Abstract
Clear cell renal cell carcinoma (ccRCC) is by far the most common type of kidney cancer and is characterized by loss of the tumor suppressor gene von Hippel-Lindau (VHL). ccRCC patients with metastatic disease has poor prognosis and today's therapy is insufficient. The cytokine Transforming Growth Factor-β (TGF-β) has been extensively studied in tumor biology and is believed to serve a variety of functions in tumor progression. We have previously shown that inhibition of NOTCH signaling causes a reduced migratory and invasive capacity of ccRCC cells, at least partly by a cross-talk with the TGF-β pathway. In the present study we aimed to further clarify the role of TGF-β signaling in ccRCC. We investigated the effects of TGF-β pathway modulation and showed that TGF-β inhibition attenuates the invasive capacity of ccRCC cells. By performing expression profiling we obtained a gene signature of the TGF-β induced response in ccRCC cells. The expression analyses revealed an extensive overlap between the TGF-β response and genes regulated by the hypoxia inducible factor (HIF). The link between the hypoxic and the TGF-β pathways was further corroborated by functional experiments, which demonstrated that TGF-β pathway activity was attenuated upon reintroduction of functional VHL in ccRCC.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Benzamides / pharmacology
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Blotting, Western
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Carcinoma, Renal Cell / genetics
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Carcinoma, Renal Cell / metabolism
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Carcinoma, Renal Cell / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dioxoles / pharmacology
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Enzyme-Linked Immunosorbent Assay
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic / drug effects*
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Humans
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Kidney Neoplasms / genetics
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Kidney Neoplasms / metabolism
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Kidney Neoplasms / pathology
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Oligonucleotide Array Sequence Analysis
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / antagonists & inhibitors
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Receptors, Transforming Growth Factor beta / metabolism
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Signal Transduction*
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Smad2 Protein / metabolism
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Transforming Growth Factor beta / metabolism*
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Transforming Growth Factor beta / pharmacology*
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Von Hippel-Lindau Tumor Suppressor Protein / genetics
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Von Hippel-Lindau Tumor Suppressor Protein / metabolism
Substances
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4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
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Benzamides
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Dioxoles
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Receptors, Transforming Growth Factor beta
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Smad2 Protein
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Transforming Growth Factor beta
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Von Hippel-Lindau Tumor Suppressor Protein
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type I