Publication Date
5-15-2024
Journal
Nature Communications
DOI
10.1038/s41467-024-48347-5
PMID
38750026
PMCID
PMC11096375
PubMedCentral® Posted Date
5-15-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Animals, Jagged-1 Protein, Homeostasis, Esophageal Neoplasms, Esophagus, Stem Cells, Mice, Jagged-2 Protein, Humans, Carcinogenesis, Esophageal Squamous Cell Carcinoma, Mice, Knockout, Signal Transduction, Carcinoma, Squamous Cell, Receptors, Notch, Cell Differentiation, Male, Female, Differentiation, Cell proliferation, Oesophageal cancer, Adult stem cells
Abstract
Basal progenitor cells are crucial for maintaining foregut (the esophagus and forestomach) homeostasis. When their function is dysregulated, it can promote inflammation and tumorigenesis. However, the mechanisms underlying these processes remain largely unclear. Here, we employ genetic mouse models to reveal that Jag1/2 regulate esophageal homeostasis and foregut tumorigenesis by modulating the function of basal progenitor cells. Deletion of Jag1/2 in mice disrupts esophageal and forestomach epithelial homeostasis. Mechanistically, Jag1/2 deficiency impairs activation of Notch signaling, leading to reduced squamous epithelial differentiation and expansion of basal progenitor cells. Moreover, Jag1/2 deficiency exacerbates the deoxycholic acid (DCA)-induced squamous epithelial injury and accelerates the initiation of squamous cell carcinoma (SCC) in the forestomach. Importantly, expression levels of JAG1/2 are lower in the early stages of human esophageal squamous cell carcinoma (ESCC) carcinogenesis. Collectively, our study demonstrates that Jag1/2 are important for maintaining esophageal and forestomach homeostasis and the onset of foregut SCC.
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