Claudins are transmembrane proteins that seal tight junctions, bind with peripheral protein zonula occludens (ZO)-1, and are known to play an important role in several normal tissues and cancers. However, the role of claudin-1 and claudin-7 expressions in esophageal squamous cell carcinoma remains to be clarified. In the present study, we confirmed the expressions of claudin-1, claudin-7, and ZO-1 in the prickle cell layer of the normal human esophageal squamous epithelium. The expressions of claudin-1 and claudin-7 at the invasive front of the esophageal squamous cell carcinoma were analyzed immunohistochemically to clarify their role in tumor progression. Reduced expression of claudin-7 at the invasive front of the esophageal cancer was significantly associated with the depth of invasion (P = .004), stage (P = .038), lymphatic vessel invasion (P = .001), and lymph node metastasis (P = .014). In contrast, significant association was not detected between claudin-1 expression and clinicopathologic factors except for histologic differentiation of the tumor (P = .0029). Comparison of claudin-7 expression at the invasive front of the primary tumor and its corresponding metastatic lymph nodes revealed significant reduction in claudin-7 expression in the metastatic lymph nodes (P = .007). These results suggest that the reduced expression of claudin-7 at the invasive front of esophageal squamous cell carcinoma may lead to tumor progression and subsequent metastatic events. Thus, claudin-7 can be a novel marker for the prediction of lymph node metastasis.

B ased on a tendency of gland formation, GC is classified histologically as differentiated type versus undifferentiated type or as intestinal type versus diffuse type.(1,2) Immunohistochemical examinations have demonstrated that gastric and intestinal mucin phenotypic cell markers are widely expressed in GC, irrespective of the histological characteristics: human gastric mucins (MUC5AC and MUC6), which are specifically expressed in gastric surface mucous cells and pyloric gland cells, and human intestinal mucins (CD10 and MUC2), which are closely correlated with mature intestinal epithelial cells and goblet cells, have been detected in various types of GC.(3,4) Although tumors with gastric mucin expression are associated with poor patient outcome and greater malignancy potential in the incipient phase of invasion and metastasis compared with other tumor phenotypes, (3) there is little understanding of whether or not mucin phenotypic classification could be used for evaluating tumor aggressiveness and the grade of GC malignancy.The Cdx2 homeobox gene is important in the early differentiation, maintenance and proliferation of intestinal epithelial cells in mice. (5,6) In fact, aberrant expression of Cdx2 has been observed consistently in IM of gastric mucosa and in a subset of GC.(7) In addition, Cdx2-mediated transactivation of the MUC2 promoter controls gastric cell differentiation.(8) Thus, Cdx2 plays an important role in the aberrant intestinal differentiation program of IM and GC. Interestingly, Cdx2 can upregulate the levels of claudin-2, a claudin TJ molecule, by activating the CLDN2 promoter.(9) These findings suggest a possible relationship between mucin phenotype and claudins in controlling the differentiation of stomach epithelium, most likely by Cdx2 transcription activity. TJs are located on the most apical side of the intercellular adherent structure of epithelial cells in the gastrointestinal tract, (10) and claudins are crucial components of TJ in the formation of tightly connected cell sheets, the creation of physiological barriers separating the apical and basolateral spaces, and the control of electrolytes permeability across a paracellular barrier via the formation of hetero-or homodimers. (11,12) Claudins also bind to ZO-1, a TJ protein that promotes interaction between TJ and the actin cytoskeleton.(13) Therefore, claudins are believed to determine cell polarity through cytoskeleton rearrangement. (14,15) In general, the dissociation of cancer cells from the primary nests is a crucial step in metastasis. Suppression of cell-to-cell adhesiveness may trigger the release of cancer cells from primary cancer nests and confer invasive properties on tumors. (16) Therefore, dysfunction of TJ by altered expression of claudins is thought to promote cancer cell invasion and metastasis. (17)(18)(19)(20) In the present study, on the hypothesis that disruption of TJs may enhance the grade of malignancy of cancer cells, we examined the expression of both 'gastric' (claudin-18) and 'intestinal' (claudin-3 an...

Objective: Claudin-4 plays a key role in constructing the tight junction (TJ), and altered claudin-4 expression has been documented in various human malignancies; however, little is known about the biological significance of claudin-4 in colorectal cancers (CRCs). The aim of this study is to investigate the significance of claudin-4 expression in CRC and its association with clinicopathological factors. Methods: The levels of claudin-4 expression in a total of 129 CRCs and 44 metastatic tumors were examined by immunohistochemistry. A small interfering RNA (siRNA)-mediated claudin-4 knockdown examination was also conducted to assess the biological role(s) of claudin-4 in cultured cells. Results: Expression of claudin-4 at the intercellular membrane was well preserved at the surface of the tumor; however, decreased claudin-4 expression was detected in 57% of CRCs, particularly at the invasive front. Interestingly, decreased claudin-4 expression was detected in metastatic lesions of CRC. The siRNA-mediated claudin-4 knockdown in SW480 claudin-4-positive CRC cells upregulated cell motility, whereas no significant change was detected in cell proliferation. Conclusions: These observations suggested that disruption of claudin-4-mediated TJ construction enhances cancer cell invasion and metastasis in human CRC. Claudin-4 might be a good biomarker for diagnosing the risk of distant metastasis.

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An orally active dual CysLT1 and CysLT2 antagonist possessing a distinctive structure which consists of triple bond and dicarboxylic acid moieties is described. Gemilukast (ONO-6950) was generated via isomerization of the core indole and the incorporation of a triple bond into a lead compound. Gemilukast exhibited antagonist activities with IC50 values of 1.7 and 25 nM against human CysLT1 and human CysLT2, respectively, and potent efficacy at an oral dose of 0.1 mg/kg given 24 h before LTD4 challenge in a CysLT1-dependent guinea pig asthmatic model. In addition, gemilukast dose-dependently reduced LTC4-induced bronchoconstriction in both CysLT1- and CysLT2-dependent guinea pig asthmatic models, and it reduced antigen-induced constriction of isolated human bronchi. Gemilukast is currently being evaluated in phase II trials for the treatment of asthma.