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

Fang,Peipei; Xiang,Luxia; Huang,Shanshan; Jin,Lingxiang; Zhou,Guangyao; Zhuge,Lu; Li,Jie; Fan,Hengwei; Zhou,Lingli; Pan,Chenwei; Zheng,Yi

doi:10.3892/ol.2018.9176

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

Authors:
- Peipei Fang
- Luxia Xiang
- Shanshan Huang
- Lingxiang Jin
- Guangyao Zhou
- Lu Zhuge
- Jie Li
- Hengwei Fan
- Lingli Zhou
- Chenwei Pan
- Yi Zheng
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Affiliations: Department of Infectious Disease, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China, Department of Hepatobiliary Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China, Department of Pathology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China
Published online on: July 19, 2018 https://doi.org/10.3892/ol.2018.9176
Pages: 4729-4736

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Abstract

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.

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