The functional synergism of microRNA clustering provides therapeutically relevant epigenetic interference in glioblastoma

Abstract

MicroRNA deregulation is a consistent feature of glioblastoma, yet the biological effect of each single gene is generally modest, and therapeutically negligible. Here we describe a module of microRNAs, constituted by miR-124, miR-128 and miR-137, which are co-expressed during neuronal differentiation and simultaneously lost in gliomagenesis. Each one of these miRs targets several transcriptional regulators, including the oncogenic chromatin repressors EZH2, BMI1 and LSD1, which are functionally interdependent and involved in glioblastoma recurrence after therapeutic chemoradiation. Synchronizing the expression of these three microRNAs in a gene therapy approach displays significant anticancer synergism, abrogates this epigenetic-mediated, multi-protein tumor survival mechanism and results in a 5-fold increase in survival when combined with chemotherapy in murine glioblastoma models. These transgenic microRNA clusters display intercellular propagation in vivo, via extracellular vesicles, extending their biological effect throughout the whole tumor. Our results support the rationale and feasibility of combinatorial microRNA strategies for anticancer therapies.

Increased miR‐34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS‐JNK‐p53 pathway in Alzheimer’s Disease

“…MicroRNAs (miRNAs) are small, endogenous, noncoding RNAs that negatively regulate gene expression at the post‐transcriptional level by binding to the “seed region” located in the 3’‐untranslated region (3’‐UTR) of their target mRNA (Mahmoudi & Cairns, ). MiRNAs are considered as a group of regulators in various biological processes, such as cell proliferation, differentiation, apoptosis, and cycle regulation (Bhaskaran et al, ; Mansini et al, ; Nowakowski et al, ). Changes in miRNA expression may cause cellular malfunction and result in disease phenotypes, including AD and cancers (Nagaraj et al, ).…”

“…MiRNAs are considered as a group of regulators in various biological processes, such as cell proliferation, differentiation, apoptosis, and cycle regulation (Bhaskaran et al, 2019;Mansini et al, 2018;Nowakowski et al, 2018). Changes in miRNA expression may cause cellular malfunction and result in disease phenotypes, including AD and cancers (Nagaraj et al, 2019).…”

Hypoxia-induced lncRNA PDIA3P1 promotes mesenchymal transition via sponging of miR-124-3p in glioma

“…Several studies have elucidated the tumor suppressive role of miR-124-3p in glioma 30,31 . First, we transfected miR-124-3p mimics into U87MG and A172 cells and observed obvious morphological changes in the miR-124-3p overexpressing cells.…”

Inhibition of miR-153 ameliorates ischemia/reperfusion-induced cardiomyocytes apoptosis by regulating Nrf2/HO-1 signaling in rats

“…The mechanisms of myocardial I/R injury are not fully understood, and the practical strategy for preventing myocardial I/R injury is still limited. miRNAs are small endogenous non-coding RNAs composed of [19][20][21][22][23][24] nucleotides that bind to imperfect sequence sites of target mRNA and recruit the RNA-induced silencing complex, causing either degradation or inhibition of protein translation [11]. Generally, one gene can be repressed by multiple miRNAs, and one miRNA may repress multiple target genes, so miRNAs are recognized as important regulators involved in various cellular processes, including differentiation, proliferation, necrosis, and apoptosis [12][13][14].…”