N6-Methylandenosine-Related lncRNAs Predict Prognosis and Immunotherapy Response in Bladder Cancer.
N6-Methylandenosine-Related lncRNAs Predict Prognosis and Immunotherapy Response in Bladder Cancer.
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N6-甲基腺苷相关 lncRNA 预测膀胱癌的预后和免疫治疗反应
DOI：
10.3389/fonc.2021.710767
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发表时间：
2021
影响因子：
4.7
通讯作者：
Zeng J
中科院分区：
文献类型：
--
作者：
Zhang Y;Zhu B;He M;Cai Y;Ying X;Jiang C;Ji W;Zeng J
lncRNA和N6-甲基腺苷（m6 A）修饰都是肿瘤发生和先天免疫的关键调节因子。然而，对lncRNA的m6 A修饰及其在膀胱癌中的临床和免疫相关性知之甚少。在这项研究中，我们使用癌症基因组图谱（TCGA）和IMvigor 210数据集中的Pearson相关性分析鉴定了m6 A相关的lncRNA。接下来，使用TCGA数据集进行单变量考克斯回归以过滤预后m6 A相关的lncRNA，其进一步经受最小绝对收缩和选择算子（LASSO）考克斯回归以建立12个m6 A相关的lncRNA预后评分（m6 A-LRS）。在IMvigor 210数据集中验证了m6 A-LRS。此外，在IMvigor 210数据集中，以肿瘤突变负荷和新抗原负荷降低为特征的高m6 A-LRS肿瘤对免疫治疗的反应比低m6 A-LRS肿瘤差。此外，我们构建了一个基于m6 A-LRS的列线图，该列线图显示出预测膀胱癌患者总生存期的强大能力。此外，富集分析显示，肿瘤相关的生物学过程、致癌信号传导和肿瘤标志物通常与高m6 A-LRS相关。基因集变异分析还表明，高m6 A-LRS与典型致癌特征（如上皮-间充质转化、细胞周期调节因子和DNA复制）的激活以及免疫抑制特征（如T细胞耗竭和泛成纤维细胞-TGF-β反应特征）的激活相关。此外，我们观察到高风险和低风险肿瘤之间不同的肿瘤微环境细胞浸润特征。高m6 A-LRS肿瘤显示CD 8 + T细胞浸润减少，巨噬细胞和成纤维细胞浸润增强。此外，我们建立了一个竞争的内源性RNA网络的基础上12 m6 A相关的lncRNA。最后，选择三种lncRNA（SNHG 16、SBF 2-AS 1和BDNF-AS）用于进一步验证。对10对膀胱癌和邻近正常对照样品的定性PCR测定验证了差异表达，并且甲基化RNA免疫沉淀（MeRIP）分析表明，与正常尿路上皮细胞（SVHUC-1）相比，T24膀胱癌细胞中存在稳健的m6 A富集。总之，本研究引入了一种m6 A相关的lncRNA特征，该特征鉴定了一组具有不良膀胱炎和次优免疫应答的患者，从而为膀胱癌的治疗反应预测和患者分层提供了新的方法。
Both lncRNAs and the N6-methyladenosine (m6A) modification are key regulators of tumorigenesis and innate immunity. However, little is known about the m6A modification of lncRNAs and their clinical and immune relevance in bladder cancer. In this study, we identified m6A-related lncRNAs using Pearson correlation analysis in The Cancer Genome Atlas (TCGA) and the IMvigor210 datasets. Next, univariate Cox regression was performed using the TCGA dataset to filter prognostic m6A-related lncRNAs, which were further subjected to the least absolute shrinkage and selection operator (LASSO) Cox regression to establish a 12 m6A-related lncRNA prognostic score (m6A-LRS). The m6A-LRS was validated in the IMvigor210 dataset. In addition, high m6A-LRS tumors, characterized by decreased tumor mutation load and neoantigen load, showed poorer response to immunotherapy than those with low m6A-LRS in the IMvigor210 dataset. Further, we constructed an m6A-LRS-based nomogram that demonstrated a strong ability to predict overall survival in patients with bladder cancer. Moreover, enrichment analysis revealed that tumor-associated biological processes, oncogenic signaling, and tumor hallmarks were commonly associated with a high m6A-LRS. Gene set variation analysis also indicated that high m6A-LRS was associated with activation of canonical oncogenic signatures, such as the epithelial-to-mesenchymal transition, cell cycle regulators, and DNA replication, as well as activation of immunosuppressive signatures, such as the T-cell exhaustion and pan-fibroblast-TGF-β response signatures. Furthermore, we observed distinct tumor microenvironment cell infiltration characteristics between high- and low-risk tumors. High m6A-LRS tumors showed reduced infiltration of CD8+ T-cells and enhanced infiltration of macrophages and fibroblasts. Additionally, we established a competing endogenous RNA network based on the12 m6A-related lncRNAs. Finally, three lncRNAs (SNHG16, SBF2-AS1, and BDNF-AS) were selected for further validation. The qualitative PCR assay on 10 pairs of bladder cancer and adjacent normal control samples validated the differential expression, and methylated RNA immunoprecipitation (MeRIP) analysis demonstrated a robust m6A enrichment in T24 bladder cancer cells compared with normal uroepithelial cells (SVHUC-1). In conclusion, this study introduced an m6A-related lncRNA signature that identified a subgroup of patients with poor prognoses and suboptimal immune responses, thus providing novel approaches for treatment response prediction and patient stratification in bladder cancer.
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