A novel AR translational regulator lncRNA LBCS inhibits castration resistance of prostate cancer
A novel AR translational regulator lncRNA LBCS inhibits castration resistance of prostate cancer
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一种新型AR翻译调节因子lncRNA LBCS抑制前列腺癌的去势抵抗
DOI：
10.1186/s12943-019-1037-8
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发表时间：
2019-06-20
期刊：
影响因子：
37.3
通讯作者：
Lin, Tianxin
中科院分区：
文献类型：
--
作者：
Gu, Peng;Chen, Xu;Lin, Tianxin
背景进展为去势抵抗状态是前列腺癌（PCa）患者死亡的主要原因。雄激素受体（Androgen receptor，AR）信号通路在去势抵抗性前列腺癌（castration resistant Prostate Cancer，CRPC）的发生发展中起着重要作用，因此了解低雄激素环境下AR的激活机制对于探索CRPC治疗的新途径具有重要意义。在三个独立的大规模队列中分析lnc-LBCS的表达和临床特征。Lnc-LBCS的功能作用和机制进一步研究通过获得和功能丧失assays. ResultsLnc-LBCS在CRPC细胞系和组织中的表达较低。LBCS表达下调与PCa患者Gleason评分、T分期及预后相关。在雄激素去除或AR阻断条件下，LBCS过表达降低前列腺癌细胞的去势抵抗性，而LBCS敲低则增加。此外，在雄激素缺乏的情况下，LBCS的敲低足以通过提高AR蛋白的翻译来激活AR信号传导。结论Lnc-LBCS是一种新型的AR翻译调节因子，通过与hnRNPK相互作用抑制前列腺癌去势抵抗。这为lncRNA介导的AR激活对CRPC的调控提供了新的见解，LBCS-hnRNPK-AR轴为CRPC的治疗提供了有希望的方法。
BackgroundProgression to a castration resistance state is the main cause of deaths in prostate cancer (PCa) patients. Androgen Receptor (AR) signaling plays the central role in progression of Castration Resistant Prostate Cancer (CRPC), therefore understanding the mechanisms of AR activation in the milieu of low androgen is critical to discover novel approach to treat CRPC.MethodsFirstly, we explore the CRPC associated lncRNAs by transcriptome microarray. The expression and clinical features of lnc-LBCS are analyzed in three independent large-scale cohorts. The functional role and mechanism of lnc-LBCS are further investigated by gain and loss of function assays in vitro.ResultsThe expression of Lnc-LBCS was lower in CRPC cells lines and tissues. LBCS downregulation was correlated with higher Gleason Score, T stage and poor prognosis of PCa patients. LBCS overexpression decreases, whereas LBCS knockdown increases, the traits of castration resistance in prostate cancer cells under androgen ablated or AR blocked condition. Moreover, knockdown of LBCS was sufficient to activate AR signaling in the absence of androgen by elevating the translation of AR protein. Mechanistically, LBCS interacted directly with hnRNPK to suppress AR translation efficiency by forming complex with hnRNPK and AR mRNA.ConclusionsLnc-LBCS functions as a novel AR translational regulator that suppresses castration resistance of prostate cancer by interacting with hnRNPK. This sheds a new insight into the regulation of CRPC by lncRNA mediated AR activation and LBCS-hnRNPK-AR axis provides a promising approach to the treatment of CRPC.