H19 in Serum Extracellular Vesicles Reflects Resistance to AR Axis-targeted Therapy Among CRPC Patients.

IF 2.6 4区医学 Q2 GENETICS & HEREDITY

Cancer Genomics & Proteomics Pub Date : 2023-09-01 DOI:10.21873/cgp.20397

Taku Kato, Kyojiro Kawakami, Kosuke Mizutani, Tatsuya Ando, Yasuhiro Sakai, Kouhei Sakurai, Shohei Toyota, Hidetoshi Ehara, Hiroyasu Ito, Masafumi Ito

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引用次数: 0

Abstract

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.

Patients and methods: 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.

Results: 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.

Conclusion: EV-H19 may negatively correlate with AR-signaling activity and could be a marker to diagnose ARAT-resistance among CRPC patients.

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血清细胞外小泡中的H19反映CRPC患者对AR轴靶向治疗的耐药性。

背景/目的：我们旨在评估癌症（PC）患者血清细胞外小泡（EVs）中雄激素受体（AR）信号相关长非编码RNA（lncRNA）的变化，以确定去势抵抗PC（CRPC）患者AR轴靶向治疗（ARAT）耐药性的新生物标志物。患者和方法：从2例ARAT耐药前后的患者中分离EVs。EVs的RNA图谱通过RNA测序进行。通过数字液滴PCR（ddPCR）分析了58例确诊时的定位和14例转移性PC患者、7例ARAT幼稚和6例ARAT耐药的CRPC患者的EVs中所选lncRNA的表达水平。使用已发表的数据检测PC组织中LncRNA H19的表达。为了分析H19的作用，对PC患者的预后进行了分析，并对22Rv1 PC细胞进行了蛋白质组学分析。结果：RNA测序显示，在获得ARAT抗性后，AR调节的RNA在EVs中富集最多。其中，ddPCR证实了AR信号相关lncRNA（PCAT1、H19、HOXA-11AS、ZEB1-AS1、ARLNC1、PART1、CTBP1-AS和PCA3）的上调。与ARAT幼稚CRPC或转移性PC患者相比，ARAT耐药患者的EVs（EV-H19）中含有的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低表达的神经内分泌CRPC组织中上调。此外，EV-H19的表达与雄激素剥夺治疗的不良结果显著相关。蛋白质组学分析表明H19敲除增强了PC相关蛋白的表达。结论：EV-H19可能与AR信号活性呈负相关，可作为诊断CRPC患者ARAT耐药性的标志物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Genomics & Proteomics ONCOLOGY-GENETICS & HEREDITY

CiteScore

5.00

自引率

8.00%

发文量

期刊介绍： Cancer Genomics & Proteomics (CGP) is an international peer-reviewed journal designed to publish rapidly high quality articles and reviews on the application of genomic and proteomic technology to basic, experimental and clinical cancer research. In this site you may find information concerning the editorial board, editorial policy, issue contents, subscriptions, submission of manuscripts and advertising. The first issue of CGP circulated in January 2004. Cancer Genomics & Proteomics is a journal of the International Institute of Anticancer Research. From January 2013 CGP is converted to an online-only open access journal. Cancer Genomics & Proteomics supports (a) the aims and the research projects of the INTERNATIONAL INSTITUTE OF ANTICANCER RESEARCH and (b) the organization of the INTERNATIONAL CONFERENCES OF ANTICANCER RESEARCH.