Open Access

Exosomes derived from endoplasmic reticulum‑stressed liver cancer cells enhance the expression of cytokines in macrophages via the STAT3 signaling pathway

  • Authors:
    • Chengqun He
    • Wei Hua
    • Jiatao Liu
    • Lulu Fan
    • Hua Wang
    • Guoping Sun
  • View Affiliations

  • Published online on: May 13, 2020     https://doi.org/10.3892/ol.2020.11609
  • Pages: 589-600
  • Copyright: © He et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Previous studies have shown that endoplasmic reticulum (ER) stress serves an important role in shaping the immunosuppressive microenvironment by modulating resident immune cells. However, the communication between ER‑stressed tumor cells and immune cells is not fully understood. Exosomes have been reported to play a vital role in intercellular communication. Therefore, in order to investigate the role of ER stress‑related exosomes in liver cancer cells mediated macrophage function remodeling, immunohistochemical analysis, western‑blotting immunofluorescence and cytokine bead array analyses were performed. The results demonstrated that glucose‑regulated protein 78 (GRP78) expression was upregulated in human liver cancer tissue. Moreover, 69.09% of GRP78‑positive liver cancer tissues possessed macrophages expressing CD68+ (r=0.55; P<0.001). In addition to these CD68+ macrophages, interleukin (IL)‑10 and IL‑6 expression levels were increased in liver cancer tissues. It was also demonstrated that exosomes released by ER‑stressed HepG2 cells significantly enhanced the expression levels of several cytokines, including IL‑6, monocyte chemotactic protein‑1, IL‑10 and tumor necrosis factor‑α in macrophages. Furthermore, incubation of cells with ER stress‑associated exosomes resulted inactivation of the Janus kinase 2/STAT3 pathway, and inhibition of STAT3 using S3I‑201 in RAW264.7 cells significantly reduced cytokine production. Collectively, the present study identified a novel function of ER stress‑associated exosomes in mediating macrophage cytokine secretion in the liver cancer microenvironment, and also indicated the potential of treating liver cancer via an ER stress‑exosomal‑STAT3 pathway.

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July 2020
Volume 20 Issue 1

Print ISSN: 1792-1074
Online ISSN:1792-1082

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APA
He, C., Hua, W., Liu, J., Fan, L., Wang, H., & Sun, G. (2020). Exosomes derived from endoplasmic reticulum‑stressed liver cancer cells enhance the expression of cytokines in macrophages via the STAT3 signaling pathway. Oncology Letters, 20, 589-600. https://doi.org/10.3892/ol.2020.11609
MLA
He, C., Hua, W., Liu, J., Fan, L., Wang, H., Sun, G."Exosomes derived from endoplasmic reticulum‑stressed liver cancer cells enhance the expression of cytokines in macrophages via the STAT3 signaling pathway". Oncology Letters 20.1 (2020): 589-600.
Chicago
He, C., Hua, W., Liu, J., Fan, L., Wang, H., Sun, G."Exosomes derived from endoplasmic reticulum‑stressed liver cancer cells enhance the expression of cytokines in macrophages via the STAT3 signaling pathway". Oncology Letters 20, no. 1 (2020): 589-600. https://doi.org/10.3892/ol.2020.11609