Dynamics of Claudins Expression in Colitis and Colitis-Associated Cancer in Rat

Abstract

Claudins comprise a multigene family of 24 species and have been shown to constitute the backbone of tight junction strands in simple epithelial cells and to be directly involved in their barrier functions. Apical-most tight junction protein complexes (TJs) are implicated in inflammatory bowel disease (IBD) pathophysiology. Except for claudin-8, TJs explored in this study (including ZO-1, claudin-1, -2, -3, -7, -12, and -15) were found to be expressed in rat colonic tissues. ZO-1 and claudin-7 were ubiquitously expressed in all study groups. As depicted in Fig. 1b, expressions of claudin-2, -12, and -15 significantly diminished after combined treatment with dextran sulfate sodium (DSS) and busulfan (BU) (lane 5), compared with either agent alone (lanes 2 and 4). Despite the lack of significance, there appeared to be a subtle dose-dependent decrease with DSS treatment (lanes 2 and 3). In contrast to these results obtained from DSS colitis, expression of claudin-1 was significantly downregulated, while expression of claudin-15 was upregulated in colitis-associated cancer tissues in the azoxymethane (AOM)/DSS model (Fig. 2b). It is very intriguing that claudins’ expression dynamics were mutually exclusive between colitis and colitis-associated cancer in rats. However, the biological significance of disease-specific claudin expression profiles will remain elusive until the specific expression and function of each claudin in a tissue- and cell-type relationship are comprehensively clarified. Currently, the physiologic consequences of the diversity of TJ barrier function resulting from multiple combinations of claudins are only beginning to be recognized. Full unraveling of these complexities could inspire a new paradigm of inflammation and cancer, and eventually translate to clinical practice on IBD.