Please use this identifier to cite or link to this item:
http://hdl.handle.net/2445/178674
Title: | The phosphatase PRL-3 affects intestinal homeostasis by altering the crypt cell composition |
Author: | Rubio, Teresa Weyershaeuser, Judith Montero, Marta G. Hoffmann, Andreas Lujan, Pablo Jechlinger, Martin Sotillo, Rocio Köhn, Maja |
Keywords: | Càncer Homeòstasi Cancer Homeostasis |
Issue Date: | 15-Jun-2021 |
Publisher: | Springer Nature |
Abstract: | Expression of the phosphatase of regenerating liver-3 (PRL-3) is known to promote tumor growth in gastrointestinal adenocarcinomas, and the incidence of tumor formation upon inflammatory events correlates with PRL-3 levels in mouse models. These carcinomas and their onset are associated with the impairment of intestinal cell homeostasis, which is regulated by a balanced number of Paneth cells and Lgr5 expressing intestinal stem cells (Lgr5+ ISCs). Nevertheless, the consequences of PRL-3 overexpression on cellular homeostasis and ISC fitness in vivo are unexplored. Here, we employ a doxycycline-inducible PRL-3 mouse strain to show that aberrant PRL-3 expression within a non-cancerous background leads to the death of Lgr5+ ISCs and to Paneth cell expansion. A higher dose of PRL-3, resulting from homozygous expression, led to mice dying early. A primary 3D intestinal culture model obtained from these mice confirmed the loss of Lgr5+ ISCs upon PRL-3 expression. The impaired intestinal organoid formation was rescued by a PRL inhibitor, providing a functional link to the observed phenotypes. These results demonstrate that elevated PRL-3 phosphatase activity in healthy intestinal epithelium impairs intestinal cell homeostasis, which correlates this cellular mechanism of tumor onset with PRL-3-mediated higher susceptibility to tumor formation upon inflammatory or mutational events.Key messages• Transgenic mice homozygous for PRL-3 overexpression die early.• PRL-3 heterozygous mice display disrupted intestinal self-renewal capacity.• PRL-3 overexpression alone does not induce tumorigenesis in the mouse intestine.• PRL-3 activity leads to the death of Lgr5+ ISCs and Paneth cell expansion.• Impairment of cell homeostasis correlates PRL-3 action with tumor onset mechanisms. |
Note: | Reproducció del document publicat a: https://doi.org/10.1007/s00109-021-02097-9 |
It is part of: | Journal of Molecular Medicine, 2021 |
URI: | http://hdl.handle.net/2445/178674 |
Related resource: | https://doi.org/10.1007/s00109-021-02097-9 |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
Files in This Item:
File | Description | Size | Format | |
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Rubio2021_Article_ThePhosphatasePRL-3AffectsInte.pdf | 5.1 MB | Adobe PDF | View/Open |
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