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EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3

  • Pan, Ziwen1, 2
  • Zhao, Rongrong1, 2
  • Li, Boyan1, 2
  • Qi, Yanhua1, 2
  • Qiu, Wei1, 2
  • Guo, Qindong1, 2
  • Zhang, Shouji1, 2
  • Zhao, Shulin1, 2
  • Xu, Hao2, 3
  • Li, Ming2, 4
  • Gao, Zijie1, 2
  • Fan, Yang1, 2
  • Xu, Jianye1, 2
  • Wang, Huizhi1, 2
  • Wang, Shaobo1, 2
  • Qiu, Jiawei1, 2
  • Wang, Qingtong1, 2
  • Guo, Xing1, 2
  • Deng, Lin1, 2
  • Zhang, Ping1, 2
  • And 2 more
  • 1 Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road; Jinan, Shandong 250012, China, Jinan, Shandong, 250012, China , Jinan (China)
  • 2 Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China , Jinan (China)
  • 3 The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China , Yantai (China)
  • 4 Taian Central Hospital, Taian, Shandong, China , Taian (China)
Published Article
Molecular Cancer
Springer (Biomed Central Ltd.)
Publication Date
Jan 14, 2022
DOI: 10.1186/s12943-021-01485-6
Springer Nature
  • Research


BackgroundGliomas are the most common malignant primary brain tumours with a highly immunosuppressive tumour microenvironment (TME) and poor prognosis. Circular RNAs (circRNA), a newly found type of endogenous noncoding RNA, characterized by high stability, abundance, conservation, have been shown to play an important role in the pathophysiological processes and TME remodelling of various tumours.MethodsCircRNA sequencing analysis was performed to explore circRNA expression profiles in normal and glioma tissues. The biological function of a novel circRNA, namely, circNEIL3, in glioma development was confirmed both in vitro and in vivo. Mechanistically, RNA pull-down, mass spectrum, RNA immunoprecipitation (RIP), luciferase reporter, and co-immunoprecipitation assays were conducted.ResultsWe identified circNEIL3, which could be cyclized by EWS RNA-binding protein 1(EWSR1), to be upregulated in glioma tissues and to correlate positively with glioma malignant progression. Functionally, we confirmed that circNEIL3 promotes tumorigenesis and carcinogenic progression of glioma in vitro and in vivo. Mechanistically, circNEIL3 stabilizes IGF2BP3 (insulin-like growth factor 2 mRNA binding protein 3) protein, a known oncogenic protein, by preventing HECTD4-mediated ubiquitination. Moreover, circNEIL3 overexpression glioma cells drives macrophage infiltration into the tumour microenvironment (TME). Finally, circNEIL3 is packaged into exosomes by hnRNPA2B1 and transmitted to infiltrated tumour associated macrophages (TAMs), enabling them to acquire immunosuppressive properties by stabilizing IGF2BP3 and in turn promoting glioma progression.ConclusionsThis work reveals that circNEIL3 plays a nonnegligible multifaceted role in promoting gliomagenesis, malignant progression and macrophage tumour-promoting phenotypes polarization, highlighting that circNEIL3 is a potential prognostic biomarker and therapeutic target in glioma.

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