Circular RNA-encoded oncogenic E-cadherin variant promotes glioblastoma tumorigenicity through activation of EGFR-STAT3 signalling
Circular RNA-encoded oncogenic E-cadherin variant promotes glioblastoma tumorigenicity through activation of EGFR-STAT3 signalling
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环状 RNA 编码的致癌 E-钙粘蛋白变体通过激活 EGFR-STAT3 信号传导促进胶质母细胞瘤致瘤性。
DOI：
10.1038/s41556-021-00639-4
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发表时间：
2021-03-04
影响因子：
21.3
通讯作者：
Zhang, Nu
中科院分区：
文献类型：
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作者：
Gao, Xinya;Xia, Xin;Zhang, Nu
在50%的胶质母细胞瘤(GBM)中，激活的EGFR信号驱动肿瘤的发生。然而，EGFR靶向治疗在治疗GBM患者中被证明无效，这表明存在多余的EGFR激活。环状RNA是参与多种生理和病理过程的共价闭合RNA转录本。在这里，我们报道了通过多轮开放阅读框架翻译，由环状E-钙粘蛋白(CIRC-E-Cad)RNA编码的未知分泌型E-钙粘素蛋白变体(C-E-Cad)在GBM中激活EGFR信号的另一种机制。C-E-Cad在GBM中高表达，促进胶质瘤干细胞致瘤性。C-E-Cad通过与EGFR CR2结构域结合，利用一个独特的14个氨基酸的羧基末端，激活不依赖于EGF的EGFR，从而维持胶质瘤干细胞的致瘤性。值得注意的是，抑制C-E-Cad显著增强了GBM中治疗性抗EGFR策略的抗肿瘤活性。我们的结果揭示了C-E-Cad在刺激EGFR信号通路中的关键作用，并为治疗EGFR驱动的GBM.Gao等人提供了一种有前途的方法。结果表明，由环状RNA编码的E-钙粘蛋白的分泌型变体直接激活EGFR和STAT3信号，从而促进胶质瘤干细胞的致瘤性。
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.Gao et al. show that a secretory variant of E-cadherin encoded by a circular RNA directly activates EGFR and STAT3 signalling, thereby promoting glioma stem cell tumorigenicity.