Melanoma is a benchmark of major clinical significance for cancer development with greater aggressiveness in the male than the female population. Surprisingly little is known on the role of androgen receptor (AR) signaling in the disease. Irrespectively of expression levels, genetic and pharmacological suppression of AR activity in a large panel of melanoma cells, derived from both male and female patients, suppresses proliferation and self-renewal potential while, conversely, increased AR expression or ligand stimulation enhance proliferation. AR gene silencing in multiple melanoma lines elicits a shared gene expression signature related to interferon- and inflammatory cytokines signaling with an inverse association with DNA repair-associated genes, which is significantly linked with better patients' survival. AR plays an essential function in maintenance of genome integrity: in both cultured melanoma cells and tumors, loss of AR activity leads to chromosomal DNA breakage, leakage into the cytoplasm, and stimulator of interferon genes (STING) activation. In vivo, reduced tumorigenesis resulting from AR gene silencing or pharmacological inhibition is associated with intratumor macrophage infiltration and, in an immune competent mouse model, cytotoxic T cell activation. Although at different levels, androgens are produced in both male and female individuals and AR targeting provides an attractive therapy approach for improved management of melanoma irrespective of patients' sex and gender.

中文翻译：

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持续的雄激素受体信号传导是黑色素瘤细胞生长潜力和肿瘤发生的决定因素

黑色素瘤是癌症发展的主要临床意义基准，男性比女性人群更具侵略性。令人惊讶的是，关于雄激素受体（AR）信号在疾病中的作用知之甚少。不论表达水平如何，源自男性和女性患者的大量黑色素瘤细胞中AR活性的遗传和药理抑制作用均抑制增殖和自我更新潜能，相反，AR表达增加或配体刺激则促进增殖。多个黑色素瘤细胞系中的AR基因沉默引起与干扰素和炎性细胞因子信号传导相关的共享基因表达特征，与DNA修复相关基因呈负相关，这与患者更好的存活率显着相关。AR在维持基因组完整性方面起着至关重要的作用：在培养的黑色素瘤细胞和肿瘤中，AR活性的丧失都会导致染色体DNA断裂，渗入细胞质并刺激干扰素基因（STING）激活。在体内，由AR基因沉默或药理作用抑制导致的肿瘤发生减少与肿瘤内巨噬细胞浸润有关，在具有免疫能力的小鼠模型中，与细胞毒性T细胞活化有关。尽管雄激素水平不同，但男性和女性均会产生雄激素，而AR靶向为改善黑色素瘤的治疗提供了有吸引力的治疗方法，而不论患者的性别。和干扰素基因（STING）激活刺激物。在体内，由AR基因沉默或药理作用抑制导致的肿瘤发生减少与肿瘤内巨噬细胞浸润有关，在具有免疫能力的小鼠模型中，与细胞毒性T细胞活化有关。尽管雄激素水平不同，但男性和女性均会产生雄激素，而AR靶向为改善黑色素瘤的治疗提供了有吸引力的治疗方法，而不论患者的性别。和干扰素基因（STING）激活刺激物。在体内，由AR基因沉默或药理作用抑制导致的肿瘤发生减少与肿瘤内巨噬细胞浸润有关，在具有免疫能力的小鼠模型中，与细胞毒性T细胞活化有关。尽管雄激素水平不同，但无论男性还是女性都产生雄激素，而AR靶向治疗为改善黑色素瘤的治疗提供了有吸引力的治疗方法，而不论患者的性别。