Acid, Bile, and CDX: the ABCs of making Barrett's metaplasia

Barrett's esophagus, a squamous-to-columnar cell metaplasia that develops as a result of chronic gastroesophageal reflux disease (GERD), is a risk factor for esophageal adenocarcinoma. The molecular events underlying the pathogenesis of Barrett's metaplasia are poorly understood, but recent studies suggest that interactions among developmental signaling pathways, morphogenetic factors, and Caudal homeobox (Cdx) genes play key roles. Strong expression of Cdx genes normally is found in the intestine but not in the esophagus and stomach. When mice are genetically engineered so that their gastric cells express Cdx, the stomach develops a metaplastic, intestinal-type epithelium similar to that of Barrett's esophagus. Exposure to acid and bile has been shown to activate the Cdx promoter in certain esophageal cell lines, and Cdx expression has been found in inflamed esophageal squamous epithelium and in the specialized intestinal metaplasia of Barrett's esophagus. Barrett's metaplasia must be sustained by stem cells, which might be identified by putative, intestinal stem cell markers like leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) and doublecortin and CaM kinase-like-1 (DCAMKL-1). Emerging concepts in tumor biology suggest that Barrett's cancers may develop from growth-promoting mutations in metaplastic stem cells or their progenitor cell progeny. This report reviews the roles of developmental signaling pathways and the Cdx genes in the development of normal gut epithelia and the potential mechanisms whereby GERD may induce the esophageal expression of Cdx genes and other morphogenetic factors that mediate the development of Barrett's metaplasia. The role of stem cells in the development of metaplasia and in carcinogenesis and the potential for therapies directed at those stem cells also is addressed.

Download Full-text

In Barrett’s epithelial cells, weakly acidic bile salt solutions cause oxidative DNA damage with response and repair mediated by p38

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00329.2019 ◽

2020 ◽

Vol 318 (3) ◽

pp. G464-G478

Author(s):

Xiaofang Huo ◽

Kerry B. Dunbar ◽

Xi Zhang ◽

Qiuyang Zhang ◽

Stuart Jon Spechler ◽

...

Keyword(s):

Dna Damage ◽

Bile Salt ◽

Barrett’S Esophagus ◽

Esophageal Adenocarcinoma ◽

Dna Damage Response ◽

Barrett's Esophagus ◽

Oxidative Dna Damage ◽

Damage Response ◽

Barrett's Metaplasia ◽

Barrett’S Metaplasia

The frequency of esophageal adenocarcinoma is rising despite widespread use of proton pump inhibitors (PPIs), which heal reflux esophagitis but do not prevent reflux of weakly acidic gastric juice and bile in Barrett’s esophagus patients. We aimed to determine if weakly acidic (pH 5.5) bile salt medium (WABM) causes DNA damage in Barrett’s cells. Because p53 is inactivated frequently in Barrett’s esophagus and p38 can assume p53 functions, we explored p38’s role in DNA damage response and repair. We exposed Barrett’s cells with or without p53 knockdown to WABM, and evaluated DNA damage, its response and repair, and whether these effects are p38 dependent. We also measured phospho-p38 in biopsies of Barrett’s metaplasia exposed to deoxycholic acid (DCA). WABM caused phospho-H2AX increases that were blocked by a reactive oxygen species (ROS) scavenger. WABM increased phospho-p38 and reduced bromodeoxyuridine incorporation (an index of S phase entry). Repair of WABM-induced DNA damage proceeded through p38-mediated base excision repair (BER) associated with reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease I (Ref-1/APE1). Cells treated with WABM supplemented with ursodeoxycholic acid (UDCA) exhibited enhanced p38-mediated responses to DNA damage. All of these effects were observed in p53-intact and p53-deficient Barrett’s cells. In patients, esophageal DCA perfusion significantly increased phospho-p38 in Barrett’s metaplasia. WABM exposure generates ROS, causing oxidative DNA damage in Barrett’s cells, a mechanism possibly underlying the rising frequency of esophageal adenocarcinoma despite PPI usage. p38 plays a central role in oxidative DNA damage response and Ref-1/APE1-associated BER, suggesting potential chemopreventive roles for agents like UDCA that increase p38 activity in Barrett’s esophagus. NEW & NOTEWORTHY We found that weakly acidic bile salt solutions, with compositions similar to the refluxed gastric juice of gastroesophageal reflux disease patients on proton pump inhibitors, cause oxidative DNA damage in Barrett’s metaplasia that could contribute to the development of esophageal adenocarcinoma. We also have elucidated a critical role for p38 in Barrett’s metaplasia in its response to and repair of oxidative DNA damage, suggesting a potential chemopreventive role for agents like ursodeoxycholic acid that increase p38 activity in Barrett’s esophagus.

Download Full-text

Gain of allelic gene expression for IGF-II occurs frequently in Barrett's esophagus

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00383.2005 ◽

2006 ◽

Vol 290 (5) ◽

pp. G871-G875 ◽

Cited By ~ 8

Author(s):

Linda A. Feagins ◽

Nathan Susnow ◽

Hui Ying Zhang ◽

Stephanie Pearson ◽

Charles Owen ◽

...

