Datta Indrani, Noushmehr Houtan, Brodie Chaya, Poisson Laila M
Department of Public Health Sciences, Center for Bioinformatics, Henry Ford Health System, 1 Ford Place, 3C, Detroit, MI, 48202, USA.
Department of Neurosurgery, Hermelin Brain Tumor Center, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, USA.
J Transl Med. 2021 Apr 29;19(1):182. doi: 10.1186/s12967-021-02844-z.
Clinically relevant glioma subtypes, such as the glioma-CpG island methylator phenotype (G-CIMP), have been defined by epigenetics. In this study, the role of long non-coding RNAs in association with the poor-prognosis G-CMIP-low phenotype and the good-prognosis G-CMIP-high phenotype was investigated. Functional associations of lncRNAs with mRNAs and miRNAs were examined to hypothesize influencing factors of the aggressive phenotype.
RNA-seq data on 250 samples from TCGA's Pan-Glioma study, quantified for lncRNA and mRNAs (GENCODE v28), were analyzed for differential expression between G-CIMP-low and G-CIMP-high phenotypes. Functional interpretation of the differential lncRNAs was performed by Ingenuity Pathway Analysis. Spearman rank order correlation estimates between lncRNA, miRNA, and mRNA nominated differential lncRNA with a likely miRNA sponge function.
We identified 4371 differentially expressed features (mRNA = 3705; lncRNA = 666; FDR ≤ 5%). From these, the protein-coding gene TP53 was identified as an upstream regulator of differential lncRNAs PANDAR and PVT1 (p = 0.0237) and enrichment was detected in the "development of carcinoma" (p = 0.0176). Two lncRNAs (HCG11, PART1) were positively correlated with 342 mRNAs, and their correlation estimates diminish after adjusting for either of the target miRNAs: hsa-miR-490-3p, hsa-miR-129-5p. This suggests a likely sponge function for HCG11 and PART1.
These findings identify differential lncRNAs with oncogenic features that are associated with G-CIMP phenotypes. Further investigation with controlled experiments is needed to confirm the molecular relationships.
临床上相关的胶质瘤亚型，如胶质瘤CpG岛甲基化表型（G-CIMP），已通过表观遗传学进行定义。在本研究中，调查了长链非编码RNA与预后不良的G-CMIP低表型和预后良好的G-CMIP高表型之间的关系。研究了lncRNA与mRNA和miRNA的功能关联，以推测侵袭性表型的影响因素。
对来自TCGA泛胶质瘤研究的250个样本的RNA测序数据进行分析，这些样本针对lncRNA和mRNA（GENCODE v28）进行了定量，以分析G-CIMP低表型和G-CIMP高表型之间的差异表达。通过 Ingenuity Pathway Analysis对差异lncRNA进行功能解释。lncRNA、miRNA和mRNA之间的Spearman等级相关估计确定了具有可能的miRNA海绵功能的差异lncRNA。
我们鉴定出4371个差异表达特征（mRNA = 3705；lncRNA = 666；FDR≤5%）。从中，蛋白质编码基因TP53被鉴定为差异lncRNA PANDAR和PVT1的上游调节因子（p = 0.0237），并且在“癌发生”中检测到富集（p = 0.0176）。两个lncRNA（HCG11、PART1）与342个mRNA呈正相关，在针对任一靶miRNA（hsa-miR-490-3p、hsa-miR-129-5p）进行校正后，它们的相关估计值降低。这表明HCG11和PART1可能具有海绵功能。
这些发现确定了具有致癌特征的差异lncRNA，它们与G-CIMP表型相关。需要通过对照实验进行进一步研究以确认分子关系。
