ArticleCell cycle (Georgetown, Tex.)2014
Inhibition of Notch signaling enhances transdifferentiation of the esophageal squamous epithelium towards a Barrett's-like metaplasia via KLF4.
Article in Cell cycle (Georgetown, Tex.), 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 52 citations in OpenAlex.
- MRPL13 sustains mitochondrial integrity and MAPK-associated aggressiveness in esophageal squamous cell carcinoma.Cancer cell international · 2026Article
- Targeting notch signaling pathway in esophageal cancer: from molecular insights to therapies.Oncology reviews · 2026Review
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- Comprehensive genomic and transcriptomic analyses reveal prognostic stratification for esophageal squamous cell carcinoma.Signal transduction and targeted therapy · 2025Article
- Essential and dual effects of Notch activity on a natural transdifferentiation event.Nature communications · 2025Article
- Cellular Origins and Lineage Plasticity in Cancer.Cold Spring Harbor perspectives in medicine · 2024Review
- The occurrence and development mechanisms of esophageal stricture: state of the art review.Journal of translational medicine · 2024Review
- Promising preclinical patient-derived organoid (PDO) and xenograft (PDX) models in upper gastrointestinal cancers: progress and challenges.BMC cancer · 2023Review
- Signaling Pathways in the Pathogenesis of Barrett's Esophagus and Esophageal Adenocarcinoma.International journal of molecular sciences · 2023Review
- The role of bile acid in intestinal metaplasia.Frontiers in physiology · 2023Review
- Understanding the cellular origin and progression of esophageal cancer using esophageal organoids.Cancer letters · 2021Review
- Pediatric Patient With Concurrent Eosinophilic Esophagitis, Erosive Reflux Esophagitis, and Barrett's Esophagus.ACG case reports journal · 2020Article
- Functional role of kallikrein 5 and proteinase-activated receptor 2 in eosinophilic esophagitis.Science translational medicine · 2020Article
- Research progress of cancer stem cells and IL-6/STAT3 signaling pathway in esophageal adenocarcinoma.Translational cancer research · 2020Review
- Transcriptome Characterization of Reverse Development inG3 (Bethesda, Md.) · 2019Article
- From genetics to signaling pathways: molecular pathogenesis of esophageal adenocarcinoma.Biochimica et biophysica acta. Reviews on cancer · 2019Review
- The cyclical hit model: how paligenosis might establish the mutational landscape in Barrett's esophagus and esophageal adenocarcinoma.Current opinion in gastroenterology · 2019Review
- Identification of a primitive intestinal transcription factor network shared between esophageal adenocarcinoma and its precancerous precursor state.Genome research · 2019Article
- Genome-wide tracts of homozygosity and exome analyses reveal repetitive elements with Barrets esophagus/esophageal adenocarcinoma risk.BMC bioinformatics · 2019Article
- ESOPHAGEAL CANCERS AND MODEL SYSTEMS.Transactions of the American Clinical and Climatological Association · 2019Article
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Authors and funding
11 authors at 6 institutions in 1 country.
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Abstract
Barrett's esophagus (BE) is defined as an incomplete intestinal metaplasia characterized generally by the presence of columnar and goblet cells in the formerly stratified squamous epithelium of the esophagus. BE is known as a precursor for esophageal adenocarcinoma. Currently, the cell of origin for human BE has yet to be clearly identified. Therefore, we investigated the role of Notch signaling in the initiation of BE metaplasia. Affymetrix gene expression microarray revealed that BE samples express decreased levels of Notch receptors (NOTCH2 and NOTCH3) and one of the the ligands (JAG1). Furthermore, BE tissue microarray showed decreased expression of NOTCH1 and its downstream target HES1. Therefore, Notch signaling was inhibited in human esophageal epithelial cells by expression of dominant-negative-Mastermind-like (dnMAML), in concert with MYC and CDX1 overexpression. Cell transdifferentiation was then assessed by 3D organotypic culture and evaluation of BE-lineage specific gene expression. Notch inhibition promoted transdifferentiation of esophageal epithelial cells toward columnar-like cells as demonstrated by increased expression of columnar keratins (K8, K18, K19, K20) and glandular mucins (MUC2, MUC3B, MUC5B, MUC17) and decreased expression of squamous keratins (K5, K13, K14). In 3D culture, elongated cells were observed in the basal layer of the epithelium with Notch inhibition. Furthermore, we observed increased expression of KLF4, a potential driver of the changes observed by Notch inhibition. Interestingly, knockdown of KLF4 reversed the effects of Notch inhibition on BE-like metaplasia. Overall, Notch signaling inhibition promotes transdifferentiation of esophageal cells toward BE-like metaplasia in part via upregulation of KLF4. These results support a novel mechanism through which esophageal epithelial transdifferentiation promotes the evolution of BE.
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