Epigenetic Activation of lncRNA MIR155HG Mediated by Promoter Hypomethylation and SP1 is Correlated with Immune Infiltration in Glioma

Abstract

Purpose

The lncRNA MIR155 host gene (MIR155HG) plays a role in the progression of several malignant cancers. However, the specific mechanisms of MIR155HG in glioma progression have not been clearly established. The purpose of this study was to investigate the function of MIR155HG in glioma at the transcriptome level and relationship with immune infiltration.

Patients and Methods

Totally, 697 RNA-seq and 594 DNA methylation data were retrieved from The Cancer Genome Atlas (TCGA) dataset while 325 RNA-seq data were retrieved from the Chinese Glioma Genome Atlas (CGGA) dataset. The DNA methylation levels of MIR155HG CpG islands were assessed through bisulfite amplicon sequencing (BSAS). The regulatory mechanism of SP1 on MIR155HG was examined by chromatin immunoprecipitation (ChIP) and luciferase reporter assays. R language was used as the main tool for statistical analysis and graphical work.

Results

MIR155HG was predominantly expressed in the isocitrate dehydrogenase (IDH) wild-type as well as mesenchymal subtype gliomas. Promoter methylation levels of MIR155HG in glioblastoma (GBM) were remarkably decreased compared with those in lower-grade glioma (LGG). In addition, there were negative correlations between promoter methylation levels and MIR155HG expressions but positive correlations with patients’ overall survival. In vitro studies further revealed that MIR155HG expression was regulated by DNA promoter methylation and transcription factor (SP1) binding to the promoter. Moreover, there was a close association between MIR155HG expression and immune as well as stromal cell infiltrations, inflammatory activities, and immune checkpoints. Clinically, univariate and multivariate Cox analyses revealed that MIR155HG is an independent prognostic marker for glioma patients.

Conclusion

Our results established that MIR155HG is a potential biomarker for prognosis and an immunotherapeutic target in glioma.

Keywords:

• MIR155HG
• DNA methylation
• SP1
• immune infiltration
• glioma

Data Sharing Statement

Publicly available datasets were analyzed in this study. TCGA dataset can be found at: https://xenabrowser.net/datapages/?cohort=TCGA%20lower%20grade%20glioma%20and%20glioblastoma%20(GBMLGG)&removeHub$=$https%3A%2F%2Fxena.treehouse.gi.ucsc.edu%3A443,GSE16011; CGGA dataset can be found at http://www.cgga.org.cn/download.jsp.

Acknowledgments

We appreciate the generosity of TCGA and CGGA networks for sharing a great amount of data.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. These authors have contributed equally to this work and share first authorship: Xuechao Wu, Quan Wan, and Jing Wang.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

This work was supported by Jiangsu Province’s Science and Technology Project (SBK2019021295), and National Natural Science Foundation of China (82072791).