Background/Objectives: Prostate cancer (PCa) is the second leading cause of cancer-related death in men. The increase in incidence rates of more advanced and aggressive forms of the disease year-to-year fuels urgency to find new therapeutic interventions and bolster already established ones. PCa is a uniquely targetable disease in that it is fueled by male hormones (androgens) that drive tumorigenesis via the androgen receptor or AR. Current standard-of-care therapies directly target AR and its aberrant signaling axis but resistance to these therapies commonly arises, and the mechanisms behind the onset of therapy-resistance are still elusive. Research has shown that even with resistant disease, AR remains the main driver of growth and survival of PCa, and AR target genes and cofactors may help mediate resistance to therapy. Here, we focused on a homeobox transcription factor that exhibits a close relationship with AR—NKX3.1. Though NKX3.1 is traditionally thought of as a tumor suppressor, it has been previously reported to promote cancer cell survival by cooperating with AR. The role of NKX3.1 as a tumor suppressor perhaps in early-stage disease also contradicts its profile as a diagnostic biomarker for advanced prostate cancer. Methods: We investigated the physical interaction between NKX3.1 and AR, a modulated NKX3.1 expression in prostate cancer cells via overexpression and knockdown and assayed subsequent viability and downstream target gene expression. Results: We find that the expression of NKX3.1 is maintained in advanced PCa, and it is often elevated because of aberrant AR activity. Transient knockdown experiments across various PCa cell line models reveal NKX3.1 expression is necessary for survival. Similarly, stable overexpression of NKX3.1 in PCa cell lines reveals an androgen insensitive phenotype, suggesting NKX3.1 is sufficient to promote growth in the absence of an AR ligand. Conclusions: Our work provides new insight into NKX3.1’s oncogenic influence on PCa and the molecular interplay of these transcription factors in models of late-stage prostate cancer.
背景/目的：前列腺癌是男性癌症相关死亡的第二大原因。该疾病中更具侵袭性和晚期形态的发病率逐年上升，这迫切要求寻找新的治疗干预措施并加强已有疗法。前列腺癌是一种具有独特靶向性的疾病，其进展由雄性激素（雄激素）驱动，后者通过雄激素受体促进肿瘤发生。当前标准疗法直接靶向AR及其异常信号轴，但常出现耐药性，且耐药机制尚不明确。研究表明，即使在耐药状态下，AR仍是前列腺癌生长和存活的主要驱动因素，AR靶基因及其辅助因子可能介导治疗耐药。本研究聚焦于与AR关系密切的同源盒转录因子NKX3.1。尽管传统上认为NKX3.1是肿瘤抑制因子，但先前研究报道其可通过与AR协同作用促进癌细胞存活。NKX3.1在早期疾病中作为抑癌因子的作用，与其作为晚期前列腺癌诊断生物标志物的特征存在矛盾。方法：我们通过过表达和敲低技术调控前列腺癌细胞中NKX3.1的表达，检测其与AR的物理相互作用，并分析后续细胞活力及下游靶基因表达。结果：研究发现NKX3.1在晚期前列腺癌中持续表达，且常因AR异常活性而上调。在不同前列腺癌细胞模型中的瞬时敲低实验表明，NKX3.1表达是细胞存活必要条件。同样，在前列腺癌细胞系中稳定过表达NKX3.1可产生雄激素不敏感表型，提示NKX3.1足以在缺乏AR配体的情况下促进生长。结论：本研究为NKX3.1在前列腺癌中的致癌影响及这些转录因子在晚期前列腺癌模型中的分子互作机制提供了新见解。
肿瘤(癌症)患者之家