Abstract
Background
c-Met encoded by the proto-oncogene MET, also known as hepatocyte growth factor (HGF) receptor, plays a crucial role in cellular processes. MET exon 14 skipping alteration (METΔ14EX) is a newly discovered MET mutation. SMAD2 is an important downstream transcription factor in TGF-β pathway. Unfortunately, the mechanisms by which METΔ14EX leads to oncogenic transformation are scarcely understood. The relationship between METΔ14EX and SMAD2 has not been studied yet.
Methods
We generate METΔ14EX models by CRISPR-Cas9. In vitro transwell, wound-healing, soft-agar assay, in vivo metastasis and subcutaneous recurrence assay were used to study the role of METΔ14EX in tumour progression. RNA-seq, Western blotting, co-immunoprecipitation (CO-IP) and immunofluorescent were performed to explore the interaction between c-Met and SMAD2.
Results
Our results demonstrated that METΔ14EX, independent of HGF, can prolong the constitutive activation of c-Met downstream signalling pathways by impeding c-Met degradation and facilitating tumour metastasis and recurrence. Meanwhile, METΔ14EX strengthens the interaction between c-Met and SMAD2, promoting SMAD2 phosphorylation. Therapeutically, MET inhibitor crizotinib impedes METΔ14EX-mediated tumour metastasis by decreasing SMAD2 phosphorylation.
Conclusions
These data elucidated the previously unrecognised role of METΔ14EX in cancer progression via activation of SMAD2 independent of TGF-β, which helps to develop more effective therapies for such patients.
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Data availability
All data generated or analysed during this study are included in this published article and its supplementary information files.
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Funding
This study was supported by the National Natural Science Foundation of China (NSFC 82273293) and Shanghai Municipal Health Commission Health Industry Clinical Research Project (20224Y0120).
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BZ, MY, HW and QL performed all of the experiments. YH and QY participated in the research. QL, BZ and MY designed experiments, analysed data, and wrote the manuscript. HW provided c-Met inhibitors. QL and BZ are the guarantors of this work and, as such, had full access to all the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. All authors read and approved the final manuscript.
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Liang, Q., Hu, Y., Yuan, Q. et al. MET exon 14 skipping mutation drives cancer progression and recurrence via activation of SMAD2 signalling. Br J Cancer 130, 380–393 (2024). https://doi.org/10.1038/s41416-023-02495-5
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DOI: https://doi.org/10.1038/s41416-023-02495-5