Claudin-1 and claudin-2 expression is elevated in inflammatory bowel disease and may contribute to early neoplastic transformation.
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. Semiquantitative 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, beta-catenin activation was assessed as nuclear localization. Like claudin-1 and claudin-2, beta-catenin was markedly activated in IBD, sporadic dysplasia, and IBD-associated dysplasia, but was only slightly activated in ASLC. Taken together, these data suggest that beta-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 at early stages of transformation in IBD-associated neoplasia.
Weber
Christopher R
CR
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Nalle
Sam C
SC
Tretiakova
Maria
M
Rubin
David T
DT
Turner
Jerrold R
JR
D000236:Adenoma / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D062445:Claudin-1; D057167:Claudins; D015331:Cohort Studies; D003093:Colitis, Ulcerative / Q000276:immunology / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000378:metabolism*; D003424:Crohn Disease / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism
C568108:CLDN1 protein, human; C491875:CLDN2 protein, human; D062445:Claudin-1; D057167:Claudins; D008565:Membrane Proteins; D051176:beta Catenin