合并激活其表达。进一步的研究表明，由XBP1s驱动的IL-6被分泌到细胞外，并以自分泌/旁分泌方式激活信号转导子和转录激活子3（STAT3）信号，以调节Hep3B细胞的增殖。用tocilizumab阻断IL-6-STAT3信号传导减弱了IRE1α-XBP1信号传导促进Hep3B细胞增殖的作用。总之，本研究表明，IRE1α-XBP1信号传导通过调节IL-6-STAT3信号传导通路的激活来促进HCC的癌变。

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IRE1α-XBP1 signaling pathway regulates IL-6 expression and promotes progression of hepatocellular carcinoma.

Of the three unfolded protein response pathways, which are activated by endoplasmic reticulum stress, inositol-requiring enzyme 1α (IRE1α)-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 IRE1α-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 IRE1α-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 (r2=0.5846, P=0.004). Ectopic expression of IRE1α or XBP1s increased IL-6 levels in LO2 and Hep3B cells. In addition, pharmacological inhibition of IRE1α 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 IRE1α-XBP1 signaling in promoting Hep3B cell proliferation. In conclusion, the present study revealed that IRE1α-XBP1 signaling promotes carcinogenesis of HCC by regulating the activation of the IL-6-STAT3 signaling pathway.

更新日期：2019-11-01

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