Research Paper Volume 12, Issue 2 pp 1685—1703

The Interleukin-33/ST2 axis promotes glioma mesenchymal transition, stemness and TMZ resistance via JNK activation

Lin Lin 1, 2, *, , Yang Li 1, 2, *, , Mingli Liu 1, 2, , Qingbin Li 1, 2, , Quan Liu 4, , Ruiyan Li 1, 2, 3, ,

  • 1 Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
  • 2 Chinese Glioma Cooperative Group (CGCG), Beijing 100050, China
  • 3 Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, China
  • 4 Southern University of Science and Technology, Shenzhen 518055, China
* Equal contribution

received: July 15, 2019 ; accepted: January 2, 2020 ; published: January 29, 2020 ;

https://doi.org/10.18632/aging.102707
How to Cite

Copyright © 2020 Lin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

IL-33 is an important member of the IL-1 family which has pleiotropic activities in innate and adaptive immune responses. Recently, some researchers have focused on the function of cellular immunity in the development of tumor. The biological role of IL-33 in glioma is poorly understood. In this study, we showed that glioma cells and tissues expressed higher levels of IL-33 and its receptor ST2 compared to normal brain. Clinically, IL-33 expression was associated with poor survival in patients with glioma. Administration of human IL-33 enhanced cell migration, invasion, epithelial to mesenchymal transition and stemness. Anti-ST2 blocked these effects of IL-33 on tumor. Mechanistically, IL-33 activated JNK signaling pathway via ST2 and increased the expression of key transcription factors that controlled the process of EMT and stemness. Moreover, IL-33 prevented temozolomide induced tumor apoptosis. Anti-ST2 or knockdown IL-33 increased the sensitivity of tumor to temozolomide. Thus, targeting the IL-33/ST2 axis may offer an opportunity to the treatment of glioma patients.

Abbreviations

TMZ: Temozolomide; IL-33: Interleukin-33; EMT: Epithelial-mesenchymal transition; DMEM: Dulbecco’s Modified Eagle’s Medium; FBS: Fetal bovine serum; TNF: Tumor necrosis factor; MAPK: Mitogen-activated protein kinase; TGF-β1: Transforming growth factor-β1; CCK-8: Cell counting kit-8.