The potential role of miR-34a and miR-34c in the regulation of pediatric high-grade glioma 4 aggressiveness.

Abstract

Background: Pediatric diffuse high-grade gliomas grade 4 (pHGG-4), the most aggressive malignant primary brain tumors, are incurable and associated with poor prognosis. In most pHGG-4, meaningful genetic aberrations were rarely found, and the aggressiveness is derived from epigenetic changes and dysregulated gene expression. miRNAs are significant epigenetic regulators of gene expression that play important roles in many cancers.

Methods: miR-34a and miR-34c levels were analyzed in pHGG cell lines and tumor datasets. SF188 and KNS42 cells were transfected with miR-34a/miR-34c mimic or scrambled oligonucleotide, and examined for viability, migration ability, and invasiveness. Expression of survival, cell cycle arrest/progression, apoptosis, and Epithelial-Mesenchymal Transition (EMT) regulating genes was examined using quantitative PCR (qPCR), western blot, and immunofluorescence assays.

Results: miR-34a and miR-34c were scarcely expressed in pHGG-4 cell lines, and miR-34c was downregulated in pHGG-4 tumor datasets. Upregulating miR-34a/miR-34c decreased cell viability, migration ability, and invasiveness, while differentially affecting the expression of genes involved in survival, cell progression, proliferation, cell cycle arrest or death, and EMT promotion, depending on the miRNA and cell line.

Conclusions: miR-34a and miR-34c are multifunctional tumor suppressors that play an important regulatory role in pHGG-4 aggressiveness. Both miRNAs can serve as excellent and powerful therapeutic tools against pHGG-4.

Impact: This study revealed miR-34a and miR-34c as multifunctional suppressors of pHGG-4 tumor aggressiveness, both downregulated in disease models. miR-34a/miR-34c restoration decreased cell viability, migration ability, invasiveness, and stemness marker expression Both miRNAs exerted similar phenotypic effects while differentially regulated gene expression in a miRNA-associated and cell line-dependent manner The findings reinforced that epigenetic dysregulation, rather than recurrent genetic alterations, is a central driver of pHGG-4 aggressiveness. This work suggests the rational for potential miR-34-based therapeutic strategies in this otherwise incurable disease.