Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
BMC Med. 2021 Feb 25;19(1):59. doi: 10.1186/s12916-021-01925-6.
Long noncoding (lnc)RNAs and glycolysis are both recognized as key regulators of cancers. Some lncRNAs are also reportedly involved in regulating glycolysis metabolism. However, glycolysis-associated lncRNA signatures and their clinical relevance in cancers remain unclear. We investigated the roles of glycolysis-associated lncRNAs in cancers.
Glycolysis scores and glycolysis-associated lncRNA signatures were established using a single-sample gene set enrichment analysis (GSEA) of The Cancer Genome Atlas pan-cancer data. Consensus clustering assays and genomic classifiers were used to stratify patient subtypes and for validation. Fisher's exact test was performed to investigate genomic mutations and molecular subtypes. A differentially expressed gene analysis, with GSEA, transcription factor (TF) activity scoring, cellular distributions, and immune cell infiltration, was conducted to explore the functions of glycolysis-associated lncRNAs.
Glycolysis-associated lncRNA signatures across 33 cancer types were generated and used to stratify patients into distinct clusters. Patients in cluster 3 had high glycolysis scores and poor survival, especially in bladder carcinoma, low-grade gliomas, mesotheliomas, pancreatic adenocarcinomas, and uveal melanomas. The clinical significance of lncRNA-defined groups was validated using external datasets and genomic classifiers. Gene mutations, molecular subtypes associated with poor prognoses, TFs, oncogenic signaling such as the epithelial-to-mesenchymal transition (EMT), and high immune cell infiltration demonstrated significant associations with cluster 3 patients. Furthermore, five lncRNAs, namely MIR4435-2HG, AC078846.1, AL157392.3, AP001273.1, and RAD51-AS1, exhibited significant correlations with glycolysis across the five cancers. Except MIR4435-2HG, the lncRNAs were distributed in nuclei. MIR4435-2HG was connected to glycolysis, EMT, and immune infiltrations in cancers.
We identified a subgroup of cancer patients stratified by glycolysis-associated lncRNAs with poor prognoses, high immune infiltration, and EMT activation, thus providing new directions for cancer therapy.
长链非编码（lnc）RNA 和糖酵解均被认为是癌症的关键调控因子。一些 lncRNA 也被报道参与调节糖酵解代谢。然而，与糖酵解相关的 lncRNA 特征及其在癌症中的临床相关性尚不清楚。我们研究了与糖酵解相关的 lncRNA 在癌症中的作用。
使用癌症基因组图谱泛癌数据的单样本基因集富集分析（GSEA）建立糖酵解评分和糖酵解相关 lncRNA 特征。共识聚类分析和基因组分类器用于分层患者亚型并进行验证。Fisher 精确检验用于研究基因组突变和分子亚型。通过差异表达基因分析，结合 GSEA、转录因子（TF）活性评分、细胞分布和免疫细胞浸润，探讨与糖酵解相关的 lncRNA 的功能。
生成了 33 种癌症类型的糖酵解相关 lncRNA 特征，并用于将患者分为不同的聚类。聚类 3 中的患者糖酵解评分较高且生存状况较差，尤其是膀胱癌、低级别胶质瘤、间皮瘤、胰腺腺癌和葡萄膜黑色素瘤。使用外部数据集和基因组分类器验证了 lncRNA 定义的组的临床意义。基因突变更与预后不良相关的分子亚型、TFs、上皮间质转化（EMT）等致癌信号以及高免疫细胞浸润与聚类 3 患者显著相关。此外，MIR4435-2HG、AC078846.1、AL157392.3、AP001273.1 和 RAD51-AS1 这五个 lncRNA 在五种癌症中与糖酵解均表现出显著相关性。除了 MIR4435-2HG 之外，其余 lncRNA 均分布在核内。MIR4435-2HG 与癌症中的糖酵解、EMT 和免疫浸润有关。
我们确定了一组基于与糖酵解相关的 lncRNA 的癌症患者亚组，这些患者具有不良预后、高免疫浸润和 EMT 激活的特征，从而为癌症治疗提供了新的方向。
