2. Academic Validation
  3. Circular RNA encoded MET variant promotes glioblastoma tumorigenesis

Circular RNA encoded MET variant promotes glioblastoma tumorigenesis

  • Nat Commun. 2023 Jul 25;14(1):4467. doi: 10.1038/s41467-023-40212-1.
Jian Zhong # 1 2,  Xujia Wu # 1 2,  Yixin Gao # 1 2,  Junju Chen # 1 2,  Maolei Zhang 1 2,  Huangkai Zhou 1 2,  Jia Yang 1 2,  Feizhe Xiao 3,  Xuesong Yang 1 2,  Nunu Huang 1 2,  Haoyue Qi 4 5,  Xiuxing Wang 6 7 8 9,  Fan Bai 10 11,  Yu Shi 12 13,  Nu Zhang 14 15
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
  • 2 Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangdong Translational Medicine Innovation Platform, Guangzhou, Guangdong, 510080, China.
  • 3 Department of Scientific Research Section, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
  • 4 Institute of Pathology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
  • 5 Key Laboratory of Tumour Immunopathology of the Ministry of Education of China, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
  • 6 National Health Commission Key Laboratory of Antibody Techniques, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. drxiuxingwang@163.com.
  • 7 Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. drxiuxingwang@163.com.
  • 8 Jiangsu Provincial Key Laboratory of Human Functional Genomics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. drxiuxingwang@163.com.
  • 9 Institute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. drxiuxingwang@163.com.
  • 10 Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University (PKU), Beijing, China. fbai@pku.edu.cn.
  • 11 Beijing Advanced Innovation Center for Genomics (ICG), Peking University, Beijing, China. fbai@pku.edu.cn.
  • 12 Institute of Pathology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China. drshiyu@126.com.
  • 13 Key Laboratory of Tumour Immunopathology of the Ministry of Education of China, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China. drshiyu@126.com.
  • 14 Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. zhangnu2@mail.sysu.edu.cn.
  • 15 Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangdong Translational Medicine Innovation Platform, Guangzhou, Guangdong, 510080, China. zhangnu2@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 37491377 DOI: 10.1038/s41467-023-40212-1
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.

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