ArticleAmerican journal of physiology. Gastrointestinal and liver physiology2014
Dickkopf-1, the Wnt antagonist, is induced by acidic pH and mediates epithelial cellular senescence in human reflux esophagitis.
Article in American journal of physiology. Gastrointestinal and liver physiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 30 citations in OpenAlex.
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- Gastrointestinal symptoms in patients with isolated oligodontia and a Wnt gene mutation.Oral diseases · 2023Article
- A senescence-based prognostic gene signature for colorectal cancer and identification of the role of SPP1-positive macrophages in tumor senescence.Frontiers in immunology · 2023Article
- Critical role of lncEPAT in coupling dysregulated EGFR pathway and histone H2A deubiquitination during glioblastoma tumorigenesis.Science advances · 2022Article
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- Identification of Unique Transcriptomic Signatures and Hub Genes Through RNA Sequencing and Integrated WGCNA and PPI Network Analysis in Nonerosive Reflux Disease.Journal of inflammation research · 2021Article
- Expression of Wnt pathway molecules is associated with disease outcome in metastatic high-grade serous carcinoma.Virchows Archiv : an international journal of pathology · 2020Article
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- In-depth characterization of the Wnt-signaling/β-catenin pathway in an in vitro model of Barrett's sequence.BMC gastroenterology · 2019Article
- Dickkopf-1 (DKK1) promotes tumor growth via Akt-phosphorylation and independently of Wnt-axis in Barrett's associated esophageal adenocarcinoma.American journal of cancer research · 2019Article
- Acidic pH promotes nucleus pulposus cell senescence through activating the p38 MAPK pathway.Bioscience reports · 2018Article
- Epithelial cell senescence: an adaptive response to pre-carcinogenic stresses?Cellular and molecular life sciences : CMLS · 2017Review
- Expression and prognostic value of SFRP1 and β-catenin in patients with glioblastoma.Oncology letters · 2016Article
- Protective role of ALDH2 against acetaldehyde-derived DNA damage in oesophageal squamous epithelium.Scientific reports · 2015Article
- Wnt/β-Catenin Signaling Activation beyond Robust Nuclear β-Catenin Accumulation in Nondysplastic Barrett's Esophagus: Regulation via Dickkopf-1.Neoplasia (New York, N.Y.) · 2015Article
- Application of quantitative trait locus mapping and transcriptomics to studies of the senescence-accelerated phenotype in rats.BMC genomics · 2014Article
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Squamous esophageal epithelium adapts to acid reflux-mediated injury by proliferation and differentiation via signal transduction pathways. Induction of the Wnt antagonist Dickkopf-1 (Dkk1) is involved in tissue repair during inflammation and cellular injury. In this study, we aimed to identify the biological role of Dkk1 in human reflux esophagitis with respect to cell growth and regulation of Wnt signaling. Esophageal biopsies from reflux-esophagitis patients (n = 15) and healthy individuals (n = 10) were characterized in terms of Dkk1 expression. The role of Dkk1 in response to acid-mediated epithelial injury was analyzed by cellular assays in vitro utilizing squamous esophageal epithelial cell lines (EPC1-hTERT, EPC2-hTERT, and HEEC). Dkk1 was significantly overexpressed in human reflux-esophagitis tissue compared with healthy esophageal mucosa at transcriptional and translational levels. After acute and chronic acid (pH 4) exposure, esophageal squamous epithelial cell lines expressed and secreted high levels of Dkk1 in response to stress-associated DNA injury. High extracellular levels of human recombinant Dkk1 inhibited epithelial cell growth and induced cellular senescence in vitro, as demonstrated by reduced cell proliferation, G0/G1 cell cycle arrest, elevated senescence-associated β-galactosidase activity, and upregulation of p16. Acid pulsing induced Dkk1-mediated senescence, which was directly linked to the ability of Dkk1 to antagonize the canonical Wnt/β-catenin signaling. In healthy esophageal mucosa, Dkk1 expression was associated with low expression of transcriptionally active β-catenin, while in reflux-esophagitis tissue, Dkk1 overexpression correlated with increased senescence-associated β-galactosidase activity and p16 upregulation. The data indicate that, in human reflux esophagitis, Dkk1 functions as a secreted growth inhibitor by suppressing Wnt/β-catenin signaling and promoting cellular senescence. These findings suggest a significant role for Dkk1 and cellular senescence in esophageal tissue homeostasis during reflux esophagitis.
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