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1.
Nat Commun ; 14(1): 4467, 2023 07 25.
Article in English | MEDLINE | ID: mdl-37491377

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 ß 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.


Subject(s)
Brain Neoplasms , Glioblastoma , Animals , Mice , Glioblastoma/metabolism , Proto-Oncogene Proteins c-met/metabolism , RNA, Circular/genetics , Brain Neoplasms/metabolism , Cell Transformation, Neoplastic/genetics , Carcinogenesis/genetics , Cell Line, Tumor
2.
Cancer Sci ; 114(5): 2053-2062, 2023 May.
Article in English | MEDLINE | ID: mdl-36308276

ABSTRACT

YAP/TAZ have been identified as master regulators in malignant phenotypes of glioblastoma (GBM); however, YAP/TAZ transcriptional disruptor in GBM treatment remains ineffective. Whether post-transcriptional dysregulation of YAP/TAZ improves GBM outcome is currently unknown. Here, we report that insulin-like growth factor 2 (IGF2) mRNA-binding protein 1 (IGF2BP1 or IMP1) is upregulated in mesenchymal GBM compared with proneural GBM and correlates with worse patient outcome. Overexpression of IMP1 in proneural glioma stem-like cells (GSCs) promotes while IMP1 knockdown in mesenchymal GSCs attenuates tumorigenesis and mesenchymal signatures. IMP1 binds to and stabilizes m6A-YAP mRNA, leading to activation of YAP/TAZ signaling, depending on its m6A recognition and binding domain. On the other hand, TAZ functions as enhancer for IMP1 expression. Collectively, our data reveal a feedforward loop between IMP1 and YAP/TAZ maintaining GBM/GSC tumorigenesis and malignant progression and a promising molecular target in GBM.


Subject(s)
Glioblastoma , Glioma , Humans , Carcinogenesis/genetics , Cell Line, Tumor , Cell Transformation, Neoplastic , Glioblastoma/metabolism , Phosphoproteins/genetics , Phosphoproteins/metabolism , Signal Transduction , Transcription Factors/genetics , Transcription Factors/metabolism , YAP-Signaling Proteins
3.
Nat Commun ; 13(1): 4795, 2022 08 15.
Article in English | MEDLINE | ID: mdl-35970825

ABSTRACT

Glioblastoma (GBM) is a highly aggressive primary brain tumour and is resistant to nearly all available treatments, including natural killer (NK) cell immunotherapy. However, the factors mediating NK cell evasion in GBM remain largely unclear. Here, we report that EZH2-92aa, a protein encoded by circular EZH2, is overexpressed in GBM and induces the immune evasion of GBM stem cells (GSCs) from NK cells. Positively regulated by DEAD-box helicase 3 (DDX3), EZH2-92aa directly binds the major histocompatibility complex class I polypeptide-related sequence A/B (MICA/B) promoters and represses their transcription; it also indirectly represses UL16-binding protein (ULBP) transcription by stabilizing EZH2. The downregulation of NK group 2D ligands (NKG2DLs, including MICA/B and ULBPs) in GSCs mediates NK cell resistance. Moreover, stable EZH2-92aa knockdown enhances NK cell-mediated GSC eradication in vitro and in vivo and synergizes with anti-PD1 therapy. Our results highlight the immunosuppressive function of EZH2-92aa in inhibiting the NK cell response in GBM and the clinical potential of targeting EZH2-92aa for NK-cell-directed immune therapy.


Subject(s)
Enhancer of Zeste Homolog 2 Protein , Glioblastoma , NK Cell Lectin-Like Receptor Subfamily K , Tumor Escape , Enhancer of Zeste Homolog 2 Protein/genetics , GPI-Linked Proteins/genetics , Glioblastoma/genetics , Histocompatibility Antigens Class I/metabolism , Humans , Ligands , NK Cell Lectin-Like Receptor Subfamily K/genetics , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Receptors, Natural Killer Cell
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