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

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 and interleukin ( in human tissues and cells. ChIP and luciferase reporter assays were utilized to investigate the interaction between XBP1s and 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 (r=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.

Unravel the molecular mechanism of XBP1 in regulating the biology of cancer cells

“…Furthermore, IL-6 subsequently activates the intracellular JAK-STAT3 signaling pathway in an autocrine/paracrine manner 61. Activation of IRE1α-XBP1 signaling increases the proliferation of HCC cells through up regulation of IL-6 promoter activity and activation of STAT3 signaling 115.…”

Thapsigargin promotes colorectal cancer cell migration through upregulation of lncRNA MALAT1

“…The oncogenic roles of XBP1 in CRC and other types of cancer have been reported in numerous studies; the activation of the IRE1/XBP1 pathway induced cell proliferation and invasion in CRC 3, whereby XBP1 was demonstrated to promote with poor prognosis (24); in breast cancer, the expression levels of XBP1s in the nucleus were correlated with shorter survival (25); whereas in ovarian cancer, the IRE1/XBP1 signaling pathway controlled T-cell functions, thus, mediating ER stress or targeting the IRE1/XBP1 pathway may restore the antitumor ability of T-cells (26). In addition, XBP1 positively regulated the cytolytic activity of human natural killer cells against leukemia cells (27); in hepatocellular carcinoma, the IRE1/XBP1 pathway controlled the expression of interleukin-6 (IL-6) and promoted hepatocarcinoma progression (28); and in oropharyngeal carcinoma without papillomavirus, the IRE1/XBP1 pathway induced resistance to radiotherapy by mediating IL-6 production (29). Thus, the transcription factor XBP1 may be a potential target to mediate tumor immunology and block cancer progression.…”

Unraveling the Molecular Nexus between GPCRs, ERS, and EMT

“…Moreover, in hepatocellular carcinoma (HCC), the expression of XBP1s is detected in HCC cell lines and tissue samples, which is correlated with poor prognosis. Invasiveness and metastasis of HCC cells are promoted by activation of EMT with increased levels of Snail, Twist, and vimentin and decreased levels of E-cadherin and γ -catenin [ 173 ]. Also, in esophageal squamous cell carcinoma (ESCC), XBP1 is overexpressed in both cell lines as well as in clinical tumor samples, correlating with tumor stage, lymph node metastasis, and poor patient outcome.…”