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Beta-Catenin stabilization imparts crypt progenitor phenotype to hyperproliferating colonic epithelia.

ABSTRACT: Utilizing the Citrobacter rodentium (CR)-induced transmissible murine colonic hyperplasia (TMCH) model, we provide mechanistic basis of changes in beta-catenin/APC/CKIepsilon leading to progression and/or regression of hyperplasia in vivo. In response to CR-induced TMCH, crypt lengths increased significantly between days 6-27 post-infection, followed by a steep decline by day 34. beta-Cat(45)/total beta-catenin were elevated on day 1 post-infection, preceding changes in crypt length, and persisted for 27 days before declining by day 34. Importantly, cellular CKIepsilon and beta-catenin co-immunoprecipitated and exhibited remarkable parallel changes in kinetics during hyperplasia/regression phases. beta-catenin, phosphorylated at Ser33,37 and Thr41 (beta-cat(33,37/41)), was low till day 12, followed by gradual increase until day 27 before declining by day 34. GSK-3beta exhibited significant Ser(9)-phosphorylation/inactivation at days 6-12 with partial recovery at days 27-34. Wild type (wt) APC (p312) levels increased at day 6 with transient proteolysis/truncation to p130 form between days 12 and 15; p312 reappeared by day 19 and returned to baseline by day 34. The kinetics of beta-Cat(45)/beta-catenin nuclear accumulation and acetylation (Ac-beta-Cat(Lys49)) from days 6 to 27, followed by loss of phosphorylation/acetylation by day 34 was almost identical; Tcf-4 co-immunoprecipitated with beta-Cat(45)/beta-catenin and localized immunohistochemically to beta-Cat(41/45)-positive regions leading to elevated cyclin D1 expression, during the hyperproliferative, but not regression phases of TMCH. CKIepsilon mediated phosphorylation of beta-Cat(45), resulting in stabilization/nuclear translocation of beta-Cat(45) may be critical for maintaining proliferation at days 6-27. Reversal of GSK-3beta phosphorylation and APC changes may be equally critical during the regression phase from days 27 to 34.

SUBMITTER: Sellin JH

PROVIDER: S-EPMC2868370 | biostudies-other | 2009 Jan

REPOSITORIES: biostudies-other

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beta-Catenin stabilization imparts crypt progenitor phenotype to hyperproliferating colonic epithelia.

Sellin Joseph H JH Wang Yu Y Singh Pomila P Umar Shahid S

Experimental cell research 20081029 1

Utilizing the Citrobacter rodentium (CR)-induced transmissible murine colonic hyperplasia (TMCH) model, we provide mechanistic basis of changes in beta-catenin/APC/CKIepsilon leading to progression and/or regression of hyperplasia in vivo. In response to CR-induced TMCH, crypt lengths increased significantly between days 6-27 post-infection, followed by a steep decline by day 34. beta-Cat(45)/total beta-catenin were elevated on day 1 post-infection, preceding changes in crypt length, and persist ...[more]

PMID: 18996369

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Project description:Salmonella infections can become chronic and increase the risk of cancer. The mechanisms by which specific Salmonella organisms contribute to cancer, however, are still unknown. Live and attenuated Salmonella are used as vectors to target cancer cells, but there have been no systematic studies of the oncogenic potential of chronic Salmonella infections in cancer models. AvrA, a pathogenic product of Salmonella, is inserted into host cells during infection and influences eukaryotic cell pathways. In the current study, we colonized mice with Salmonella AvrA-sufficient or AvrA-deficient Salmonella typhimirium strains and induced inflammation-associated colon cancer by azoxymethane/dextran sulfate sodium (AOM/DSS). We confirmed Salmonella persisted in the colon for up to 45 weeks. Salmonella was identified not only in epithelial cells on the colonic luminal surface and base of the crypts but also in invading tumors. Tumor incidence in the AvrA+infected group was 100% compared with 51.4% in the AOM/DSS group without bacterial gavage and 56.3% in mice infected with the AvrA- strain. Infection with AvrA+ strain also altered tumor distribution from the distal to proximal colon that might reflect changes in the microbiome. AvrA-expressing bacteria also upregulated beta-catenin signaling as assessed by decreased beta-catenin ubiquitination, increased nuclear beta-catenin and increased phosphorylated-beta-catenin (Ser552), a marker of proliferating stem-progenitor cells. Other β-catenin targets increased by AvrA included Bmi1, a cancer stem cell marker, matrix metalloproteinase-7, and cyclin D1. In summary, AvrA-expressing Salmonella infection activates β-catenin signals and enhances colonic tumorigenesis. Our findings provide important new mechanistic insights into how a bacterial protein targets proliferating stem-progenitor cells and contributes to cancer development. Our observations also raise a note of caution regarding the use of mutant Salmonella organisms as vectors for anti-cancer therapy. Finally, these studies could suggest biomarkers (such as AvrA level in gut) to assess cancer risk in susceptible individuals and infection-related dysregulation of β-catenin signaling in cancer.

Dataset Information

Beta-Catenin stabilization imparts crypt progenitor phenotype to hyperproliferating colonic epithelia.

Publications

beta-Catenin stabilization imparts crypt progenitor phenotype to hyperproliferating colonic epithelia.

Similar Datasets

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