The LncRNAs PART1 and ADAMTS9-AS2 act in an Antithetic Manner on AR Signaling and Induction of Cellular Senescence in Prostate Cancer Cells.

IF 12.5 2区 医学 Q1 SURGERY
Mohammad Taheri, Katrin Schindler, Aria Baniahmad
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引用次数: 0

Abstract

Background: 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.

Methods: 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.

Results: 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. Further, 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 suggest that ADAMTS9-AS2 and PART1 control AR signaling at SAL.

Conclusion: In summary, we identified novel AR signaling pathways that involve lncRNAs oppositely regulated by SAL and in PCa tumorigenesis.

LncRNAs PART1和ADAMTS9-AS2在前列腺癌细胞的AR信号传导和细胞衰老诱导中起拮抗作用。
背景:前列腺癌(PCa)最初是一种激素依赖性疾病,其发展和扩散与雄激素受体(AR)信号活性密切相关。针对AR途径的治疗是治疗PCa的标准方法,包括AR拮抗剂和双极雄激素治疗中使用的生理上雄激素水平(SAL)。在这里,我们通过检测PCa样本和对AR拮抗剂或SAL的反应以及功能上的敲低,确定了两个lncRNAs PART1和ADAMTS9-AS2在PCa细胞中部分介导雄激素信号传导。方法:本研究对50例患者的肿瘤组织(TT)样本与相应的肿瘤邻近正常组织(NTAT)样本进行了表达分析。前列腺切除术患者体外样本的rna测序和治疗证实了SAL对lncRNAs的调控。通过qRT-PCR分析AR靶基因的雄激素信号,通过衰老标志物分析PCa衰老途径中的雄激素信号。患者肿瘤样本的相关性分析证实了共表达。在LNCaP和C4-2细胞中使用RNA免疫沉淀(RIP)检测AR-lncRNA相互作用。采用生物信息学分析鉴定配体特异性lncrna和miRNA与PART1和ADAMTS9-AS2的相互作用,并通过前列腺切除术患者样品的离体治疗得到证实。结果:PART1和ERVH48-1在TT样品中显著过表达,ADAMTS9-AS2在TT样品中的表达低于NTAT样品。SAL治疗在两种人类PCa细胞系和患者肿瘤样本中显示相反的调控。当ADAMTS9-AS2上调时,PART1被SAL抑制。此外,获得的数据表明,ADAMTS9-AS2可能作为AR信号的共同激活因子,PART1作为AR信号的共同抑制因子。有趣的是,敲低表明lncRNAs ADAMTS9-AS2和PART1都调节AR活性和蛋白水平,以及sal介导的细胞衰老。因此,这些数据表明,ADAMTS9-AS2和PART1控制SAL的AR信号。结论:总之,我们发现了新的AR信号通路,涉及由SAL反向调控的lncrna和PCa的肿瘤发生。
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
CiteScore
17.70
自引率
3.30%
发文量
0
审稿时长
6-12 weeks
期刊介绍: The International Journal of Surgery (IJS) has a broad scope, encompassing all surgical specialties. Its primary objective is to facilitate the exchange of crucial ideas and lines of thought between and across these specialties.By doing so, the journal aims to counter the growing trend of increasing sub-specialization, which can result in "tunnel-vision" and the isolation of significant surgical advancements within specific specialties.
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