N6-methyladenosine-related lncRNAs identified as potential biomarkers for predicting the overall survival of Asian gastric cancer patients.
N6-methyladenosine-related lncRNAs identified as potential biomarkers for predicting the overall survival of Asian gastric cancer patients.
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N6-甲基腺苷相关lncRNA被确定为预测亚洲胃癌患者总生存期的潜在生物标志物
DOI：
10.1186/s12885-022-09801-z
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发表时间：
2022-07-01
期刊：
影响因子：
3.8
通讯作者：
中科院分区：
文献类型：
--
作者：
胃癌是亚洲国家最常见的恶性肿瘤之一。由于lncRNA在胃癌中表达的高度特异性，研究表明lncRNA可作为胃癌的诊断和预后指标。最近，N6-甲基腺苷（m6 A）也已成为GC中lncRNA表达的重要调节剂。本研究旨在建立一种新的m6 A相关的lncRNAs的预后签名，可用于构建准确的模型，用于预测GC的预后在亚洲population.MethodsFirst，在GC样品中的m6 A修饰和m6 A甲基转移酶的表达水平进行了测定，使用斑点印迹和蛋白质印迹分析。接下来，我们评估了从癌症基因组图谱（TCGA）数据库检索的88例亚洲GC患者的lncRNA表达谱和相应的临床数据。研究胃癌和正常组织中m6 A相关lncRNA的差异表达。还分析了这些靶lncRNA与潜在免疫标记之间的关系。进行基因集富集分析（GSEA）以鉴定恶性相关通路。进行单变量考克斯回归、LASSO回归和多变量考克斯回归分析以建立新的预后m6 A相关lncRNA预后特征。此外，我们构建了一个预测诺模图，并确定了9个m6 A相关的lncRNAs的表达水平在12对临床samples.ResultsWe发现，m6 A甲基化水平显着增加，在GC肿瘤样品相比，相邻的正常组织，和增加与肿瘤分期呈正相关。然后根据m6 A相关lncRNA的差异表达将患者分为两组（组1和组2）。结果显示，两个集群之间的生存概率存在显著差异（p= 0.018）。值得注意的是，簇2中的低存活率可能与免疫细胞的高表达（静息记忆CD 4 +T细胞，p= 0.027;调节性T细胞，p= 0.0018;单核细胞，p= 0.00095;和静息树突细胞，p= 0.015）和免疫细胞的低表达（静息NK细胞，p= 0.033;和巨噬细胞M1，p= 0.045）相关。富集分析表明，恶性相关的生物过程中更常见的聚类2亚组。最后，由六种m6 A相关lncRNA组成的风险模型被确定为疾病的独立预测因子，可以将患者分为高风险组或低风险组。时间依赖性ROC分析提示，风险评分能准确预测胃癌患者的预后。高危组患者的预后差于低危组患者，且风险评分与免疫细胞呈正相关（静息记忆CD 4 +T细胞，R = 0.31，P = 0.038;调节性T细胞，R = 0.42，P = 0.0042;单核细胞，R = 0.42，P = 0.0043）。而M1巨噬细胞（R =-0.37，P = 0.012）和静息NK细胞（R =-0.31，P = 0.043）与风险评分呈负相关。此外，临床样本的分析验证的风险评分和肿瘤stages.ConclusionsThe风险模型之间的弱正相关性描述，基于六个m6 A相关的lncRNAs签名，并可以预测亚洲GC患者的临床症状和免疫反应。
ObjectiveGastric cancer (GC) is one of the most prevalent malignant tumors in Asian countries. Studies have proposed that lncRNAs can be used as diagnostic and prognostic indicators of GC due to the high specificity of lncRNAs expression involvement in GC. Recently, N6-methyladenosine (m6A) has also emerged as an important modulator of the expression of lncRNAs in GC. This study aimed at establishing a novel m6A-related lncRNAs prognostic signature that can be used to construct accurate models for predicting the prognosis of GC in the Asian population.MethodsFirst, the levels of m6A modification and m6A methyltransferases expression in GC samples were determined using dot blot and western blot analyses. Next, we evaluated the lncRNAs expression profiles and the corresponding clinical data of 88 Asian GC patients retrieved from The Cancer Genome Atlas (TCGA) database. Differential expression of m6A-related lncRNAs between GC and normal tissues was investigated. The relationship between these target lncRNAs and potential immunotherapeutic signatures was also analyzed. Gene set enrichment analysis (GSEA) was performed to identify the malignancy-associated pathways. Univariate Cox regression, LASSO regression, and multivariate Cox regression analyses were performed to establish a novel prognostic m6A-related lncRNAs prognostic signature. Moreover, we constructed a predictive nomogram and determined the expression levels of nine m6A-related lncRNAs in 12 pairs of clinical samples.ResultsWe found that m6A methylation levels were significantly increased in GC tumor samples compared to adjacent normal tissues, and the increase was positively correlated with tumor stage. Patients were then divided into two clusters (cluster 1 and cluster 2) based on the differential expression of the m6A-related lncRNAs. Results showed that there was a significant difference in survival probability between the two clusters (p= 0.018). Notably, the low survival rate in cluster 2 may be associated with high expression of immune cells (resting memory CD4+T cells,p= 0.027; regulatory T cells,p= 0.0018; monocytes,p= 0.00095; and resting dendritic cells,p= 0.015), and low expression of immune cells (resting NK cells,p= 0.033; and macrophages M1,p= 0.045). Enrichment analysis indicated that malignancy-associated biological processes were more common in the cluster 2 subgroup. Finally, the risk model comprising of six m6A-related lncRNAs was identified as an independent predictor of prognoses, which could divide patients into high- or low-risk groups. Time-dependent ROC analysis suggested that the risk score could accurately predict the prognosis of GC patients. Patients in the high-risk group had worse outcomes compared to patients in the low-risk group, and the risk score showed a positive correlation with immune cells (resting memory CD4+T cells, R = 0.31,P= 0.038; regulatory T cells, R = 0.42,P= 0.0042; monocytes, R = 0.42,P= 0.0043). However, M1 macrophages (R = -0.37,P= 0.012) and resting NK cells (R = -0.31,P= 0.043) had a negative correlation with risk scores. Furthermore, analysis of clinical samples validated the weak positive correlation between the risk score and tumor stage.ConclusionsThe risk model described here, based on the six m6A-related lncRNAs signature, and may predict the clinical prognoses and immunotherapeutic response in Asian GC patients.
影响因子：
29.4
作者：
Mills JC;Samuelson LC
通讯作者：
Samuelson LC
影响因子：
5.2
作者：
Cuadros M;García DJ;Andrades A;Arenas AM;Coira IF;Baliñas-Gavira C;Peinado P;Rodríguez MI;Álvarez-Pérez JC;Ruiz-Cabello F;Camós M;Jiménez-Velasco A;Medina PP
通讯作者：
Medina PP