DNA Hypomethylation of MIR21 Drives Hsa-miR-21-5p Expression in High-Grade Meningiomas and Reshapes Transcriptomic Signatures of Oncogenic Pathways and Intercellular Communication.

Meningiomas are the most common intracranial tumors. DNA methylation analysis in benign and aggressive meningiomas showed decreased MIR21 methylation and overexpression of hsa-miR-21-5p in atypical and anaplastic tumors. Transcriptomic analysis of distinct WHO grade meningiomas showed multiple predicted hsa-miR-21-5p target genes as differentially expressed. They were mainly related to processes of intercellular and intracellular signaling. Intercellular communication in meningioma was investigated using the deposited scRNA-seq dataset and deconvolution of our RNA-seq data. We found WHO grade-related differences in the microenvironment including inverse correlation between the count of border-associated macrophages (BAM) and the level of hsa-miR-21-5p. Single-cell transcriptomics suggests the role of interleukin 6 in direct communication between tumor cells and BAMs. IL6R and IL6ST are predicted targets of hsa-miR-21-5p downregulated in atypical/anaplastic meningiomas. IL6R downregulation was also confirmed by immunohistochemistry. Hsa-miR-21-5p enhanced proliferation and viability of KT21-MG1 meningioma cells and showed a regulatory effect on IL6R, IL6ST and other predicted target genes TIMP3, PIK3R, RHOB, and SASH1 by interacting with 3'UTRs. DNA hypomethylation-related overexpression of hsa-miR-21-5p contributes to aggressive meningioma growth by interaction with multiple target genes, and probably affects microenvironment communication between meningioma cells and BAMs by lowering the IL6R level in tumor tissue.