Titel (eng)

JUN mediates the senescence associated secretory phenotype and immune cell recruitment to prevent prostate cancer progression

Autor*in

Torben Redmer   University of Veterinary Medicine Vienna

Lukas Kenner   University of Veterinary Medicine Vienna / Medical University of Vienna / CBmed GmbH

Sabine Lagger   University of Veterinary Medicine Vienna

Gerda Egger   Medical University of Vienna

Olaf Merkel   Medical University of Vienna

Sarka Pospisilova   Masaryk University

Birgit Strobl   University of Veterinary Medicine Vienna

Fritz Aberger   Paris-Lodron University of Salzburg

Stephan Mathas

Jenny L Persson   Umeå University / Malmö Universitet

Vojtech Bystry   Masaryk University

Boris Tichy   Masaryk University

Jean-Philippe Theurillat

Richard Moriggl   Paris-Lodron University of Salzburg

Ines Garces de Los Fayos Alonso   University of Veterinary Medicine Vienna / Medical University of Vienna

Nora S. Harbusch   CBmed GmbH

Martina Tomberger   CBmed GmbH

Sara Miranda   University of Veterinary Medicine Vienna

Heidi A. Neubauer   University of Veterinary Medicine Vienna

Marco Bolis

Monika Oberhuber   CBmed GmbH

Stefan Stoiber   Medical University Vienna

Michaela Schlederer   Medical University of Vienna

Sandra Högler   University of Veterinary Medicine Vienna

Petra Kodajova   University of Veterinary Medicine Vienna

Karolina Trachtova   Medical University of Vienna / Masaryk University

Tanja Limberger   Medical University of Vienna

Astrid Aufinger   Medical University Vienna

Desiree Lindner   University of Veterinary Medicine Vienna / Medical University of Vienna

Clara Probst   University of Veterinary Medicine Vienna / Medical University of Vienna

Roman Ziegler   University of Veterinary Medicine Vienna / Charles University

Martin Raigel   University of Veterinary Medicine Vienna / Medical University of Vienna

Christina Sternberg   University of Veterinary Medicine Vienna / Medical University of Vienna / University of Kiel

Verlag

BMC

Beschreibung (eng)

Prostate cancer develops through malignant transformation of the prostate epithelium in a stepwise, mutation-driven process. Although activator protein-1 transcription factors such as JUN have been implicated as potential oncogenic drivers, the molecular programs contributing to prostate cancer progression are not fully understood.We analyzed JUN expression in clinical prostate cancer samples across different stages and investigated its functional role in a Pten-deficient mouse model. We performed histopathological examinations, transcriptomic analyses and explored the senescence-associated secretory phenotype in the tumor microenvironment.Elevated JUN levels characterized early-stage prostate cancer and predicted improved survival in human and murine samples. Immune-phenotyping of Pten-deficient prostates revealed high accumulation of tumor-infiltrating leukocytes, particularly innate immune cells, neutrophils and macrophages as well as high levels of STAT3 activation and IL-1? production. Jun depletion in a Pten-deficient background prevented immune cell attraction which was accompanied by significant reduction of
active STAT3 and IL-1? and accelerated prostate tumor growth. Comparative transcriptome profiling of prostate epithelial cells revealed a senescence-associated gene signature, upregulation of pro-inflammatory processes involved in immune cell attraction and of chemokines such as IL-1?, TNF-?, CCL3 and CCL8 in Pten-deficient prostates. Strikingly, JUN depletion reversed both the senescence-associated secretory phenotype and senescence-associated immune cell infiltration but had no impact on cell cycle arrest. As a result, JUN depletion in Pten-deficient prostates interfered with the senescence-associated immune clearance and accelerated tumor growth.Our results suggest that JUN acts as tumor-suppressor and decelerates the progression of prostate cancer by transcriptional regulation of senescence- and inflammation-associated genes. This study opens avenues for novel treatment strategies that could impede disease progression and improve patient outcomes.

Sprache des Objekts

Englisch

Datum

2024

Rechte

Dieses Werk bzw. dieser Inhalt steht unter einer
CC BY 4.0 - Creative Commons Namensnennung 4.0 International Lizenz.

CC BY 4.0 International

http://creativecommons.org/licenses/by/4.0/

Klassifikation

Male; Prostatic Neoplasmspathologygeneticsmetabolism; Animals; Mice; Humans; PTEN Phosphohydrolasegeneticsmetabolism; Disease Progression; Tumor Microenvironmentimmunology; Senescence-Associated Secretory Phenotype; Proto-Oncogene Proteins c-junmetabolism; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Gene Expression Profiling; Cellular Senescencegenetics; Disease Models, Animal

Mitglied in der/den Collection(s) (1)