Targeting Stem Cells and Dysplastic Features With Dual MEK/ERK and STAT3 Suppression in Gastric Carcinogenesis
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View abstract on PubMed
Summary
This summary is machine-generated.Pyrvinium halts metaplasia and kills dysplasia cells by blocking MEK/ERK and STAT3 pathways. This drug shows promise for preventing gastric cancer by reprogramming precancerous conditions.
Area Of Science
- Gastroenterology and Oncology
- Cancer Stem Cell Biology
- Molecular Signaling Pathways
Background
- Gastric cancer risk increases with metaplasia progression to dysplasia.
- Effective targeted therapies for precancerous gastric lesions are lacking.
- Key signaling pathways in metaplasia and dysplasia stem cells require identification.
Purpose Of The Study
- Identify signaling pathways in metaplasia-dysplasia progression.
- Evaluate pyrvinium as a targeted therapy for precancerous gastric lesions.
- Assess pyrvinium's efficacy in mouse models and human organoids.
Main Methods
- Organoid models from Mist1-Kras mice and human gastric precancerous lesions.
- Phospho-antibody array and single-cell RNA-sequencing.
- In vivo efficacy study of pyrvinium in Mist1-Kras mice.
Main Results
- Pyrvinium induced growth arrest in metaplasia and cell death in dysplasia.
- Pyrvinium downregulated ERK and STAT3 phosphorylation and target genes.
- Pyrvinium targeted CD133+/CD166+ stem cells and proliferating cells.
- Pyrvinium inhibited metaplasia and restored normal gastric glands in vivo.
- Pyrvinium suppressed human dysplastic organoid growth by blocking MEK/ERK and STAT3.
Conclusions
- Pyrvinium effectively induces growth arrest in metaplasia and cell death in dysplasia.
- Dual blockade of MEK/ERK and STAT3 signaling is the mechanism of action.
- Pyrvinium is a potential therapeutic agent for preventing gastric cancer development.
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