학술논문
JUN mediates the senescence associated secretory phenotype and immune cell recruitment to prevent prostate cancer progression.
Document Type
Article
Author
Redmer, Torben; Raigel, Martin; Sternberg, Christina; Ziegler, Roman; Probst, Clara; Lindner, Desiree; Aufinger, Astrid; Limberger, Tanja; Trachtova, Karolina; Kodajova, Petra; Högler, Sandra; Schlederer, Michaela; Stoiber, Stefan; Oberhuber, Monika; Bolis, Marco; Neubauer, Heidi A.; Miranda, Sara; Tomberger, Martina; Harbusch, Nora S.; Garces de los Fayos Alonso, Ines
Source
Subject
*PROSTATE cancer
*CANCER invasiveness
*PHENOTYPES
*AGING
*AP-1 transcription factor
*GENETIC transcription regulation
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Language
ISSN
1476-4598
Abstract
Background: 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. Methods: 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. Results: 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-1β production. Jun depletion in a Pten-deficient background prevented immune cell attraction which was accompanied by significant reduction of active STAT3 and IL-1β 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-1β, TNF-α, 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]