Barretts esophagus, bile salts

PURPOSE: Chronic gastroesophageal reflux disease (GERD) causes the abnormal reflux of acid and bile salts, which would induce Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). EGFR, as one of main components of the exosome, plays an important role in cancer progression. Here, we investigated the role of acidic bile salts (ABS)-induced exosomal EGFR in EAC cell proliferation. METHODS: Electronic microscopic examination and Western blot were used to identify exosomes...

Barrett's esophagus (BE) is a precancerous lesion of esophageal adenocarcinoma (EAC). It is a pathological change in which the squamous epithelium distal esophagus is replaced by columnar epithelium. Loss of P53 is involved in the development of BE and is taken as a risk factor for the progression. We established a HET1A cell line with P53 stably knockdown by adenovirus vector infection, followed by 30 days of successive acidic bile salt treatment. MTT, transwell assay, and wound closure assay were applied to assess cell proliferation and migration ability...

Esophageal adenocarcinoma (EAC), the predominant type of esophageal cancer in the United States, develops through Barrett's esophagus (BE)-dysplasia-carcinoma cascade. Gastroesophageal reflux disease, where acidic bile salts refluxate into the esophagus, is the main risk factor for the development of BE and its progression to EAC. The NFE2-related factor 2 (NRF2) is the master cellular antioxidant regulator. We detected high NRF2 protein levels in the EAC cell lines and primary tissues. Knockdown of NRF2 significantly enhanced acidic bile salt-induced oxidative stress, DNA damage, and inhibited EAC cell growth...

BACKGROUND: Esophageal adenocarcinoma (EAC) is characterized by poor prognosis and low survival rate. Chronic gastroesophageal reflux disease (GERD) is the main risk factor for the development of Barrett's esophagus (BE), a preneoplastic metaplastic condition, and its progression to EAC. Yes-associated protein 1 (YAP1) activation mediates stem-like properties under cellular stress. The role of acidic bile salts (ABS) in promoting YAP1 activation under reflux conditions remains unexplored...

AIMS: Investigate the effect and mechanism of COX-2 on viability, intestinal metaplasia, and atypia in human esophageal squamous and Barrett esophageal cell lines. METHODS: Human esophageal squamous and Barrett esophageal cell lines were transfected with a COX-2 expression vector and a COX-2 siRNA, and then were treated with acid, bile salts, and a mixture of both. Cell viability, the expression of COX-2, NF-κB(p65), CDX-2, MUC2, c-myb, and BMP-4, and the morphology and microstructure of cells were then observed...

The pathogenesis of subsquamous intestinal metaplasia (SSIM), in which glands of Barrett's esophagus (BE) are buried under esophageal squamous epithelium, is unknown. In a rat model of reflux esophagitis, we found that columnar-lined esophagus developed via a wound-healing process involving epithelial-mesenchymal plasticity (EMP) that buried glands under ulcerated squamous epithelium. To explore a role for reflux-induced EMP in BE, we established and characterized human Barrett's organoids and sought evidence of EMP after treatment with acidic bile salts (AB)...

Barrett's esophagus arises in the process of wound healing in distal esophageal epithelium damaged by gastroesophageal reflux disease. Differentiation of fibroblast into myofibroblasts, a smooth muscle cell-like phenotype and tissue contraction are crucial processes in wound healing. No study has evaluated mechanism by which luminal esophageal nitric oxide (NO) affect Rho-associated coiled coil-forming protein kinase (Rho-ROCK) signaling pathway, a key factor of tissue contraction, in stromal fibroblasts to develop Barrett's esophagus...

BACKGROUND: Chronic gastroesophageal reflux disease (GERD) is a major risk factor for the development of metaplastic Barrett's esophagus (BE) and its progression to esophageal adenocarcinoma (EAC). Uncontrolled accumulation of reactive oxygen species (ROS) in response to acidic bile salts (ABS) in reflux conditions can be lethal to cells. In this study, we investigated the role of APE1/REF1 in regulating nuclear erythroid factor-like 2 (NRF2), the master antioxidant transcription factor, in response to reflux conditions...

Multiple genome-wide association studies (GWAS) have linked Forkhead Box F1 (FOXF1) to Barrett's esophagus (BE). Understanding whether FOXF1 is involved in initiation of Barrett's metaplasia could allow FOXF1 to be used for risk stratification and for therapy. Two-dimensional cell cultures and three-dimensional organoid cultures and well-annotated human biopsies were used to determine the role of FOXF1 in BE pathogenesis. Multiple established esophageal squamous and BE cell lines were tested in gain- and loss-of-function studies...

The frequency of esophageal adenocarcinoma is rising despite widespread use of 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. Since 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...

Reflux esophagitis is a result of esophageal exposure to acid and bile during episodes of gastroesophageal reflux. Aside from chemical injury to the esophageal epithelium, it has been shown that acid and bile induce cytokine-mediated injury by stimulating the release of pro-inflammatory cytokines. During the repair and healing process following reflux injury, the squamous esophageal cells are replaced with a columnar epithelium causing Barrett's metaplasia, which predisposes patients to esophageal adenocarcinoma...

