Claudin-18: a dominant tight junction protein in Barrett's esophagus and likely contributor to its acid resistance

Jovov, Biljana; Itallie, Christina M. Van; Shaheen, Nicholas J.; Carson, Johnny L.; Gambling, Todd M.; Anderson, James M.; Orlando, Roy C.

doi:10.1152/ajpgi.00158.2007

Cited by 120 publications

(102 citation statements)

References 46 publications

(57 reference statements)

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“…In the present experiments involving acidic bile salts, the levels of claudin-1 and -4 in the insoluble fraction significantly decreased following treatment with acidic GCA or TCA. Although claudin-3 has been detected in rat esophagus and claudin-18 has been detected in Barrett's esophageal epithelia (17,23,27), claudin-3 and claudin-18 were not detected in normal human esophagus or ALI-cultured cultured HEECs. As a limitation of the present study, although we previously detected the delocalization of claudin-4 in both colonic epithelial cell model and stratified epithelial cell model with NHBE cells after stimulation (29,31), differences in the staining pattern of TJ proteins after acidic bile acid stimulation were not detected in our HEECs model.…”

Section: Discussionmentioning

confidence: 92%

Bile salts disrupt human esophageal squamous epithelial barrier function by modulating tight junction proteins

Chen

Oshima

Shan

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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of acid and bile acids contributes to epithelial tissue injury in gastro-esophageal reflux disease. However, the influence of refluxed material on human esophageal stratified epithelial barrier function and tight junction (TJ) proteins has not been fully elucidated. Here, we investigated the influence of acid and bile acids on barrier function and TJ protein distribution using a newly developed air-liquid interface (ALI) in vitro culture model of stratified squamous epithelium based on primary human esophageal epithelial cells (HEECs). Under ALI conditions, HEECs formed distinct epithelial layers on Transwell inserts after 7 days of culture. The epithelial layers formed TJ, and the presence of claudin-1, claudin-4, and occludin were detected by immunofluorescent staining. The NP-40-insoluble fraction of these TJ proteins was significantly higher by day 7 of ALI culture. Exposure of HEECs to pH 2, and taurocholic acid (TCA) and glycocholic acid (GCA) at pH 3, but not pH 4, for 1 h decreased transepithelial electrical resistance (TEER) and increased paracellular permeability. Exposure of cell layers to GCA (pH 3) and TCA (pH 3) for 1 h also markedly reduced the insoluble fractions of claudin-1 and -4. We found that deoxycholic acid (pH 7.4 or 6, 1 h) and pepsin (pH 3, 24 h) significantly decreased TEER and increased permeability. Based on these findings, ALIcultured HEECs represent a new in vitro model of human esophageal stratified epithelium and are suitable for studying esophageal epithelial barrier functions. Using this model, we demonstrated that acid, bile acids, and pepsin disrupt squamous epithelial barrier function partly by modulating TJ proteins. These results provide new insights into understanding the role of TJ proteins in esophagitis. esophageal epithelium; claudin; air-liquid interface THE HUMAN ESOPHAGUS IS LINED with a layer of nonkeratinizing stratified squamous epithelium, which serves as an effective barrier against the influx of luminal contents. The esophageal epithelium consists of the basal, suprabasal, and superficial layers (14). In the pathogenesis of reflux esophagitis, acids, bile acids, and pepsin play a major role in damaging the esophageal epithelium (34). However, the mechanisms by which the luminal contents affect the barrier function of the stratified epithelial cell layers remain unclear.Tight junctions (TJs) separate the apical and basolateral cell surface domains to establish cell polarity and establish barrier function. TJs are composed of several proteins, including occludin, claudins, junctional adhesion molecule (22), and the scaffold protein zonula occludens (ZO). Of these proteins, claudins, which form specialized cellular structures that regulate the permeability of cellular layers, are the most important structural and functional components of TJ strands (1,6,10,30). Claudins are an integral transmembrane protein family consisting of at least 27 subtypes in mammals (22,40) and are essential for establishing and maintaining epithelial cell polarity by controlling the m...

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Section: Discussionmentioning

confidence: 92%

Bile salts disrupt human esophageal squamous epithelial barrier function by modulating tight junction proteins

Chen

Oshima

Shan

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…In all tumor types, we observed associations with distinct histologic subtypes, suggesting that CLDN18.2 is linked to a specialized genetic program. Jovov et al (36) have recently described that CLDN18.2 is activated during the course of metaplastic transition of stratified squamous cell epithelium of the esophagus to specialized columnar epithelium. This alteration arises in the setting of gastroesophageal reflux and predisposes for the development of distal esophageal adenocarcinoma.…”

Section: Discussionmentioning

confidence: 99%

Claudin-18 Splice Variant 2 Is a Pan-Cancer Target Suitable for Therapeutic Antibody Development

