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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.
Highlights
Deregulation of the PI3K pathway has been implicated in a range of human epithelial tumours
Since AKT/PI3K/mTOR pathway regulation is implicated in hypoxia [23,24,25,26,27,28] we examined the expression of glucose transporter-1 protein (GLUT1), which has been reported to mark hypoxia in human bladder cancer [46] and functions as part of the glucose uptake machinery dependent on TSC2 phosphorylation and TSC inhibition of mTOR [47]
epithelial-mesenchymal transition (EMT) can be initiated by a spectrum of mutations or alterations in a range of signal transduction pathways and AKT/ PI3K pathway has suggested to be at the centre in this mechanism [13], Here we report a new mouse model of bladder neoplasia with combined deletion of two genes controlling AKT/PI3K/ mTOR pathway, Lkb1 and Pten in the urothelium (Fig. 1, A, B) and we show that this pathway has a crucial role in EMT occurring in this tissue (Fig. 6, A, B)
Summary
Deregulation of the PI3K pathway has been implicated in a range of human epithelial tumours. Both Pten and Lkb play fundamental roles in regulating this pathway, and mutations of both genes are associated with neoplasia. Pten suppresses the PI3K pathway by dephosphorylating phosphatidylinositol-3, 4, 5-trisphosphates (PIP3) [1,2]. Phosphorylated Akt can inhibit TSC2 with the subsequent activation of Rheb, mTOR, S6K p70 and stimulation of protein synthesis and cell growth [4]. Germline mutation of PTEN, LKB1 or TSC1/2 are all associated with human tumorigenesis (Cowden syndrome, Peutz-Jeghers syndrome and tuberous sclerosis respectively), and it is notable that all three syndromes share characteristic features, an increased predisposition to hamartoma development [7]
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