Tumor suppression in basal keratinocytes via dual non-cell-autonomous functions of a Na,K-ATPase beta subunit

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Abstract

Molecular pathways underlying tumor suppression are incompletely understood. Here, we identify cooperative non-cell-autonomous functions of one and the same gene as a novel mechanism of tumor suppression in basal keratinocytes of zebrafish embryos. A loss-of-function mutation in atp1b1a, encoding the beta subunit of a Na,K-ATPase pump, causes edema and epidermal malignancy. Strikingly, basal cell carcinogenesis only occurs when Atp1b1a function is compromised in both the overlying periderm (resulting in compromised epithelial polarity and adhesiveness) and in kidney and heart (resulting in hypotonic stress). Blockade of the ensuing PI3K-AKT-mTORC1-NFκB-MMP9 pathway activation in basal cells, as well as systemic isotonicity, prevents malignant transformation. Our results identify hypotonic stress as a thus far unrecognized contributor to tumor development and establish a novel paradigm of tumor suppression.

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Julia Hatzold

Institute for Zoology, Developmental Biology Unit, University of Cologne, Cologne, Germany

Competing interests
The authors declare that no competing interests exist.
Filippo Beleggia

Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany

Competing interests
The authors declare that no competing interests exist.
Hannah Herzig

Institute of Cardiology and Sports Medicine, German Sport University Cologne, Cologne, Germany

Competing interests
The authors declare that no competing interests exist.
Janine Altmüller

Institute of Human Genetics, University Hospital Cologne, Cologne, Germany

Competing interests
The authors declare that no competing interests exist.
Peter Nürnberg

Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany

Competing interests
The authors declare that no competing interests exist.
Wilhelm Bloch

Institute of Cardiology and Sports Medicine, German Sport University Cologne, Cologne, Germany

Competing interests
The authors declare that no competing interests exist.
Bernd Wollnik

Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany

Competing interests
The authors declare that no competing interests exist.
Matthias Hammerschmidt

Institute for Zoology, Developmental Biology Unit, University of Cologne, Cologne, Germany

For correspondence
mhammers@uni-koeln.de

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: All zebrafish experiments were approved by the national animal care committees (LANUV Nordrhein-Westfalen; 8.87-50.10.31.08.129; 84-02.04.2012.A251; City of Cologne; 576.1.36.6.3.01.10 Be) and the University of Cologne.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.