Expression of tight-junction-associated proteins in human gastric cancer: downregulation of claudin-4 correlates with tumor aggressiveness and survival

Ohtani, S.; Terashima, Masanori; Satoh, Jun; Soeta, Nobutoshi; Saze, Zenichiroh; Kashimura, Seigo; Ohsuka, Fumihiko; Hoshino, Yutaka; Kogure, Michihiko; Gotoh, Mitsukazu

doi:10.1007/s10120-008-0497-0

Cited by 70 publications

(56 citation statements)

References 18 publications

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“…This upregulation correlated with expression of the transcription factor Cdx2 and with intestinal mucin expression which are related to intestinal metaplasia [50,54,59]. These data also indicate that expression of these CLDNs is not the primary cause of gastric cancer development [60].…”

Section: Gastric Cancermentioning

confidence: 64%

Gastrointestinal mucosal barrier function and diseases

2016

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The gastrointestinal mucosal barrier plays an essential role in the separation of the inside of the body from the outside environment. Tight junctions (TJs) are the most important component for construction of a constitutive barrier of epithelial cells, and they regulate the permeability of the barrier by tightly sealing the cell-cell junctions. TJ proteins are represented by claudins, occludin, junctional adhesion molecules, and scaffold protein zonula occludens. Among these TJ proteins, claudins are the major components of TJs and are responsible for the barrier and the polarity of the epithelial cells. Gastrointestinal diseases including reflux esophagitis, inflammatory bowel disease, functional gastrointestinal disorders, and cancers may be regulated by these molecules, and disruption of their functions leads to chronic inflammatory conditions and chronic or progressive disease. Therefore, regulation of the barrier function of epithelial cells by regulating the expression and localization of TJ proteins is a potential new target for the treatment of these diseases. Treatment strategies for these diseases might thus be largely altered if symptom generation and/or immune dysfunction could be regulated through improvement of mucosal barrier function. Since TJ proteins may also modify tumor infiltration and metastasis, other important goals include finding a good TJ biomarker of cancer progression and patient prognosis, and developing TJ protein-targeted therapies that can modify patient prognosis. This review summarizes current understanding of gastrointestinal barrier function, TJ protein expression, and the mechanisms underlying epithelial barrier dysregulation in gastrointestinal diseases.

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Section: Gastric Cancermentioning

confidence: 64%

Gastrointestinal mucosal barrier function and diseases

2016

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“…There is a relationship between the levels of claudin-1/claudin-4 and the metastasis of human cancers, including hepatic, colonic, ovarian, and gastric cancers (Agarwal et al, 2005;Resnick et al, 2005;Halder et al, 2008;Lee et al, 2008). The overexpression of claudin suppressed cancer metastasis in human pancreatic and gastric cancers (Michl et al, 2003;Mima et al, 2005;Ohtani et al, 2009). Claudin-4 suppressed or accelerated in vitro and in vivo metastasis of human cancer cells (Agarwal et al, 2005;Ohtani et al, 2009).…”

Section: Downloaded Frommentioning

confidence: 99%

A Claudin-Targeting Molecule as an Inhibitor of Tumor Metastasis

Saeki¹,

Kondoh²,

Kakutani³

et al. 2010

J Pharmacol Exp Ther

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Tumor metastasis of epithelium-derived tumors is the major cause of death from malignant tumors. Overexpression of claudin is observed frequently in malignant tumors. However, claudin-targeting antimetastasis therapy has never been investigated. We previously prepared a claudin-4-targeting antitumor molecule that consisted of the C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) fused to protein synthesis inhibitory factor (PSIF) derived from Pseudomonas exotoxin. In the present study, we investigated whether claudin CPE receptors can be a target for tumor metastasis by using the C-CPE-fused PSIF as a claudintargeting agent. One of the most popular murine metastasis models is the lung metastasis of intravenously injected B16 cells. Therefore, we first investigated the effects of the C-CPE-fused PSIF on lung metastasis of claudin-4-expressing B16 (CL4-B16) cells. Intravenous administration of the C-CPE-fused PSIF suppressed lung metastasis of CL4-B16 cells but not B16 cells. Injection of C-CPE-fused PSIF also inhibited tumor growth and spontaneous lung metastasis of murine breast cancer 4T1 cells inoculated into the subcutis. Treatment with C-CPE-fused PSIF did not show apparent side effects in mice. These findings indicate that claudin targeting may be a novel strategy for inhibiting some tumor metastases.

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“…23 However, although there have been a few studies into the association of claudin-4 expression and prognosis, it remains unclear whether claudin-4 expression is associated with clinical outcomes in gastric cancer. Although moderateto-strong claudin-4 staining was shown to be associated with decreased survival in the study by Resnick et al, 24 a recent study by Ohtani et al, 25 reported that low claudin-4 expression was independently associated with a significant decrease in overall survival. On the other hand, another study showed no significant correlation between claudin-4 expression and patient survival.…”

mentioning

confidence: 95%

Claudin-4 overexpression is associated with epigenetic derepression in gastric carcinoma

Kwon

Kim

Jeong

et al. 2011

Laboratory Investigation

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The tight junction (TJ) protein claudin-4 is aberrantly upregulated in gastric cancer, but its clinical significance and the molecular mechanisms underlying claudin-4 overexpression in gastric cancer remain unclear. Here, we investigated its roles and epigenetic mechanisms regulating CLDN4 expression in gastric cancer. We show that increased membranous expression of claudin-4 in gastric carcinoma is associated with better patient prognosis, whereas cytoplasmic claudin-4 expression did not show a significant association with prognosis. Consistent with the correlation of increased membranous claudin-4 with favorable clinicopathological factors, claudin-4 overexpression inhibited the migration and invasion of gastric cancer cells; in contrast, it did not affect cell growth. Claudin-4 expression also increased the barrier function of TJs. Claudin-4 upregulation was strongly correlated with DNA hypomethylation in both gastric tissues and gastric cancer cells. Moreover, CLDN4 expression was repressed in normal gastric tissues in association with bivalent histone modifications, and loss of repressive histone methylations and gain of active histone modifications were associated with CLDN4 overexpression in gastric cancer cells. Interestingly, CLDN4 repression could be markedly derepressed by combined treatments that simultaneously target both histone modifications and DNA demethylation in CLDN4-hypermethylated cells, whereas concomitant changes in histone methylations and acetylations are required for CLDN4 induction in CLDN4-repressed cells with low DNA methylation. Taken together, this study reveals that membranous claudin-4 expression is associated with gastric cancer progression and that it is an independent positive prognosis marker in gastric carcinoma. Furthermore, our findings suggest that epigenetic derepression may be a possible mechanism underlying CLDN4 overexpression in gastric cancer and that claudin-4 may have potential as a promising target for the treatment of gastric cancer.

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Expression of tight-junction-associated proteins in human gastric cancer: downregulation of claudin-4 correlates with tumor aggressiveness and survival

Cited by 70 publications

References 18 publications

Gastrointestinal mucosal barrier function and diseases

Gastrointestinal mucosal barrier function and diseases

A Claudin-Targeting Molecule as an Inhibitor of Tumor Metastasis

Claudin-4 overexpression is associated with epigenetic derepression in gastric carcinoma

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