Circular RNA encoded MET variant promotes glioblastoma tumorigenesis.
Jian ZhongXujia WuYixin GaoJunju ChenMaolei ZhangHuangkai ZhouJia YangFeizhe XiaoXuesong YangNunu HuangHaoyue QiXiuxing WangFan BaiYu ShiNu ZhangPublished in: Nature communications (2023)
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 N 6 -methyladenosine (m 6 A) 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.
Keyphrases
- tyrosine kinase
- poor prognosis
- epidermal growth factor receptor
- stem cells
- end stage renal disease
- chronic kidney disease
- newly diagnosed
- type diabetes
- amino acid
- mesenchymal stem cells
- zika virus
- gene expression
- atrial fibrillation
- insulin resistance
- copy number
- liver injury
- adipose tissue
- genome wide
- drug induced
- locally advanced
- neoadjuvant chemotherapy
- protein kinase
- aedes aegypti