Jovov, B. et al. Claudin-18: a dominant tight junction protein in Barrett's esophagus and likely contributor to its acid resistance. Am. J. Physiol. Gastrointest. Liver Physiol. 293, G1106-G1113

Dept. of Medicine, Univ. of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.8). 01/2008; 293(6):G1106-13. DOI: 10.1152/ajpgi.00158.2007
Source: PubMed


Barrett's esophagus (BE) is a specialized columnar epithelium (SCE) that develops as replacement for damaged squamous epithelium (SqE) in subjects with reflux disease, and as such it is apparently more acid resistant than SqE. How SCE resists acid injury is poorly understood; one means may involve altered tight junctions (TJs) since the TJ in SqE is an early target of attack and damage by acid in reflux disease. To assess this possibility, quantitative RT-PCR for 21 claudins was performed on endoscopic biopsies on SCE of BE and from healthy SqE from subjects without esophageal disease. In SCE, Cldn-18 was the most highly expressed at the mRNA level and this finding is paralleled by marked elevation in protein expression on immunoblots. In contrast in SqE, Cldn-18 was minimally expressed at the mRNA level and undetectable at the protein level. Immunofluorescence studies showed membrane localization of Cldn-18 and colocalization with the tight junction protein, zonula occludens-1. When Cldn-18 was overexpressed in MDCK II cells and mounted as monolayers in Ussing chambers, it raised electrical resistance and, as shown by lower dilution potentials to a NaCl gradient and lower diffusion potentials to acidic gradients, selectively reduced paracellular permeability to both Na(+) and H(+) compared with parental MDCK cells. We conclude that Cldn-18 is the dominant claudin in the TJ of SCE and propose that the change from a Cldn-18-deficient TJ in SqE to a Cldn-18-rich TJ in SCE contributes to the greater acid resistance of BE.

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    • "The role of CLDN18 in the gastric or gastric-type epithelia is still poorly understood. In a specialized columnar epithelium of the Barrett esophagus, in which CLDN18 is reported to be the dominant claudin, CLDN18 contributes to greater acid resistance (Jovov et al. 2007). It remains unknown whether aberrant CLDN18 expression in the pancreatic ductal epithelium exerts a similar functional role under unknown stimuli toward carcinogenesis. "
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    ABSTRACT: Pancreatic ductal neoplasms exhibit gastric epithelium-like characteristics. In this study, we evaluated the expression of claudin-18 (CLDN18), a gastric epithelium-associated claudin, in pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), and pancreatic ductal adenocarcinomas (PDACs) using immunohistochemistry. We observed a high level of expression of CLDN18 in PanINs (31/32, 97%), IPMNs (61/65, 95%), and MCNs (4/5, 80%) using ordinary tissue section analysis. Furthermore, we observed a high level of CLDN18 expression in PDACs (109/156, 70%) using tissue microarray analysis. However, the normal pancreatic duct or the ductal metaplasia of the acinar cells was not immunoreactive. Comparative analysis of CLDN18 and phenotypic markers in IPMNs revealed that simultaneous expression of CLDN18 and intestinal markers frequently occurred, even in intestinal-type IPMNs. CLDN18 variant 2 mRNA was expressed and was similarly upregulated by phorbol 12-myristate 13-acetate (PMA) treatment in pancreatic cancer cell lines and in a gastric cancer cell line. An inhibitor of pan-PKC (GF109203X) completely suppressed this upregulation in pancreatic cancer cells. These results indicate that CLDN18, a marker for the early carcinogenetic process, is commonly expressed in precursor lesions of PDAC. Activation of the PKC pathway might be involved in CLDN18 expression associated with pancreatic carcinogenesis.
    Full-text · Article · Aug 2011 · Journal of Histochemistry and Cytochemistry
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    • "This manner of claudin expression is thought to provide functional diversity for the barrier properties of TJs, such as conductance and charge selectivity of ions, depending on the environment of the extracellular domains of the claudins [10]. Indeed, a number of studies have revealed that overexpression of a certain claudin in cultured epithelial cells changes the barrier or channel properties of TJs, as evaluated by measuring the TER and diffusion potential, which indicate the charge selectivity of TJs [10] [11] [12] [13] [14] [15] [16] [17] [18]. The effects of overexpression of each claudin depend not only on the type of claudin overexpressed but also on the cell lines used, since each cell line has its own barrier properties of TJs based on its unique background expression pattern of claudins [19]. "
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    ABSTRACT: Two sides of functions of tight junctions; the barrier and the channel in the paracellular pathway are believed to be essential for the development and physiological functions of organs. Recent identification of molecular components of tight junctions has enabled us to analyze their functions by generating knockout mice of the corresponding genes. In addition, positional cloning has identified mutations in the genes of several components of tight junctions in hereditary diseases. These studies have highlighted in vivo functions of tight junctions.
    Preview · Article · Apr 2009 · Biochimica et Biophysica Acta
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