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.