Şahin

Koslowski²,

Dhaene³

et al. 2008

Clinical Cancer Research

250

285

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Purpose: Antibody-based cancer therapies have emerged as the most promising therapeutics in oncology. The purpose of this study was to discover novel targets for therapeutic antibodies in solid cancer. Experimental Design:We combined data mining and wet-bench experiments to identify strictly gastrocyte lineage^specific cell surface molecules and to validate them as therapeutic antibody targets. Results: We identified isoform 2 of the tight junction molecule claudin-18 (CLDN18.2) as a highly selective cell lineage marker. Its expression in normal tissues is strictly confined to differentiated epithelial cells of the gastric mucosa, but it is absent from the gastric stem cell zone. CLDN18.2 is retained on malignant transformation and is expressed in a significant proportion of primary gastric cancers and the metastases thereof. In addition to its orthotopic expression, we found frequent ectopic activation of CLDN18.2 in pancreatic, esophageal, ovarian, and lung tumors, correlating with distinct histologic subtypes. The activation of CLDN18.2 depends on the binding of the transcription factor cyclic AMP^responsive element binding protein to its unmethylated consensus site. Most importantly, we were able to raise monoclonal antibodies that bind to CLDN18.2 but not to its lung-specific splice variant and recognize the antigen on the surface of cancer cells. Conclusions: Its highly restricted expression pattern in normal tissues, its frequent ectopic activation in a diversity of human cancers, and the ability to specifically target this molecule at the cell surface of tumor cells qualify CLDN18.2 as a novel, highly attractive pan-cancer target for the antibody therapy of epithelial tumors.Gastroesophageal and pancreatic cancers are among the malignancies with the highest unmet medical needs (1). Gastric cancer is the second leading cause of cancer death worldwide. In 2002, f1.4 million people worldwide developed gastroesophageal cancers and 1.1 million died (2). Esophageal cancer incidence has increased in recent decades, coinciding with a shift in histologic type and primary tumor location. Adenocarcinoma of the esophagus is now more prevalent than squamous cell carcinoma in the United States and Western Europe, with most tumors located in the distal esophagus (3).The overall 5-year survival rates for gastroesophageal cancers are 20% to 25% despite the aggressiveness of established standard treatments associated with substantial side effects (4, 5). For pancreatic cancer, there is an even greater medical need. Due to the advanced state of the disease at the time of diagnosis, the prognosis is extremely poor, with median survival times of less than 6 months and a 5-year survival rate of <5.5%. The lack of a major benefit from the various newergeneration combination chemotherapy regimens for these cancers has stimulated research into the use of targeted agents, such as small molecule -based kinase inhibitors and monoclonal antibodies (mAb; ref. 6). However, mAbs, such as bevacizumab, cetuximab, and trastuzumab...

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“…Claudins 2 (Furuse et al 2001;Colegio et al 2002;Amasheh et al 2002) (Hou et al 2005;Ikari et al 2008), 18 (Jovov et al 2007), and 19 tend to make leaky monolayers tighter. Claudins 2, 15 (Amasheh et al 2002;Colegio et al 2003), 16, and19 (Hou et al 2008) have a preference for cations over anions.…”

Section: Claudin Charge Selectivity and Termentioning

confidence: 99%

Physiology and Function of the Tight Junction

Anderson

Itallie²

2009

Cold Spring Harbor Perspectives in Biology

843

783

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Understanding of tight junctions has evolved from their historical perception as inert solute barriers to recognition of their physiological and biochemical complexity. Many proteins are specifically localized to tight junctions, including cytoplasmic actin-binding proteins and adhesive transmembrane proteins. Among the latter are claudins, which are critical barrier proteins. Current information suggests that the paracellular barrier is most usefully modeled as having two physiologic components: a system of charge-selective small pores, 4 Å in radius, and a second pathway created by larger discontinuities in the barrier, lacking charge or size discrimination. The first pathway is influenced by claudin expression patterns and the second is likely controlled by different proteins and signals. Recent information on claudin function and disease-causing mutations have led to a more complete understanding of their role in barrier formation, but progress is impeded by lack of high resolution structural information.T ight junctions form the continuous intercellular barrier between epithelial cells, which is required to separate tissue spaces and regulate selective movement of solutes across the epithelium. Although there are now .40 proteins (Schneeberger and Lynch 2004;Yamazaki et al. 2008) identified within the tight junction, the claudin family of transmembrane proteins, named from the Latin claudere to close, has emerged as the most critical for defining tight junction selectivity. Here, we review evidence that claudins regulate permselectivity (including size, electrical resistance, and ionic charge preference) derived from studies in cultured epithelial cell models and the phenotypes of knockout mice and human mutants. We highlight the physiologic relevance of selectivity but only briefly discuss how it might be physiologically regulated and altered in pathologic situations. We develop the perspective that the barrier is usefully described as having two pathways: first a system of charge-selective claudin-based pores that are 4 Å in radius and a second pathway created by larger discontinuities in the barrier and that lacks charge and size discrimination. The two pathways may be controlled by different proteins and signals.

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Claudin-18: a dominant tight junction protein in Barrett's esophagus and likely contributor to its acid resistance

Cited by 120 publications

References 46 publications

Bile salts disrupt human esophageal squamous epithelial barrier function by modulating tight junction proteins

Bile salts disrupt human esophageal squamous epithelial barrier function by modulating tight junction proteins

Claudin-18 Splice Variant 2 Is a Pan-Cancer Target Suitable for Therapeutic Antibody Development

Physiology and Function of the Tight Junction

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