Role of E-cadherin in the Pathogenesis of Gastroesophageal Reflux Disease

Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
The American Journal of Gastroenterology (Impact Factor: 10.76). 03/2011; 106(6):1039-47. DOI: 10.1038/ajg.2011.102
Source: PubMed


An early event in the pathogenesis of gastroesophageal reflux disease (GERD) is an acid-induced increase in junctional (paracellular) permeability in esophageal epithelium (EE). The molecular events that account for this change are unknown. E-cadherin is a junctional protein important in barrier function in EE. Therefore, defects in barrier function in EE were sought in GERD as well as whether their presence correlated with abnormalities in e-cadherin.
Endoscopic biopsies of EE from GERD (n=20; male 10; female 10; mean age 50 ± 10 years) and subjects with a healthy esophagus (controls; n=23; male 11; female 12; mean age 51 ± 11 years) were evaluated in mini-Ussing chambers and by western blot and immunochemistry; and serum analyzed by enzyme-linked immunosorbent assay (ELISA). A role for e-cadherin was also assessed using a unique conditional knockout of e-cadherin in adult mouse esophagus.
EE from GERD patients had lower electrical resistance and higher fluorescein flux than EE from controls; and the findings in GERD associated with cleavage of e-cadherin. Cleavage of e-cadherin in GERD was documented in EE by the presence of a 35-kDa, C-terminal fragment of the molecule on western blot and by an increase in soluble N-terminal fragments of the molecule in serum. Activation of the membrane metalloproteinase, A Disintegrin And Metalloproteinase (ADAM-10), was identified as a likely cause for cleavage of e-cadherin by western blot and immunostaining and a role for e-cadherin in the increased junctional permeability in EE from GERD supported by showing increased permeability after deletion of e-cadherin in mouse EE.
The EE in GERD has increased junctional permeability and this is in association with proteolytic cleavage of e-cadherin. As loss of e-cadherin can, alone, account for the increase in junctional permeability, cleavage of e-cadherin likely represents a critical molecular event in the pathogenesis of GERD, and identification of cleaved fragments may, if confirmed in larger studies, be valuable as a biomarker of GERD.

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Available from: Biljana Jovov,
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    • "Immunoreactivity of occludin was found in almost all cell layers and also staining of E-cadherin was observed mainly in the lower compartments of the epithelium in the esophageal biopsies. Previously, the study by Jovov et al. showed that the deletion of E-cadherin results in DIS and a marked increase in paracellular permeability in GERD patients [5]. This was not supported in the present GERD-patient groups, even if a tendency of decreased E-cadherin as well as occludin expressions were observed. "
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    • "patients. As E-cadherin is a junctional protein important in barrier function in esophageal epithelium, its cleavage likely explains the increase in junctional permeability in the esophageal epithelium of these patients [35] [36]. These studies, however, had no focus on respiratory symptoms. "
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    • "To test whether Sox2+ve basal cells can self-renew and differentiate in vivo, we exploited a KRT5-CreER transgenic mouse line to perform lineage tracing in combination with the Rosa26- lacZ reporter allele (Jovov et al., 2011; Rock et al., 2009). By using a low dose of Tamoxifen to label individual basal cells in the esophagus and following their behavior for 3 days, we found that single cells can divide to duplicate themselves and also differentiate to form columns of squamous epithelium (Figure 1H). "
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