Abstract Activation of β-catenin is recognized as a critical early factor in tumorigenesis. Citrobacter rodentium (CR) induces transmissible murine colonic hyperplasia (TMCH) and variable degrees of inflammation and necrosis depending upon the genetic background. Utilizing the CR-induced hyperplasia and/or inflammation in C3H/HeNHsd (C3H) inbred mice, we observed a dual phase wherein initially, an increase in proliferation at days 5 and 7 was followed by development of colitis at day 9 of TMCH. When sequential changes in proteins involved in adherens and tight junctions were analyzed in isolated colonic crypts, increasing levels of β-catenin, ZO-1, ZO-2 and claudin-2 were measured in TritonX100-soluble fraction at days 5 and 7 of TMCH, while E-cadherin and claudin-5 were mainly present in TritonX100-insoluble (cytoskeletal) pool. Interestingly, the cytoskeletal pools exhibited extensive degradation of β-catenin/E-cadherin/ZO-1 and ZO-2 but not of claudin-5 at days 5 and 7 of TMCH and preceded active colitis at day 9. Immunohistochemically, almost complete loss of membrane-bound β-catenin/E-cadherin and ZO-2 was recorded between 9 and 11 days post-infection. However, changes in permeability, as measured by increases in serum FITC-dextran levels, increased significantly at days 5 and 7 and peaked between day 9 and 11 post-infection paralleling bacterial dissemination to spleen and liver at these time points. Mechanistically, β-catenin translocated to the nucleus, interacted with increasing levels of T-cell factor-4 and upregulated downstream targets, cyclinD1 and c-myc thereby promoting crypt hyperplasia at days 5 and 7 of TMCH. When CR-infected mice were placed on: 6% pectin (source of colonic butyrate), 4% curcumin and 4% bael extract diets for 9 days starting 2 days post-CR infection, all three dietary interventions: i) reduced the morbidity and mortality of CR-infected C3H mice, ii) restored the junctional labeling of β-catenin/E-cadherin and ZO-2, iii) blocked increases in colonic permeability thereby preventing bacterial dissemination to distant organs and finally, iv) promoted β-catenin-independent increases in colonic crypt proliferation as was revealed by increased Ki-67 labeling. Thus, i) fragmentation of β-catenin/E-cadherin/ZO-1 and ZO-2 precedes loss of barrier function and onset of colitis and, ii) epithelial hyperproliferation in response to dietary interventions may facilitate epithelial recovery following inflammatory insult but may also promote mucosal priming for neoplasia. TMCH model therefore provides an excellent tool to separate the anti-inflammatory effects of dietary ingredients from pro-proliferatory functions in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5654.
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Jan 8, 2012
M.J Wheeler + 7
Open Access