新型长链非编码 RNA lncAMPC 通过刺激 LIF/LIFR 表达促进前列腺癌转移和免疫抑制。
Novel Long Non-coding RNA lncAMPC Promotes Metastasis and Immunosuppression in Prostate Cancer by Stimulating LIF/LIFR Expression.
机构信息
Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
出版信息
Mol Ther. 2020 Nov 4;28(11):2473-2487. doi: 10.1016/j.ymthe.2020.06.013. Epub 2020 Jun 15.
Long non-coding RNAs (lncRNAs) participate in the development and progression of prostate cancer (PCa). We aimd to identify a novel lncRNA, named lncRNA activated in metastatic PCa (lncAMPC), and investigate its mechanisms and clinical significance in PCa. First, the biological capacity of lncAMPC in PCa was demonstrated both in vitro and in vivo. The lncAMPC was overexpressed in tumor tissue and urine of metastatic PCa patients and promoted PCa tumorigenesis and metastasis. Then, a mechanism study was conducted to determine how the lncAMPC-activated pathway contributed to PCa metastasis and immunosuppression. In the cytoplasm, lncAMPC upregulated LIF expression by sponging miR-637 and inhibiting its activity. In the nucleus, lncAMPC enhanced LIFR transcription by decoying histone H1.2 away from the upstream sequence of the LIFR gene. The lncAMPC-activated LIF/LIFR expressions stimulated the Jak1-STAT3 pathway to simultaneously maintain programmed death-ligand 1 (PD-L1) protein stability and promote metastasis-associated gene expression. Finally, the prognostic value of the expression of lncAMPC and its downstream genes in PCa patients was evaluated. High LIF/LIFR levels indicated shorter biochemical recurrence-free survival among patients who underwent radical prostatectomy. Therefore, the lncAMPC/LIF/LIFR axis plays a critical role in PCa metastasis and immunosuppression and may serve as a prognostic biomarker and potential therapeutic target.
长链非编码 RNA（lncRNAs）参与前列腺癌（PCa）的发生和发展。本研究旨在鉴定一种新型 lncRNA，命名为 lncRNA 在转移性 PCa 中激活（lncAMPC），并研究其在 PCa 中的机制和临床意义。首先，在体外和体内证明了 lncAMPC 在 PCa 中的生物学功能。lncAMPC 在转移性 PCa 患者的肿瘤组织和尿液中高表达，并促进了 PCa 的发生和转移。然后，进行了一项机制研究，以确定 lncAMPC 激活途径如何促进 PCa 转移和免疫抑制。在细胞质中，lncAMPC 通过海绵吸附 miR-637 并抑制其活性而上调 LIF 表达。在细胞核中，lncAMPC 通过将组蛋白 H1.2 从 LIFR 基因的上游序列中分离出来，增强 LIFR 转录。lncAMPC 激活的 LIF/LIFR 表达刺激 Jak1-STAT3 通路，同时维持程序性死亡配体 1（PD-L1）蛋白稳定性并促进转移相关基因表达。最后，评估了 lncAMPC 和其下游基因在 PCa 患者中的表达的预后价值。LIF/LIFR 水平高的患者接受根治性前列腺切除术，其生化无复发生存期较短。因此，lncAMPC/LIF/LIFR 轴在 PCa 转移和免疫抑制中起关键作用，可能作为预后生物标志物和潜在的治疗靶点。
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