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Inhibition of Notch signaling enhances transdifferentiation of the esophageal squamous epithelium towards a Barrett's-like metaplasia via KLF4
- Publication Year :
- 2014
- Publisher :
- Taylor & Francis, 2014.
-
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.
- Subjects :
- JAG1
Notch signaling pathway
Cell Culture Techniques
Kruppel-Like Transcription Factors
Stratified squamous epithelium
Biology
Cell Line
Proto-Oncogene Proteins c-myc
Barrett Esophagus
Kruppel-Like Factor 4
Esophagus
Metaplasia
Report
medicine
Humans
Serrate-Jagged Proteins
Molecular Biology
Homeodomain Proteins
Receptors, Notch
Transdifferentiation
Calcium-Binding Proteins
Mucins
Intestinal metaplasia
Membrane Proteins
Epithelial Cells
Cell Biology
Anatomy
medicine.disease
DNA-Binding Proteins
medicine.anatomical_structure
Gene Expression Regulation
Tissue Array Analysis
Barrett's esophagus
Cell Transdifferentiation
Cancer research
Intercellular Signaling Peptides and Proteins
Keratins
RNA Interference
medicine.symptom
Jagged-1 Protein
Developmental Biology
Signal Transduction
Transcription Factors
Subjects
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....e66754cfc7ab6c78ef520da718c004db
- Full Text :
- https://doi.org/10.6084/m9.figshare.1284399.v1