Identifier to cite or link to this item: http://hdl.handle.net/20.500.13003/15020
Loss of Janus Associated Kinase 1 Alters Urothelial Cell Function and Facilitates the Development of Bladder Cancer
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ISSN: 1664-3224
WOS ID: 000484955000001
Scopus EID: 2-s2.0-85072623380
PMID: 31552026
Embase PUI: L629462701
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2019-09-10Document type
research articleCitation
Daza-Cajigal V, Albuquerque AS, Pearson J, Hinley J, Mason AS, Stahlschmidt J, et al. Loss of Janus Associated Kinase 1 Alters Urothelial Cell Function and Facilitates the Development of Bladder Cancer. Front Immunol. 2019 Sep 10;10:2065.Abstract
Inherited Primary Immunodeficiency (PID) disorders are associated with increased risk of malignancy that may relate to impaired antitumor immune responses or a direct role for PID germline mutations in tumorigenesis. We recently identified germline loss of function mutations in Janus Associated Kinase 1 (JAK1) causing primary immunodeficiency characterized by infections and associated with early onset, fatal high-grade bladder carcinoma. Somatic mutations in JAK1, required for immune cell signaling in response to interferon gamma (IFN gamma), have been associated with several non-hematopoietic and hematopoietic cancer cell types but pathogenic mechanisms remain largely unexplored. Here we demonstrate that JAK1 is required for the intrinsic IFN gamma response of urothelial cells impacting immunogenicity and cell survival. Specifically, JAK1 -deficient urothelial cells showed reduced surface expression of major histocompatibility complex class II (MHC II), intercellular adhesion molecule-1 (ICAM-1) and programmed death-ligand-1 (PD-L1) after IFN gamma stimulation and were resistant to IFN gamma-induced apoptosis and lymphocyte-mediated killing. In addition, we identify a previously unknown role for IFNy signaling in modulating urothelial differentiation. Together, our findings support a role for urothelial cell JAK1 in immune surveillance and development of bladder cancer. Our results have implications for patients with rare JAK1 PID and, more broadly, inform development of biomarker and targeted therapies for urothelial carcinoma.
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https://dx.doi.org/10.3389/fimmu.2019.02065MeSH
Urinary Bladder NeoplasmsCytotoxicity, Immunologic
Epithelial Cells
Telomerase
Humans
Cell Line, Tumor
Disease Susceptibility
Lymphocytes
Biomarkers
Interferon-gamma
Immunohistochemistry
STAT1 Transcription Factor
Mucous Membrane
RNA, Messenger
Janus Kinase 1
Gene Expression Regulation, Neoplastic
DeCS
Línea Celular TumoralRegulación Neoplásica de la Expresión Génica
Biomarcadores
Membrana Mucosa
Inmunohistoquímica
Susceptibilidad a Enfermedades
Interferón gamma
Linfocitos
Humanos
Janus Quinasa 1
Células Epiteliales
Telomerasa
Citotoxicidad Inmunológica
ARN Mensajero
Factor de Transcripción STAT1
Neoplasias de la Vejiga Urinaria
This item appears in following Docusalut collections
Hospital Universitario Son Espases - HUSE > Comunicación científicaInstituto de Investigación Sanitaria Islas Baleares - IDISBA > Comunicación científica