Claudin-1 and claudin-2 expression is elevated in inflammatory bowel disease and may contribute to early neoplastic transformation

Abstract

Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal adenocarcinoma. The factors that result in IBD-associated carcinogenesis are not understood. We hypothesized that altered expression of intestinal epithelial tight junction proteins might contribute to neoplastic progression. Semi-quantitative immunohistochemical staining of human biopsies was used to assess expression of the tight junction proteins claudin-1, claudin-2, claudin-4, and occludin in IBD, IBD-associated dysplasia, acute, self-limited colitis (ASLC), and sporadic adenomas. Claudin-1 and claudin-2 expression was elevated in active IBD, adenomas, and IBD-associated dysplasia, but not ASLC. In contrast, claudin-4 expression was elevated in both active IBD and ASLC. Occludin expression was similar to control in all cases. Importantly, in IBD, claudin-1 and claudin-2 expression correlated positively with inflammatory activity. To investigate mechanisms underlying altered claudin expression, β-catenin activation was assessed as nuclear localization. Like claudin-1 and claudin-2, β-catenin was markedly activated in IBD, dysplasia, IBD-associated dysplasia, but only slightly activated in ASLC. Taken together, these data suggest that β-catenin transcriptional activity is elevated in chronic injury and that this may contribute to increased claudin-1 and claudin-2 expression. We speculate that increased claudin-1 and claudin-2 expression may be involved in early stages of transformation in IBD-associated neoplasia.

EMMPRIN Modulates Epithelial Barrier Function through a MMP–Mediated Occludin Cleavage

“…A growing body of evidence has indicated that cancer progression is associated with decreased tight junctions, and the loss of occludin is generally correlated with tumor development. 34,35 It has also largely demonstrated that EMMPRIN expression is greatly increased in cancer tissues and is correlated with progression and, in some cases, with poor prognosis. 36,37 In view of our results presented here, it is tempting to speculate that EMMPRIN induction during tumor progression may lead to an MMP-dependent cleavage of occludin and may decrease cell contact, thus promoting invasion.…”

Gastrointestinal mucosal barrier function and diseases

“…JAM-A expression was downregulated in UC and in Crohn's disease (CD) at the inflamed mucosa [105]. In contrast, CLDN1 and CLDN2 were reported to be increased in UC and CD [107]. Occludin and CLDN8 were down-regulated and CLDN2 was up-regulated in patients with mild to moderate CD [108].…”

Neutrophil-Epithelial Interactions

“…23 Similar alterations in claudin family members have been described under conditions of inflammation, as seen in the intestinal mucosa of individuals with IBD. 98,99 Furthermore, selective disruption of specific subsets of tight junction proteins can be seen after exposure to inflammatory cytokines. As an example, Figure 5A highlights the effect of exposing cultured epithelial monolayers to the cytokine interferon-g that results in selective disorganization of several tight junction proteins while preserving architecture for the adherens junction proteins E-cadherin and b-catenin.…”

“…103 Aberrant claudin, CAR, and JAM-A protein expression has been correlated with cancer progression, altered barrier, and certain inflammatory diseases. 99,104,105 These associations, epithelial functions of junction-associated proteins, have been investigated using forward genetic approaches. These approaches have begun to provide a better appreciation of the consequences of inflammation on the functional biology of many tight and adherens junction molecules as well as desmosomal proteins.…”

“…113 Similarly, altered expression of CAR, occluding, and certain claudins are associated with defective epithelial homeostasis and, in some cases, links to cancer progression. 99,104,114 Inflammation-induced alterations in expression of apical junctional complex proteins are not specific to tight and adherens junctions structures because disruption of intestinal epithelial desmosomal structure during inflammation has also been shown to have potent functional consequences. 115 However, in contrast to the decreased protein expression observed for tight junction molecules, unpublished studies suggest that expression of the desmosomal cadherin desmoglein 2 (Dsg2) may be increased under certain inflammatory conditions.…”