title: Tumor suppression in basal keratinocytes via dual non-cell-autonomous functions of a Na,K-ATPase beta subunit.
abstract: The molecular pathways underlying tumor suppression are incompletely understood. Here, we identify cooperative non-cell-autonomous functions of a single gene that together provide 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 (previously unrecognized) contributor to tumor development and establish a novel paradigm of tumor suppression.
authors.affiliation: Institute for Zoology, Developmental Biology Unit, University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Hatzold
authors.affiliation: Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.|Institute of Human Genetics, University Hospital Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
authors.forename: Filippo
authors.initials: F
authors.lastname: Beleggia
authors.affiliation: Institute of Cardiology and Sports Medicine, German Sport University Cologne, Cologne, Germany.
authors.forename: Hannah
authors.initials: H
authors.lastname: Herzig
authors.affiliation: Institute of Human Genetics, University Hospital Cologne, Cologne, Germany.|Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.|Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Institute of Cardiology and Sports Medicine, German Sport University Cologne, Cologne, Germany.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Bloch
authors.affiliation: Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.|Institute of Human Genetics, University Hospital Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.|Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
authors.affiliation: Institute for Zoology, Developmental Biology Unit, University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
authors.forename: Matthias
authors.identifier: 0000-0002-3709-8166
authors.initials: M
authors.lastname: Hammerschmidt
mesh_terms: D000818:Animals; D002280:Basal Cell Carcinoma / Q000503:physiopathology*; D015603:Keratinocytes / Q000201:enzymology* / Q000502:physiology*; D009997:Osmotic Pressure; D000254:Sodium-Potassium-Exchanging ATPase / Q000172:deficiency / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D000254:Sodium-Potassium-Exchanging ATPase
keywords: Na/K-ATPase; basal cell carcinogenesis; cancer biology; developmental biology; epithelial polarity; stem cells; zebrafish