Xue Jia, Chen Haoran, Lu Jinqi, Zhang Haojun, Geng Jie, He Peifeng, Lu Xuechun
School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, Shanxi, China.
School of Management, Shanxi Medical University, Taiyuan, Shanxi, China.
Front Genet. 2023 Jun 14;14:1203345. doi: 10.3389/fgene.2023.1203345. eCollection 2023.
Using bioinformatics analyses, this study aimed to identify lncRNAs related to the immune status of acute myeloid leukemia (AML) patients and ascertain the potential impact in immunity-related competing endogenous RNA (ceRNA) networks on AML prognosis. AML-related RNA-seq FPKM data, AML-related miRNA expression microarray data, and gene sets associated with immunity-related pathways were, respectively, obtained from the TCGA, GEO, and ImmReg databases. An immunity-related ceRNA network was then constructed according to the predicted interactions between AML-related mRNAs, lncRNAs, and miRNAs. After performing LASSO and multivariate Cox regression analyses, lncRNAs in the ceRNA network were used to establish an AML prognostic model. According to mutual regulatory relationships and consistent trends of expression among candidate ceRNAs, two ceRNA subnetworks related to the AML prognostic model were determined. Finally, the correlation between the expression levels of mRNAs, lncRNAs, and miRNAs in each ceRNA subnetwork and immune cell infiltration (assessed by combining the ESTIMATE and CIBERSORT methods and ssGSEA) was analyzed. A total of 424 immunity-related differentially expressed (IR-DE) mRNAs (IR-DEmRNAs), 191 IR-DElncRNAs, and 69 IR-DEmiRNAs were obtained, and a ceRNA network of 20 IR-DElncRNAs, 6 IR-DEmRNAs, and 3 IR-DEmiRNAs was established. Univariate Cox regression analysis was conducted on 20 IR-DElncRNAs, and 7 of these were identified to be significantly correlated with the overall survival (OS) time in AML patients. Then, two IR-DElncRNAs (MEG3 and HCP5) were screened as independent OS-related factors by LASSO and multivariable Cox regression analyses, and a prognostic model was constructed to evaluate the survival risk in AML patients. Survival analyses indicated that the OS of patients was often poor in the high-risk group. Additionally, from this model, two ceRNA regulatory pathways, namely, MEG3/miR-125a-5p/SEMA4C and HCP5/miR-125b-5p/IL6R, which were potentially involved in the immune regulation of AML prognosis were identified. lncRNAs HCP5 and MEG3 may act as key ceRNAs in the pathogenesis in AML by regulating immune cell representation as part of the regulatory lncRNA-miRNA-mRNA axes. The candidate mRNAs, lncRNAs, and miRNAs included in the ceRNA network identified here may serve as useful prognostic biomarkers and immunotherapeutic targets for AML.
本研究利用生物信息学分析，旨在鉴定与急性髓系白血病（AML）患者免疫状态相关的长链非编码RNA（lncRNA），并确定免疫相关竞争性内源RNA（ceRNA）网络对AML预后的潜在影响。分别从TCGA、GEO和ImmReg数据库中获取AML相关的RNA测序每百万映射读取中每千碱基转录本的片段数（FPKM）数据、AML相关的miRNA表达微阵列数据以及与免疫相关途径相关的基因集。然后根据AML相关mRNA、lncRNA和miRNA之间的预测相互作用构建免疫相关ceRNA网络。在进行LASSO和多变量Cox回归分析后，使用ceRNA网络中的lncRNA建立AML预后模型。根据候选ceRNA之间的相互调控关系和一致的表达趋势，确定了两个与AML预后模型相关的ceRNA子网。最后，分析了每个ceRNA子网中mRNA、lncRNA和miRNA表达水平与免疫细胞浸润（通过联合使用ESTIMATE和CIBERSORT方法以及单样本基因集富集分析（ssGSEA）进行评估）之间的相关性。共获得424个免疫相关差异表达（IR-DE）mRNA（IR-DEmRNAs）、191个IR-DElncRNAs和69个IR-DEmiRNAs，并建立了一个由20个IR-DElncRNAs、6个IR-DEmRNAs和3个IR-DEmiRNAs组成的ceRNA网络。对20个IR-DElncRNAs进行单变量Cox回归分析，其中7个被确定与AML患者的总生存期（OS）时间显著相关。然后，通过LASSO和多变量Cox回归分析筛选出两个IR-DElncRNAs（MEG3和HCP5）作为独立的OS相关因素，并构建了一个预后模型来评估AML患者的生存风险。生存分析表明，高风险组患者的OS通常较差。此外，从该模型中鉴定出两条可能参与AML预后免疫调节的ceRNA调控途径，即MEG3/miR-125a-5p/SEMA4C和HCP5/miR-125b-5p/IL6R。lncRNAs HCP5和MEG3可能作为调控lncRNA-miRNA-mRNA轴的一部分，通过调节免疫细胞表现，在AML发病机制中充当关键ceRNA。本文鉴定的ceRNA网络中包含的候选mRNA、lncRNA和miRNA可能作为AML有用的预后生物标志物和免疫治疗靶点。
