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Lkb1 and Pten synergise to suppress mTOR-mediated tumorigenesis and epithelial-mesenchymal transition in the mouse bladder

Shorning, Boris, Griffiths, David Francis Rees and Clarke, Alan Richard 2011. Lkb1 and Pten synergise to suppress mTOR-mediated tumorigenesis and epithelial-mesenchymal transition in the mouse bladder. PLoS ONE 6 (1) , e16209. 10.1371/journal.pone.0016209

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Abstract

The AKT/PI3K/mTOR pathway is frequently altered in a range of human tumours, including bladder cancer. Here we report the phenotype of mice characterised by deletion of two key players in mTOR regulation, Pten and Lkb1, in a range of tissues including the mouse urothelium. Despite widespread recombination within the range of epithelial tissues, the primary phenotype we observe is the rapid onset of bladder tumorigenesis, with median onset of approximately 100 days. Single deletion of either Pten or Lkb1 had no effect on bladder cell proliferation or tumour formation. However, simultaneous deletion of Lkb1 and Pten led to an upregulation of the mTOR pathway and the hypoxia marker GLUT1, increased bladder epithelial cell proliferation and ultimately tumorigenesis. Bladder tissue also exhibited characteristic features of epithelial-mesenchymal transition, with loss of the epithelial markers E-cadherin and the tight junction protein ZO-1, and increases in the mesenchymal marker vimentin as well as nuclear localization of epithelial-mesenchymal transition (EMT) regulator Snail. We show that these effects were all dependent upon mTOR activity, as rapamycin treatment blocked both EMT and tumorigenesis. Our data therefore establish clear synergy between Lkb1 and Pten in controlling the mTOR pathway within bladder epithelium, and show that loss of this control leads to the disturbance of epithelial structure, EMT and ultimately tumorigenesis.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Subjects: Q Science > Q Science (General)
Q Science > QH Natural history > QH426 Genetics
Publisher: PLoS
ISSN: 1932-6203
Date of First Compliant Deposit: 30 March 2016
Last Modified: 04 Jun 2017 03:45
URI: http://orca.cf.ac.uk/id/eprint/26086

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Cited 32 times in Web of Science. View in Web of Science.

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