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Published on: May 14, 2016
Tumor suppression in basal keratinocytes via dual non-cell-autonomous functions of a Na,K-ATPase beta subunit
Julia Hatzold1,2, Filippo Beleggia2,3,4, Hannah Herzig5
1Institute for Zoology, Developmental Biology Unit, University of Cologne, Cologne, Germany.
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.
Insights
A zebrafish gene mutation causes cancer by disrupting cell adhesion and causing hypotonic stress. Restoring cell adhesion and fluid balance prevents tumor development, revealing a new tumor suppression mechanism.
Area of Science:
- Developmental Biology
- Cancer Research
- Molecular Biology
Background:
- Tumor suppression mechanisms are not fully understood.
- The role of non-cell-autonomous gene functions in cancer is an emerging area of research.
Purpose of the Study:
- To investigate the molecular pathways of tumor suppression in zebrafish embryos.
- To identify novel mechanisms of tumor suppression involving cooperative gene functions.
Main Methods:
- Utilized a loss-of-function mutation in the atp1b1a gene in zebrafish embryos.
- Analyzed the effects of compromised Atp1b1a function on basal keratinocytes, periderm, kidney, and heart.
- Investigated the PI3K-AKT-mTORC1-NFκB-MMP9 pathway and systemic isotonicity.
Main Results:
- Loss of atp1b1a function in basal cells, periderm, kidney, and heart leads to edema and epidermal malignancy.
- Compromised periderm function affects epithelial polarity and adhesiveness, while kidney/heart dysfunction causes hypotonic stress.
- Blocking the PI3K-AKT-mTORC1-NFκB-MMP9 pathway and maintaining systemic isotonicity prevents malignant transformation.
Conclusions:
- Hypotonic stress is a previously unrecognized contributor to tumor development.
- Cooperative non-cell-autonomous functions of a single gene (atp1b1a) provide a novel mechanism for tumor suppression.
- This study establishes a new paradigm in understanding tumor suppression.
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