Keyword(s):

Gene Expression ◽

Barrett’S Esophagus ◽

Restriction Enzyme ◽

Barrett's Esophagus ◽

Enzyme Digestion ◽

Restriction Enzyme Digestion ◽

Allelic Gene ◽

Barrett's Metaplasia ◽

Apai Polymorphism ◽

Barrett’S Metaplasia

The IGF-II gene normally exhibits genomic imprinting, a DNA modification that allows the expression of only one of the two inherited alleles. With loss of imprinting, there is a gain of allelic gene expression (GOAGE) due to IGF-II being expressed by both alleles. GOAGE for IGF-II has been demonstrated in a number of malignancies and in normal epithelia surrounding malignancies, but not in epithelia without associated neoplasia. We hypothesized that nonneoplastic Barrett's epithelium might have GOAGE for IGF-II that could facilitate its progression to neoplasia. Endoscopic biopsies were obtained from metaplastic esophageal, normal gastric, and normal duodenal epithelia from 43 patients with Barrett's esophagus. Genomic DNA were analyzed using PCR followed by ApaI restriction enzyme digestion or allele-specific PCR to identify an ApaI polymorphism of IGF-II. cDNA from patients with the ApaI polymorphism were analyzed for IGF-II GOAGE using exon connection PCR, followed by a secondary nested PCR and ApaI restriction enzyme digestion. We found that 13 (30%) of 43 samples of Barrett's metaplasia contained the ApaI polymorphism and were thus informative for IGF-II, and sufficient material was available for GOAGE analysis in 9 of those 13 cases. GOAGE for IGF-II was demonstrated in five (56%) of those nine cases. All patients with GOAGE in Barrett's metaplasia also demonstrated GOAGE in the gastric and duodenal epithelia. In contrast, patients without GOAGE in Barrett's metaplasia also had no GOAGE in their gastric and duodenal epithelia. We conclude that in patients with Barrett's esophagus, GOAGE for IGF-II is found frequently in the metaplastic esophageal epithelium as well as in normal gastric and duodenal epithelia.

Download Full-text

Drug delivery of zinc to Barrett’s metaplasia by oral administration to Barrett’s esophagus patients

Therapeutic Delivery ◽

10.4155/tde.13.151 ◽

2014 ◽

Vol 5 (3) ◽

pp. 257-264 ◽

Cited By ~ 2

Author(s):

Mary C Valenzano ◽

Joanna M Mercado ◽

Xuexuan Wang ◽

E Peter Zurbach ◽

Jonathan Raines ◽

...

Keyword(s):

Drug Delivery ◽

Oral Administration ◽

Barrett’S Esophagus ◽

Barrett's Esophagus ◽

Barrett's Metaplasia ◽

Barrett’S Metaplasia

Download Full-text

Sa1543 Buried Barrett's Metaplasia in Patients Undergoing Radiofrequency Ablation for Barrett's Esophagus: A Closer Look

Gastrointestinal Endoscopy ◽

10.1016/j.gie.2011.03.277 ◽

2011 ◽

Vol 73 (4) ◽

pp. AB202-AB203

Author(s):

Jose C. Hernandez ◽

Jay Yuan ◽

Shiva K. Ratuapli ◽

Kevin C. Ruff ◽

Giovanni DePetris ◽

...

Keyword(s):

Radiofrequency Ablation ◽

Barrett’S Esophagus ◽

Barrett's Esophagus ◽

Barrett's Metaplasia ◽

Barrett’S Metaplasia

Download Full-text

In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00085.2014 ◽

2014 ◽

Vol 307 (2) ◽

pp. G129-G139 ◽

Cited By ~ 24

Author(s):

Sui Peng ◽

Xiaofang Huo ◽

Davood Rezaei ◽

Qiuyang Zhang ◽

Xi Zhang ◽

...

Keyword(s):

Dna Damage ◽

Ursodeoxycholic Acid ◽

Bile Acids ◽

Barrett’S Esophagus ◽

Cell Lines ◽

Barrett's Esophagus ◽

Oxidative Dna Damage ◽

Protective Effects ◽

Barrett's Metaplasia ◽

Barrett’S Metaplasia

Hydrophobic bile acids like deoxycholic acid (DCA), which cause oxidative DNA damage and activate NF-κB in Barrett's metaplasia, might contribute to carcinogenesis in Barrett's esophagus. We have explored mechanisms whereby ursodeoxycholic acid (UDCA, a hydrophilic bile acid) protects against DCA-induced injury in vivo in patients and in vitro using nonneoplastic, telomerase-immortalized Barrett's cell lines. We took biopsies of Barrett's esophagus from 21 patients before and after esophageal perfusion with DCA (250 μM) at baseline and after 8 wk of oral UDCA treatment. DNA damage was assessed by phospho-H2AX expression, neutral CometAssay, and phospho-H2AX nuclear foci formation. Quantitative PCR was performed for antioxidants including catalase and GPX1. Nrf2, catalase, and GPX1 were knocked down with siRNAs. Reporter assays were performed using a plasmid construct containing antioxidant responsive element. In patients, baseline esophageal perfusion with DCA significantly increased phospho-H2AX and phospho-p65 in Barrett's metaplasia. Oral UDCA increased GPX1 and catalase levels in Barrett's metaplasia and prevented DCA perfusion from inducing DNA damage and NF-κB activation. In cells, DCA-induced DNA damage and NF-κB activation was prevented by 24-h pretreatment with UDCA, but not by mixing UDCA with DCA. UDCA activated Nrf2 signaling to increase GPX1 and catalase expression, and protective effects of UDCA pretreatment were blocked by siRNA knockdown of these antioxidants. UDCA increases expression of antioxidants that prevent toxic bile acids from causing DNA damage and NF-κB activation in Barrett's metaplasia. Elucidation of this molecular pathway for UDCA protection provides rationale for clinical trials on UDCA for chemoprevention in Barrett's esophagus.

Download Full-text