TLR4 activation in BE results in a strong increase in COX-2 and may contribute to malignant transformation.
These results imply that miRNA-145 indirectly targets BMP4 via GATA6 and is potentially involved in the development of BE.
BackgroundCirculating microRNAs (miRNAs) have been suggested as novel markers for various diseases. The goal of this pilot study was to identify circulating miRNAs differentially expressed comparing Barrett’s esophagus (BE), esophageal adenocarcinoma (EAC), and controls.MethodsMicroRNA expression profiling was performed by qPCR array using plasma from six controls and eight BE and eight EAC patients. Validation was performed by analyzing the expression of six selected miRNAs, by qRT-PCR in 115 plasma samples of controls, BE, and EAC patients. Diagnostic accuracy was evaluated by area under the curve (AUC) analysis.ResultsWe identified three miRNAs that were elevated in EAC and four miRNAs that were elevated in BE. Further validation showed that miRNA-382-5p was significantly increased and miRNA-133a-3p significantly decreased in EAC. miRNA-194-5p and miRNA-451a were significantly increased and miRNA-136-5p significantly decreased in BE versus controls. A combination of three or more miRNAs was found to have a good diagnostic performance in discriminating BE from controls (AUC: 0.832), EAC from controls (AUC: 0.846), and BE from EAC (AUC: 0.797).ConclusionOur data suggest that circulating miRNAs are differentially expressed in BE and EAC. The miRNAs identified may be used for future non-invasive screening of BE and EAC.Electronic supplementary materialThe online version of this article (doi:10.1007/s00535-015-1133-5) contains supplementary material, which is available to authorized users.
Barrett's esophagus (BE) is a metaplastic condition of the distal esophagus that occurs because of chronic gastroesophageal reflux. Previous studies have identified BE-specific microRNAs (miRNAs) in comparison with normal squamous epithelium (SQ). We hypothesized that BE-specific miRNAs could be induced in esophageal SQ cells by exposure to acid and/or bile salts. We aimed to determine whether BE-specific miRNAs are upregulated in an esophageal SQ cell line (Het-1A) in an environment with acid and/or bile salts and whether this is nuclear factor-κB (NF-κB) dependent. Acid and/or bile salt incubations were performed in Het-1A cells. Experiments were performed with or without inhibiting the NF-κB pathway. Quantitative reverse transcriptase polymerase chain reaction was performed to determine expression of miRNA-143, -145, -192, -194, cyclo-oxygenase-2 (COX2), mucin 2 (MUC2), and sex determining region Y-box 9. For validation, we determined levels of these miRNAs in biopsies from patients with reflux esophagitis and normal SQ. Significantly increased expression levels of miRNA-143 (2.7-fold), -145 (2.6-fold), -192 (2.0-fold), -194 (2.2-fold), COX2, MUC2, and sex determining region Y-box 9 were found upon acidic bile salt incubation, but not upon acid or bile salt alone. NF-κB pathway inhibition significantly decreased miRNA-143, -192, -194, COX2, and MUC2 expression. Additionally, miRNA-143, -145 and -194 expression was increased in reflux esophagitis biopsies compared with normal SQ, but no changes were found in miRNA-192 expression. Our findings suggest that upregulation of BE-specific miRNAs by acidic bile may be an early event in the transition of SQ to BE and that their expression is partly regulated by the NF-κB pathway.
BackgroundBarrett’s esophagus (BE) is a premalignant condition caused by chronic gastroesophageal reflux. BE patients have an increased risk of developing esophageal adenocarcinoma (EAC). As many aspects of this condition are still unknown, there is a need for in vitro models to study BE development.AimTo review the literature on cell lines and incubation conditions for studying BE development.MethodsA literature search was performed using PubMed, EMBASE and the Cochrane library, combining the words esophagus, cell line, culture, Barrett’s, bile, acid, exposure, reflux and adenocarcinoma.ResultsA wide range of cell lines and incubation conditions to study BE development have been reported. The most commonly used cell lines are derived from epithelium from patients with BE or EAC. A 25-minute incubation with 200 μM bile salts induced cell proliferation and Akt phosphorylation. However, increased CDX2 and MUC2 expression was only observed with longer incubations or higher bile salt concentrations. Two-hundred μM bile at pH 6 showed a higher toxicity to EAC cells than the same concentration at pH 7. Multiple 5-minute exposures with 200 μM bile at pH 4 or pH 7 increased CK8/18 and COX2 in BE epithelial cells.ConclusionsTwo-hundred μM conjugated primary or secondary bile salts at pH 4 for multiple short exposures is able to induce BE specific factors in BE cell lines. In SQ and EAC cell lines; however, higher concentrations of secondary bile salts for 8 h are needed to induce BE specific molecules. Due to the high variability in reported methods, it is difficult to determine the most effective in vitro setup for studying the development of BE.
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