Circular RNA encoded MET variant promotes glioblastoma tumorigenesis

Jian Zhong, Xujia Wu, Yixin Gao, Junju Chen, Maolei Zhang, Huangkai Zhou, Jia Yang, Feizhe Xiao, Xuesong Yang, Nunu Huang, Haoyue Qi, Xiuxing Wang (), Fan Bai (), Yu Shi () and Nu Zhang ()
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Jian Zhong: The First Affiliated Hospital of Sun Yat-sen University
Xujia Wu: The First Affiliated Hospital of Sun Yat-sen University
Yixin Gao: The First Affiliated Hospital of Sun Yat-sen University
Junju Chen: The First Affiliated Hospital of Sun Yat-sen University
Maolei Zhang: The First Affiliated Hospital of Sun Yat-sen University
Huangkai Zhou: The First Affiliated Hospital of Sun Yat-sen University
Jia Yang: The First Affiliated Hospital of Sun Yat-sen University
Feizhe Xiao: The First Affiliated Hospital of Sun Yat-sen University
Xuesong Yang: The First Affiliated Hospital of Sun Yat-sen University
Nunu Huang: The First Affiliated Hospital of Sun Yat-sen University
Haoyue Qi: Southwest Hospital, Third Military Medical University (Army Medical University)
Xiuxing Wang: Nanjing Medical University
Fan Bai: Peking University (PKU)
Yu Shi: Southwest Hospital, Third Military Medical University (Army Medical University)
Nu Zhang: The First Affiliated Hospital of Sun Yat-sen University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Activated by its single ligand, hepatocyte growth factor (HGF), the receptor tyrosine kinase MET is pivotal in promoting glioblastoma (GBM) stem cell self-renewal, invasiveness and tumorigenicity. Nevertheless, HGF/MET-targeted therapy has shown limited clinical benefits in GBM patients, suggesting hidden mechanisms of MET signalling in GBM. Here, we show that circular MET RNA (circMET) encodes a 404-amino-acid MET variant (MET404) facilitated by the N6-methyladenosine (m6A) reader YTHDF2. Genetic ablation of circMET inhibits MET404 expression in mice and attenuates MET signalling. Conversely, MET404 knock-in (KI) plus P53 knock-out (KO) in mouse astrocytes initiates GBM tumorigenesis and shortens the overall survival. MET404 directly interacts with the MET β subunit and forms a constitutively activated MET receptor whose activity does not require HGF stimulation. High MET404 expression predicts poor prognosis in GBM patients, indicating its clinical relevance. Targeting MET404 through a neutralizing antibody or genetic ablation reduces GBM tumorigenicity in vitro and in vivo, and combinatorial benefits are obtained with the addition of a traditional MET inhibitor. Overall, we identify a MET variant that promotes GBM tumorigenicity, offering a potential therapeutic strategy for GBM patients, especially those with MET hyperactivation.

Date: 2023
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DOI: 10.1038/s41467-023-40212-1

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