Circular RNA-encoded oncogenic E-cadherin variant promotes glioblastoma tumorigenicity through activation of EGFR–STAT3 signalling

Xinya Gao, Xin Xia, Fanying Li, Maolei Zhang, Huangkai Zhou, Xujia Wu, Jian Zhong, Zheng Zhao, Kun Zhao, Dawei Liu, Feizhe Xiao, Qiang Xu, Tao Jiang, Bo Li, Shi Yuan Cheng, Nu Zhang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Activated EGFR signalling drives tumorigenicity in 50% of glioblastoma (GBM). However, EGFR-targeting therapy has proven ineffective in treating patients with GBM, indicating that there is redundant EGFR activation. Circular RNAs are covalently closed RNA transcripts that are involved in various physiological and pathological processes. Herein, we report an additional activation mechanism of EGFR signalling in GBM by an undescribed secretory E-cadherin protein variant (C-E-Cad) encoded by a circular E-cadherin (circ-E-Cad) RNA through multiple-round open reading frame translation. C-E-Cad is overexpressed in GBM and promotes glioma stem cell tumorigenicity. C-E-Cad activates EGFR independent of EGF through association with the EGFR CR2 domain using a unique 14-amino-acid carboxy terminus, thereby maintaining glioma stem cell tumorigenicity. Notably, inhibition of C-E-Cad markedly enhances the antitumour activity of therapeutic anti-EGFR strategies in GBM. Our results uncover a critical role of C-E-Cad in stimulating EGFR signalling and provide a promising approach for treating EGFR-driven GBM.

Original languageEnglish (US)
Pages (from-to)278-291
Number of pages14
JournalNature Cell Biology
Volume23
Issue number3
DOIs
StatePublished - Mar 2021

ASJC Scopus subject areas

  • Cell Biology

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