前列腺癌是通过前列腺上皮在突变驱动的逐步过程中发生恶性转化而发生的。尽管JUN等激活蛋白1转录因子被认为是潜在的致癌驱动因素，但导致前列腺癌进展的分子程序尚未完全了解。我们分析了不同阶段的临床前列腺癌样本中JUN的表达，并研究了其在前列腺癌中的功能作用。 Pten 缺陷小鼠模型。我们进行了组织病理学检查、转录组分析，并探索了肿瘤微环境中与衰老相关的分泌表型。JUN 水平升高是早期前列腺癌的特征，并预测人类和小鼠样本中生存率的提高。 Pten 缺陷前列腺的免疫表型显示肿瘤浸润白细胞的大量积累，特别是先天免疫细胞、中性粒细胞和巨噬细胞，以及高水平的 STAT3 激活和 IL-1β 产生。 Pten 缺陷背景下的 Jun 耗竭阻止了免疫细胞的吸引，同时伴随着活性 STAT3 和 IL-1β 的显着减少，并加速了前列腺肿瘤的生长。前列腺上皮细胞的比较转录组分析揭示了衰老相关基因特征、参与免疫细胞吸引的促炎过程以及 Pten 缺陷前列腺中 IL-1β、TNF-α、CCL3 和 CCL8 等趋化因子的上调。引人注目的是，JUN 的消耗逆转了衰老相关的分泌表型和衰老相关的免疫细胞浸润，但对细胞周期停滞没有影响。因此，Pten 缺陷前列腺中的 JUN 缺失会干扰衰老相关的免疫清除并加速肿瘤生长。我们的结果表明，JUN 可以作为肿瘤抑制剂，通过衰老和炎症的转录调节来减缓前列腺癌的进展。相关基因。这项研究为新的治疗策略开辟了途径，可以阻止疾病进展并改善患者的治疗结果。© 2024。作者。

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-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.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.© 2024. The Author(s).