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Wnt Signaling Inhibition Deprives Small Intestinal Stem Cells of Clonogenic Capacity.

ABSTRACT: The Wnt pathway plays a crucial role in self-renewal and differentiation of cells in the adult gut. In the present study, we revealed the functional consequences of inhibition of canonical Wnt signaling in the intestinal epithelium. The study was based on generation of a novel transgenic mouse strain enabling inducible expression of an N-terminally truncated variant of nuclear Wnt effector T cell factor 4 (TCF4). The TCF4 variant acting as a dominant negative (dn) version of wild-type (wt) TCF4 protein decreased transcription of ?-catenin-TCF4-responsive genes. Interestingly, suppression of Wnt/?-catenin signaling affected asymmetric division of intestinal stem cells (ISCs) rather than proliferation. ISCs expressing the transgene underwent several rounds of division but lost their clonogenic potential and migrated out of the crypt. Expression profiling of crypt cells revealed that besides ISC-specific markers, the dnTCF4 production downregulated expression levels of epithelial genes produced in other crypt cells including markers of Paneth cells. Additionally, in Apc conditional knockout mice, dnTCF activation efficiently suppressed growth of Apc-deficient tumors. In summary, the generated mouse strain represents a convenient tool to study cell-autonomous inhibition of ?-catenin-Tcf-mediated transcription.

SUBMITTER: Janeckova L

PROVIDER: S-EPMC5067622 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Wnt Signaling Inhibition Deprives Small Intestinal Stem Cells of Clonogenic Capacity.

Janeckova Lucie L Fafilek Bohumil B Krausova Michaela M Horazna Monika M Vojtechova Martina M Alberich-Jorda Meritxell M Sloncova Eva E Galuskova Katerina K Sedlacek Radislav R Anderova Miroslava M Korinek Vladimir V

Genesis (New York, N.Y. : 2000) 20160216 3

The Wnt pathway plays a crucial role in self-renewal and differentiation of cells in the adult gut. In the present study, we revealed the functional consequences of inhibition of canonical Wnt signaling in the intestinal epithelium. The study was based on generation of a novel transgenic mouse strain enabling inducible expression of an N-terminally truncated variant of nuclear Wnt effector T cell factor 4 (TCF4). The TCF4 variant acting as a dominant negative (dn) version of wild-type (wt) TCF4 ...[more]

PMID: 26864984

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Project description:Colorectal cancer exhibits aberrant activation of Wnt/β-catenin signaling. Many inhibitors of the Wnt/β-catenin pathway have been tested for Wnt-dependent cancers including colorectal cancer, but are unsuccessful due to severe adverse reactions. FL3 is a synthetic derivative of natural products called flavaglines, which exhibit anti-inflammatory and cytoprotective properties in intestinal epithelial cells, but has not been previously tested in cell or preclinical models of intestinal tumorigenesis. In vitro studies suggest that flavaglines target prohibitin 1 (PHB1) as a ligand, but this has not been established in the intestine. PHB1 is a highly conserved protein with diverse functions that depend on its posttranslational modifications and subcellular localization. Here, we demonstrate that FL3 combats intestinal tumorigenesis in the azoxymethane-dextran sodium sulfate and ApcMin/+ mouse models and in human colorectal cancer tumor organoids (tumoroids) by inhibiting Wnt/β-catenin signaling via induction of Axin1 expression. FL3 exhibited no change in cell viability in normal intestinal epithelial cells or human matched-normal colonoids. FL3 response was diminished in colorectal cancer cell lines and human colorectal cancer tumoroids harboring a mutation at S45 of β-catenin. PHB1 deficiency in mice or in human colorectal cancer tumoroids abolished FL3-induced expression of Axin1 and drove tumoroid death. In colorectal cancer cells, FL3 treatment blocked phosphorylation of PHB1 at Thr258, resulting in its nuclear translocation and binding to the Axin1 promoter. These results suggest that FL3 inhibits Wnt/β-catenin signaling via PHB1-dependent activation of Axin1. FL3, therefore, represents a novel compound that combats Wnt pathway-dependent cancers, such as colorectal cancer. SIGNIFICANCE: Targeting of PHB1 by FL3 provides a novel mechanism to combat Wnt-driven cancers, with limited intestinal toxicity. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/17/3519/F1.large.jpg.

Dataset Information

Wnt Signaling Inhibition Deprives Small Intestinal Stem Cells of Clonogenic Capacity.

Publications

Wnt Signaling Inhibition Deprives Small Intestinal Stem Cells of Clonogenic Capacity.

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