Gastroesophageal reflux disease (GERD) is the main risk factor for Barrett's tumorigenesis. In this study, we investigated the role of NRF2 in response to exposure acidic bile salts (ABS), in conditions that mimic GERD, using Barrett's esophagus cell models. We detected an increase in NRF2 protein levels, following exposure to ABS. We found oxidization of cysteines (cysteines with oxidized thiol groups) in KEAP1 protein with a weaker interaction between NRF2 and KEAP1, following ABS exposure. Treatment with bile salts increased nuclear NRF2 levels, enhancing its transcription activity, as measured by an ARE (antioxidant response element) luciferase reporter assay...

BACKGROUND: The incidence of esophageal adenocarcinoma (EAC) is rising rapidly in the US and Western countries. The development of Barrett's esophagus (BE) and its progression to EAC have been linked to chronic gastroesophageal reflux disease (GERD). Exposure of BE and EAC cells to acidic bile salts (ABS) in GERD conditions induces high levels of oxidative stress and DNA damage. In this study, we investigated the role of insulin-like growth factor binding protein 2 (IGFBP2) in regulating ABS-induced DNA double-strand breaks...

BACKGROUND & AIMS: Metaplastic glands buried under squamous epithelium are frequently detected in patients with Barrett esophagus (BE). This subsquamous intestinal metaplasia might be responsible for cancers that develop despite endoscopic surveillance and for metaplasia recurrences after endoscopic ablation. To determine whether reflux induces BE cells to undergo an epithelial-to-mesenchymal transition (EMT) that produces subsquamous intestinal metaplasia, we assessed EMT in BE cells exposed to acidic bile salts and in rat and human esophageal tissues...

The development of Barrett's esophagus (BE) and its progression to esophageal adenocarcinoma (EAC) is highly linked to exposure to acidic bile salts due to chronic gastroesophageal reflux disease (GERD). In this study, we investigated the role of Apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/REF-1) in STAT3 activation in response to acidic bile salts. Our results indicate that APE1 is constitutively overexpressed in EAC, whereas its expression is transiently induced in response to acidic bile salts in non-neoplastic BE...

BACKGROUND: Oxidative stress secondary to bile-acid exposure has been associated with metaplastic degeneration of normal esophageal mucosa into Barrett's esophagus (BE) cells and eventually esophageal adenocarcinoma. We previously reported that the macromolecular response of BE cells to this stress was largely regulated by the expression of manganese-dependent mitochondrial superoxide dismutase (MnSOD). As the mitochondrion plays a vital role in MnSOD activation, this study sought to determine the location and activity of MnSOD within BE cells after exposure to oxidative stress...

Gastroesophageal reflux disease (GERD) is the strongest known risk factor for esophageal adenocarcinoma. In the center of tumorigenic events caused by GERD is repeated damage of esophageal tissues by the refluxate. In this study, we focused on a genotoxic aspect of exposure of esophageal cells to acidic bile reflux (BA/A). Analyzing cells generated from patients with Barrett's esophagus and human esophageal specimens, we found that BA/A cause significant DNA damage that is mediated by reactive-oxygen species...

Bile acid reflux in the esophagus plays an important role in the carcinogenesis of esophageal adenocarcinoma (EAC). The G-protein coupled bile acid receptor (TGR5) has been associated with the development of gastrointestinal cancer. However, little is known regarding the role of TGR5 in esophageal carcinoma and precancerous lesions. We analyzed genomic DNA from 116 EACs for copy number aberrations via Affymetrix SNP6.0 microarrays. The TGR5 gene locus was amplified in 12.7% (14/116) of the EACs. The TGR5 protein expression was also assessed using immunohistochemistry from tissue microarrays, including Barrett's esophagus (BE), low-(LGD) and high-grade dysplasia (HGD), columnar cell metaplasia (CM), squamous epithelium (SE), EAC and squamous cell carcinoma...

BACKGROUND: Claudins are a family of integral membrane proteins and are components of tight junctions (TJs). Many TJ proteins are known to tighten the cell structure and maintain a barrier. Claudin-2 forms gated paracellular channels and allows sodium ions and other small positively charged ions to cross between adjacent cells. Recently, we found that vitamin D receptor (VDR) enhanced Claudin-2 expression in colon and that bile salt receptors VDR and Takeda G-protein coupled receptor5 (TGR5) were highly expressed in esophageal adenocarcinoma (EAC) and precancerous lesions...

BACKGROUND AND AIMS: Inflammation plays an important role in the development of esophageal adenocarcinoma and its metaplastic precursor lesion, Barrett's esophagus. Toll-like receptor (TLR) 2 signalling and lysosomal function have been linked to inflammation-associated carcinogenesis. We examined the expression of TLR2 in the esophagus and the effect of long-term TLR2 activation on morphological changes and expression of factors involved in lysosomal function in a Barrett's esophagus epithelium cell line...