我们旨在评估前列腺癌（PC）患者血清胞外囊泡（EVs）中与雄激素受体（AR）信号通路相关的长非编码RNA（lncRNAs）的变化，以便鉴定去势抵抗PC（CRPC）患者中AR轴靶向治疗（ARAT）耐药的新生物标志物。EVs从2名患者中分离出来，分别在获得ARAT耐药之前和之后进行RNA测序。通过数字液滴PCR（ddPCR）分析选定的lncRNAs在EVs中的表达水平，在58名局部和14名转移性PC患者的诊断时，7名ARAT原发性和6名ARAT耐药CRPC患者中进行分析。使用已发表的数据检查PC组织中的LncRNA H19表达情况。为了分析H19的作用，分析了PC患者的预后，并在22Rv1 PC细胞中进行了蛋白质组分析。RNA测序发现，在获得ARAT耐药后，AR调控的RNA在EVs中最为丰富。其中，ddPCR证实了与AR信号通路相关的lncRNAs（PCAT1、H19、HOXA-11AS、ZEB1-AS1、ARLNC1、PART1、CTBP1-AS和PCA3）的上调。与ARAT原发性CRPC或转移性PC患者相比，ARAT耐药患者中EV-H19显著增加。在PC组织中，H19与AR蛋白和AR活性评分呈负相关，并在AR表达下降的神经内分泌CRPC组织中上调。此外，EV-H19表达与雄激素剥夺治疗的不良结果显著相关。蛋白质组分析表明，H19敲除增强了与PC相关的蛋白质表达。EV-H19可能与AR信号通路活性呈负相关，并且可能是诊断CRPC患者中ARAT耐药的标志物。版权所有©2023年，国际抗癌研究协会（George J. Delinasios博士），保留所有权利。

We aimed to evaluate the changes of androgen receptor (AR) signaling-related long non-coding RNAs (lncRNAs) in serum extracellular vesicles (EVs) from prostate cancer (PC) patients, in order to identify novel biomarkers for AR axis-targeted therapy (ARAT)-resistance among castration-resistant PC (CRPC) patients.EVs were isolated from 2 patients before and after acquiring ARAT-resistance. RNA profiling of EVs was performed by RNA-sequencing. The expression levels of selected lncRNAs in EVs were analyzed by digital droplet PCR (ddPCR) in 58 localized and 14 metastatic PC patients at diagnosis, 7 ARAT-naïve and 6 ARAT-resistant CRPC patients. LncRNA H19 expression in PC tissue was examined using published data. In order to analyze the role of H19, the prognosis was analyzed in PC patients and proteomic analysis was performed in 22Rv1 PC cells.RNA-sequencing revealed that AR-regulated RNAs were most enriched in EVs after acquiring ARAT-resistance. Among them, up-regulation of AR signaling-related lncRNAs (PCAT1, H19, HOXA-11AS, ZEB1-AS1, ARLNC1, PART1, CTBP1-AS and PCA3) was confirmed by ddPCR. H19 contained in EVs (EV-H19) was significantly increased among ARAT-resistant patients compared to ARAT-naïve CRPC or metastatic PC patients. In PC tissue, H19 was negatively correlated with AR protein and AR-activity score and up-regulated in neuroendocrine CRPC tissue with low AR expression. Furthermore, EV-H19 expression was significantly associated with worse outcome to androgen-deprivation therapy. Proteomic analysis demonstrated that H19 knockdown enhanced PC-related protein expression.EV-H19 may negatively correlate with AR-signaling activity and could be a marker to diagnose ARAT-resistance among CRPC patients.Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.