JUN mediates the senescence associated secretory phenotype and immune cell recruitment to prevent prostate cancer progression
| العنوان: | JUN mediates the senescence associated secretory phenotype and immune cell recruitment to prevent prostate cancer progression |
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| المؤلفون: | 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, Sternberg, Felix, Moriggl, Richard, Theurillat, Jean-Philippe, Tichy, Boris, Bystry, Vojtech, Persson, Jenny L., Professor, Mathas, Stephan, Aberger, Fritz, Strobl, Birgit, Pospisilova, Sarka, Merkel, Olaf, Egger, Gerda, Lagger, Sabine, Kenner, Lukas |
| المصدر: | Molecular Cancer. 23(1) |
| مصطلحات موضوعية: | AP-1 transcription factors, Immune infiltration, JUN, Prostate cancer, SASP, Senescence |
| الوصف: | 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. Graphical Abstract: (Figure presented.). |
| وصف الملف: | electronic |
| URL الوصول: | https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-225946 https://doi.org/10.1186/s12943-024-02022-x https://umu.diva-portal.org/smash/get/diva2:1868919/FULLTEXT01.pdf |
| قاعدة البيانات: | SwePub |
| DOI: | 10.1186/s12943-024-02022-x |
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