title: The notch and TGF-β signaling pathways contribute to the aggressiveness of clear cell renal cell carcinoma.
abstract: BACKGROUND
  Despite recent progress, therapy for metastatic clear cell renal cell carcinoma (CCRCC) is still inadequate. Dysregulated Notch signaling in CCRCC contributes to tumor growth, but the full spectrum of downstream processes regulated by Notch in this tumor form is unknown.
  
  
  RESULTS
  We show that inhibition of endogenous Notch signaling modulates TGF-β dependent gene regulation in CCRCC cells. Analysis of gene expression data representing 176 CCRCCs showed that elevated TGF-β pathway activity correlated significantly with shortened disease specific survival (log-rank test, p = 0.006) and patients with metastatic disease showed a significantly elevated TGF-β signaling activity (two-sided Student's t-test, p = 0.044). Inhibition of Notch signaling led to attenuation of both basal and TGF-β1 induced TGF-β signaling in CCRCC cells, including an extensive set of genes known to be involved in migration and invasion. Functional analyses revealed that Notch inhibition decreased the migratory and invasive capacity of CCRCC cells.
  
  
  CONCLUSIONS
  An extensive cross-talk between the Notch and TGF-β signaling cascades is present in CCRCC and the functional properties of these two pathways are associated with the aggressiveness of this disease.
authors.affiliation: Department of Laboratory Medicine, Center for Molecular Pathology, Lund University, University Hospital MAS, Malmö, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Sjölund
authors.forename: Anna-Karin
authors.initials: AK
authors.lastname: Boström
authors.forename: David
authors.initials: D
authors.lastname: Lindgren
authors.forename: Sugata
authors.initials: S
authors.lastname: Manna
authors.forename: Aristidis
authors.initials: A
authors.lastname: Moustakas
authors.forename: Börje
authors.initials: B
authors.lastname: Ljungberg
authors.forename: Martin
authors.initials: M
authors.lastname: Johansson
authors.forename: Erik
authors.initials: E
authors.lastname: Fredlund
authors.forename: Håkan
authors.initials: H
authors.lastname: Axelson
mesh_terms: D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D006801:Humans; D051881:Receptor, Notch1 / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D004149:Dioxoles; D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D051881:Receptor, Notch1; D051880:Receptors, Notch; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1