Taheri Mohammad, Schindler Katrin, Baniahmad Aria
Institute of Human Genetics, Jena University Hospital, Jena, Germany.
Int J Surg. 2025 May 1;111(5):3646-3664. doi: 10.1097/JS9.0000000000002334.
Prostate cancer (PCa) is initially a hormone-dependent disease and the development and spread of PCa are tightly linked to the androgen receptor (AR) signaling activity. Therapy that targets the AR pathway is a standard approach for treating PCa including AR antagonists and supraphysiological androgen levels (SAL) used in bipolar androgen therapy. Here, we identified that the two lncRNAs PART1 and ADAMTS9-AS2 mediate in part androgen signaling in PCa cells by examining PCa specimen and response to AR antagonists or SAL as well as functionally by knockdown.
This study utilized expression analysis of tumor tissues (TT) samples in comparison to their corresponding normal tissue adjacent to the tumor (NTAT) counterparts of 50 patients. RNA-seq and treatment of patient prostatectomy samples ex-vivo confirmed regulation of lncRNAs by SAL. Knockdown of both lncRNAs were used to analyze androgen signaling of AR target genes by qRT-PCR and in PCa senescence pathway by analyzing senescence markers. Correlation analyses of patient tumor samples confirmed co-expression. RNA immunoprecipitation (RIP) used in both LNCaP and C4-2 cells detect AR-lncRNA interaction. Bioinformatic analyses were employed to identify ligand-specific lncRNAs and miRNA interactions with PART1 and ADAMTS9-AS2 and confirmed by treatment of patient prostatectomy samples ex-vivo .
PART1 and ERVH48-1 were significantly overexpressed in TT samples, ADAMTS9-AS2 expression is lower in TT samples compared to NTAT samples. SAL treatment indicates opposite regulation in two human PCa cell lines and patient tumor samples. While ADAMTS9-AS2 is upregulated, PART1 is repressed by SAL. Furthermore, the obtained data suggest that ADAMTS9-AS2 may act as a co-activator and PART1 as a co-repressor of AR signaling. Interestingly, the knockdown indicates that both lncRNAs ADAMTS9-AS2 and PART1 regulate AR activity and protein level as well as SAL-mediated induction of cellular senescence. Thus, the data suggest that ADAMTS9-AS2 and PART1 control AR signaling at SAL.
In summary, we identified novel AR signaling pathways that involve lncRNAs oppositely regulated by SAL and in PCa tumorigenesis.
前列腺癌（PCa）最初是一种激素依赖性疾病，PCa的发生和扩散与雄激素受体（AR）信号活性密切相关。靶向AR途径的治疗是治疗PCa的标准方法，包括AR拮抗剂和双相雄激素疗法中使用的超生理雄激素水平（SAL）。在此，我们通过检测PCa标本、对AR拮抗剂或SAL的反应以及通过敲低进行功能研究，确定了两种长链非编码RNA（lncRNA）PART1和ADAMTS9-AS2在PCa细胞中介导部分雄激素信号传导。
本研究对50例患者的肿瘤组织（TT）样本及其相应的肿瘤旁正常组织（NTAT）样本进行表达分析。RNA测序以及对患者前列腺切除样本的体外处理证实了SAL对lncRNA的调控。通过qRT-PCR敲低这两种lncRNA来分析AR靶基因的雄激素信号传导，并通过分析衰老标志物来研究PCa衰老途径。对患者肿瘤样本的相关性分析证实了共表达。在LNCaP和C4-2细胞中进行的RNA免疫沉淀（RIP）检测AR-lncRNA相互作用。采用生物信息学分析来鉴定与PART1和ADAMTS9-AS2相互作用的配体特异性lncRNA和miRNA，并通过对患者前列腺切除样本的体外处理进行验证。
PART1和ERVH48-1在TT样本中显著过表达，与NTAT样本相比，ADAMTS9-AS2在TT样本中的表达较低。SAL处理在两种人PCa细胞系和患者肿瘤样本中显示出相反的调控作用。ADAMTS9-AS2被上调，而PART1被SAL抑制。此外，获得的数据表明ADAMTS9-AS2可能作为AR信号传导的共激活因子，而PART1作为共抑制因子。有趣的是，敲低表明lncRNA ADAMTS9-AS2和PART1均调节AR活性和蛋白水平以及SAL介导的细胞衰老诱导。因此，数据表明ADAMTS9-AS2和PART1在SAL时控制AR信号传导。
总之，我们鉴定了涉及lncRNA且受SAL反向调控并参与PCa肿瘤发生的新型AR信号通路。
