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Wnt/β-Catenin Signaling Activation beyond Robust Nuclear β-Catenin Accumulation in Nondysplastic Barrett's Esophagus: Regulation via Dickkopf-1.

Lyros O, Rafiee P, Nie L, Medda R, Jovanovic N, Otterson MF, Behmaram B, Gockel I, Mackinnon A, Shaker R - Neoplasia (2015)

Bottom Line: Wnt target genes (AXIN2, c-MYC, Cyclin D1, Dkk1) and Wnt3a were significantly upregulated in nondysplastic BE compared with squamous mucosa.Nuclear active β-catenin and TOPflash activity were increased in CP-A and OE33 cells compared with squamous cells.Dkk1 overexpression regulates β-catenin signaling in BE metaplastic but not in adenocarcinoma cells, suggesting that early perturbation of Dkk1-mediated signaling suppression may contribute to BE malignant transformation.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology and Hepatology of Wisconsin, Milwaukee, USA; Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital, Leipzig, Germany.

No MeSH data available.


Related in: MedlinePlus

Schematic illustration of the Dkk1-mediated suppression of the Wnt-axis in BE metaplastic cells.
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f0040: Schematic illustration of the Dkk1-mediated suppression of the Wnt-axis in BE metaplastic cells.

Mentions: The absence of higher signaling activation in BE implies the existence of a compensative mechanism. We attributed this moderate β-catenin activity in BE to the subsequent overexpression of the Wnt target gene Dkk1. It is known that Dkk1 protein suppresses the Wnt signaling by antagonizing the binding of canonical Wnts to LRP5/6 receptors in a negative feedback loop [22]. The increased signaling activation of β-catenin by Wnt3a was blocked by Dkk1, whereas Dkk1 knockdown in CP-A cells resulted in increased β-catenin transcriptional activity along with a higher sensitization of the cells to Wnt3a. Taken together, these observations suggest a Dkk1-mediated suppression of Wnt-induced β-catenin activation in BE and allow us to propose a model of a closed circuit of Wnt signaling regulation in BE metaplasia, which aims to sustain the β-catenin activity to certain low levels. The secreted endogenous Wnt3a activates the canonical signaling, resulting downstream to Dkk1 gene increased transcription and subsequently to elevated Dkk1 protein secretion, which in turn counteracts an excessive Wnt3a receptor binding (Figure 8). This proposed model explains the positive AXIN2 and Dkk1 expression observed in the basal high proliferative layer of the normal squamous mucosa, suggesting that similar expression patterns, which indicate Wnt signaling activation, are associated with increased proliferation as seen in BE. Intriguingly, despite its overexpression, Dkk1 failed to show similar suppression of β-catenin activity in BE-associated adenocarcinoma cells, indicating that early perturbation of Dkk1-mediated signaling suppression might be responsible for esophageal tumorigenesis.


Wnt/β-Catenin Signaling Activation beyond Robust Nuclear β-Catenin Accumulation in Nondysplastic Barrett's Esophagus: Regulation via Dickkopf-1.

Lyros O, Rafiee P, Nie L, Medda R, Jovanovic N, Otterson MF, Behmaram B, Gockel I, Mackinnon A, Shaker R - Neoplasia (2015)

Schematic illustration of the Dkk1-mediated suppression of the Wnt-axis in BE metaplastic cells.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4547437&req=5

f0040: Schematic illustration of the Dkk1-mediated suppression of the Wnt-axis in BE metaplastic cells.
Mentions: The absence of higher signaling activation in BE implies the existence of a compensative mechanism. We attributed this moderate β-catenin activity in BE to the subsequent overexpression of the Wnt target gene Dkk1. It is known that Dkk1 protein suppresses the Wnt signaling by antagonizing the binding of canonical Wnts to LRP5/6 receptors in a negative feedback loop [22]. The increased signaling activation of β-catenin by Wnt3a was blocked by Dkk1, whereas Dkk1 knockdown in CP-A cells resulted in increased β-catenin transcriptional activity along with a higher sensitization of the cells to Wnt3a. Taken together, these observations suggest a Dkk1-mediated suppression of Wnt-induced β-catenin activation in BE and allow us to propose a model of a closed circuit of Wnt signaling regulation in BE metaplasia, which aims to sustain the β-catenin activity to certain low levels. The secreted endogenous Wnt3a activates the canonical signaling, resulting downstream to Dkk1 gene increased transcription and subsequently to elevated Dkk1 protein secretion, which in turn counteracts an excessive Wnt3a receptor binding (Figure 8). This proposed model explains the positive AXIN2 and Dkk1 expression observed in the basal high proliferative layer of the normal squamous mucosa, suggesting that similar expression patterns, which indicate Wnt signaling activation, are associated with increased proliferation as seen in BE. Intriguingly, despite its overexpression, Dkk1 failed to show similar suppression of β-catenin activity in BE-associated adenocarcinoma cells, indicating that early perturbation of Dkk1-mediated signaling suppression might be responsible for esophageal tumorigenesis.

Bottom Line: Wnt target genes (AXIN2, c-MYC, Cyclin D1, Dkk1) and Wnt3a were significantly upregulated in nondysplastic BE compared with squamous mucosa.Nuclear active β-catenin and TOPflash activity were increased in CP-A and OE33 cells compared with squamous cells.Dkk1 overexpression regulates β-catenin signaling in BE metaplastic but not in adenocarcinoma cells, suggesting that early perturbation of Dkk1-mediated signaling suppression may contribute to BE malignant transformation.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology and Hepatology of Wisconsin, Milwaukee, USA; Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital, Leipzig, Germany.

No MeSH data available.


Related in: MedlinePlus