Abstract
NOTCH signaling suppresses tumor growth and proliferation in several types of stratified epithelia. Here, we show that missense mutations in NOTCH1 and NOTCH2 found in human bladder cancers result in loss of function. In murine models, genetic ablation of the NOTCH pathway accelerated bladder tumorigenesis and promoted the formation of squamous cell carcinomas, with areas of mesenchymal features. Using bladder cancer cells, we determined that the NOTCH pathway stabilizes the epithelial phenotype through its effector HES1 and, consequently, loss of NOTCH activity favors the process of epithelial-mesenchymal transition. Evaluation of human bladder cancer samples revealed that tumors with low levels of HES1 present mesenchymal features and are more aggressive. Together, our results indicate that NOTCH serves as a tumor suppressor in the bladder and that loss of this pathway promotes mesenchymal and invasive features.
Publication types
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Clinical Trial
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Multicenter Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Epithelial-Mesenchymal Transition / genetics
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Female
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Male
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Mice
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Receptor, Notch1 / genetics
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Receptor, Notch1 / metabolism*
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Receptor, Notch2 / genetics
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Receptor, Notch2 / metabolism*
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Signal Transduction*
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Transcription Factor HES-1
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Urinary Bladder Neoplasms / genetics
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Urinary Bladder Neoplasms / metabolism*
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Urinary Bladder Neoplasms / mortality
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Urinary Bladder Neoplasms / pathology
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Hes1 protein, mouse
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Homeodomain Proteins
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NOTCH1 protein, human
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NOTCH2 protein, human
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Notch1 protein, mouse
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Notch2 protein, mouse
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Receptor, Notch1
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Receptor, Notch2
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Transcription Factor HES-1
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Tumor Suppressor Proteins
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HES1 protein, human