Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Aging (Upcoming)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
NOTCH pathway inactivation promotes bladder cancer progression
Antonio Maraver, … , Francisco X. Real, Manuel Serrano
Antonio Maraver, … , Francisco X. Real, Manuel Serrano
Published January 9, 2015
Citation Information: J Clin Invest. 2015;125(2):824-830. https://doi.org/10.1172/JCI78185.
View: Text | PDF
Research Article

NOTCH pathway inactivation promotes bladder cancer progression

  • Text
  • PDF
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.

Authors

Antonio Maraver, Pablo J. Fernandez-Marcos, Timothy P. Cash, Marinela Mendez-Pertuz, Marta Dueñas, Paolo Maietta, Paola Martinelli, Maribel Muñoz-Martin, Mónica Martínez-Fernández, Marta Cañamero, Giovanna Roncador, Jorge L. Martinez-Torrecuadrada, Dimitrios Grivas, Jose Luis de la Pompa, Alfonso Valencia, Jesús M. Paramio, Francisco X. Real, Manuel Serrano

×

Figure 1

NOTCH1 and NOTCH2 missense mutations found in human bladder carcinomas lead to decreased NOTCH activity.

Options: View larger image (or click on image) Download as PowerPoint
NOTCH1 and NOTCH2 missense mutations found in human bladder carcinomas l...
(A) T24 cells were cotransfected with a plasmid carrying a luciferase reporter gene directed by an RBPJ-responding promoter and with constructs carrying the indicated versions of NOTCH1 (N1) and NOTCH2 (N2). Subsequently, they were exposed to HEK293T cells overexpressing the NOTCH ligand JAGGED1 to activate NOTCH signaling and, consequently, luciferase expression. Bars represent the average of 5 independent measurements of luciferase, and error bars represent SD. The levels of overexpression were assessed by immunoblot (tubulin and FLAG immunoblots from the left panel were performed in two different but equivalent membranes; see complete unedited blots in the supplemental material). ***P < 0.001, Student’s t test. EV, empty vector. (B) Predicted structural effect of the NOTCH2-Y407C mutation is marked in red. Disulfide bridges predicted in WT and in NOTCH2-Y407C are marked in yellow.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts