Department of Joint Research Laboratory of Clinical Medicine, Fujita Health University School of Medicine, Toyoake, Japan;
Department of Urology, Asahi University Hospital, Gifu, Japan.
Cancer Genomics Proteomics. 2023 Sep-Oct;20(5):456-468. doi: 10.21873/cgp.20397.
BACKGROUND/AIM: 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.
背景/目的：我们旨在评估前列腺癌（PC）患者血清细胞外囊泡（EVs）中雄激素受体（AR）信号相关长非编码 RNA（lncRNA）的变化，以鉴定去势抵抗性 PC（CRPC）患者中针对 AR 轴靶向治疗（ARAT）耐药的新型生物标志物。
从 2 例获得 ARAT 耐药性前后的患者中分离 EVs。通过 RNA 测序对 EVs 进行 RNA 谱分析。在 58 例局限性和 14 例转移性 PC 患者的诊断时、7 例 ARAT 初治和 6 例 ARAT 耐药的 CRPC 患者中，通过数字液滴 PCR（ddPCR）分析了 EVs 中选定 lncRNA 的表达水平。使用已发表的数据检查 PC 组织中 lncRNA H19 的表达。为了分析 H19 的作用，在 PC 患者中分析了预后，并在 22Rv1 PC 细胞中进行了蛋白质组学分析。
RNA 测序显示，在获得 ARAT 耐药性后，AR 调节的 RNA 最丰富地富集在 EVs 中。其中，ddPCR 证实 AR 信号相关 lncRNA（PCAT1、H19、HOXA-11AS、ZEB1-AS1、ARLNC1、PART1、CTBP1-AS 和 PCA3）的上调。与 ARAT 初治 CRPC 或转移性 PC 患者相比，ARAT 耐药患者中 EV 中包含的 H19（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，在 AR 表达较低的神经内分泌 CRPC 组织中上调。此外，EV-H19 的表达与雄激素剥夺治疗的预后显著相关。蛋白质组学分析表明，H19 的敲低增强了与 PC 相关的蛋白质表达。
EV-H19 可能与 AR 信号活性呈负相关，并且可能是诊断 CRPC 患者 ARAT 耐药的标志物。
