Wu Haoming, Liu Ning, He Aifeng, Li Haiyang, Liu Hui, Qian Jinke, Mao Weipu, Fu Guangbo
Department of Urology, Binhai County People's Hospital Yancheng 224500, Jiangsu, China.
Medical College, Xuzhou Medical University Xuzhou 221000, Jiangsu, China.
Am J Cancer Res. 2023 Aug 15;13(8):3384-3400. eCollection 2023.
Numerous studies have demonstrated that long non-coding RNAs (lncRNAs) play crucial roles in tumor progression. This study aimed to identify lncRNAs associated with overall survival (OS) and progression-free interval (PFI) in prostate cancer (PCa) patients and to elucidate the driving mechanisms and functions of these lncRNAs. We utilized the TCGA database to screen for lncRNAs linked with OS and PFI. KM survival analysis, ROC curve analysis, and Cox survival analysis were employed to assess the prognostic significance of lncRNAs in PCa patients. We conducted a loss-of-function assay to explore the role of lncRNAs in PCa. Correlation analysis was performed to study the relationship between lncRNAs and immune cell infiltration. Lasso regression analysis was performed to screen proteins which might interact with lncRNAs, while rescue experiments verified the integrity of the signaling pathway. LMNTD2-AS1 was found to be the only lncRNA in PCa patients associated with both OS and PFI with significantly elevated levels in PCa. Elevated LMNTD2-AS1 expression was significantly linked to advanced stage, grade, primary treatment outcomes, residual tumors, and Gleason scores in PCa patients. Moreover, multivariate Cox regression analysis revealed that high LMNTD2-AS1 expression independently predicted PFI in PCa patients. The AUC of LMNTD2-AS1 for predicting 3-year OS and 5-year OS in PCa patients was 0.877 and 0.807, respectively, while for 3-year PFI and 5-year PFI it was 0.751 and 0.727, respectively. Overexpression of LMNTD2-AS1 correlated with infiltration of neutrophils, macrophages, pDC, NK CD56bright cells, and other immune cells. Furthermore, FUS and NRF2 are both potential binding proteins and related signaling pathways downstream of LMNTD2-AS1. Functional experiments demonstrated that LMNTD2-AS1 knockdown significantly inhibited migration, invasion, and proliferation of PCa cells while overexpression of FUS was found to rescue the functional inhibition caused by LMNTD2-AS1 knockdown. LMNTD2-AS1 functions as an oncogene in PCa, influencing patient prognosis and the immune microenvironment; it may regulate immune cell infiltration and promote PCa progression by interacting with the NRF2 signaling pathway via FUS binding.
众多研究表明，长链非编码RNA（lncRNA）在肿瘤进展中发挥着关键作用。本研究旨在确定前列腺癌（PCa）患者中与总生存期（OS）和无进展生存期（PFI）相关的lncRNA，并阐明这些lncRNA的驱动机制和功能。我们利用TCGA数据库筛选与OS和PFI相关的lncRNA。采用KM生存分析、ROC曲线分析和Cox生存分析来评估lncRNA在PCa患者中的预后意义。我们进行了功能缺失实验以探索lncRNA在PCa中的作用。进行相关性分析以研究lncRNA与免疫细胞浸润之间的关系。进行Lasso回归分析以筛选可能与lncRNA相互作用的蛋白质，同时通过挽救实验验证信号通路的完整性。发现LMNTD2-AS1是PCa患者中唯一与OS和PFI均相关的lncRNA，其在PCa中的水平显著升高。LMNTD2-AS1表达升高与PCa患者的晚期、分级、初始治疗结果、残留肿瘤和Gleason评分显著相关。此外，多变量Cox回归分析显示，高LMNTD2-AS1表达独立预测PCa患者的PFI。LMNTD2-AS1预测PCa患者3年OS和5年OS的AUC分别为0.877和0.807，而预测3年PFI和5年PFI的AUC分别为0.751和0.727。LMNTD2-AS1的过表达与中性粒细胞、巨噬细胞、浆细胞样树突状细胞、自然杀伤CD56bright细胞和其他免疫细胞的浸润相关。此外，FUS和NRF2都是LMNTD2-AS1下游潜在的结合蛋白和相关信号通路。功能实验表明，敲低LMNTD2-AS1可显著抑制PCa细胞的迁移、侵袭和增殖，而发现过表达FUS可挽救敲低LMNTD2-AS1所导致的功能抑制。LMNTD2-AS1在PCa中作为癌基因发挥作用，影响患者预后和免疫微环境；它可能通过FUS结合与NRF2信号通路相互作用来调节免疫细胞浸润并促进PCa进展。
