MicroRNA 3928 Suppresses Glioblastoma through Downregulation of Several Oncogenes and Upregulation of p53

Abstract

Glioblastoma (GBM) is the most frequent and lethal primary malignant brain tumor. Despite decades of research, therapeutic advances that significantly prolong life are non-existent. In recent years, microRNAs (miRNAs) have been a focus of study in the pathobiology of cancer because of their ability to simultaneously regulate multiple genes. The aim of this study was to determine the functional and mechanistic effects of miR-3928 in GBM both in vitro and in vivo. To the best of our knowledge, this is the first article investigating the role of miR-3928 in GBM. We measured endogenous miR-3928 expression levels in a panel of patient-derived GBM tissue samples and cell lines. We found that GBM tissue samples and cell lines express lower levels of miR-3928 than normal brain cortex and astrocytes, respectively. Therefore, we hypothesized that miR-3928 is a tumor suppressive microRNA. We verified this hypothesis by showing that exogenous expression of miR-3928 has a strong inhibitory effect on both cell growth and invasiveness of GBM cells. Stable ex vivo overexpression of miR-3928 in GBM cells led to a reduction in tumor size in nude mice xenografts. We identified many targets (MDM2, CD44, DDX3X, HMGA2, CCND1, BRAF, ATOH8, and BMI1) of miR-3928. Interestingly, inhibition of the oncogene MDM2 also led to an upregulation of wild-type p53 expression and phosphorylation. In conclusion, we find that miR-3928, through the downregulation of several oncogenes and upregulation and activation of wild-type p53, is a strong tumor suppressor in GBM. Furthermore, the fact that miR-3928 can target many important dysregulated proteins in GBM suggests it might be a “master” regulatory microRNA that could be therapeutically exploited.

A Comprehensive Integrated Analysis of DDX3X Expression, Prognostic Value and Potential Implications for Pan-Cancer Immunity

“…DDX3X is likewise a persuasive resource to eradicate malignancy stem cells (CSCs) [12], DDX3X overexpression induces ERα phosphorylation in breast epithelial cells [30]; DDX3X advocates the G1/S cycle conversion of medulloblastoma cells and induces oral squamous cells by combining accompanying unusual activating of ATK/mTOR pathway by KRT17, all of that generates the malignant proliferation of normal cells [31], DDX3X can also embark on the RNA metabolic modi cation process [32], bind to proteins to promote distant carcinoma metastasis, and evade immune attack. DDX3X will bind to Casein Kinase Iisoformepsilon (CK1ε) to cause Wnt/β-catenin signaling pathway activation [33], culminating in distant metastasis of lung adenocarcinoma (LAD) cells [34], it reverses the translation process of circular RNA (circRNA) in glioblastoma stem cells (GSCs) [35,36], acknowledging carcinoma tissue to evade immune attack, accordingly, it commits metastasis in diverse tissues; high DDX3 expression via a KRAS/ROS/HIF-1α reaction loop takes care of reinforce CTX subtlety in KRAS-WT colorectal malignancy [37]; DDX3X keep downregulate IFNB1-STAT1 signaling pathway accompanying lncRNARFPL1S-202 to inhibit the chemoresistance and progression of ovarian tumor [38], and high expression levels of DDX3 in head and neck squamous cell carcinoma (HNSCC) correlate with lymph node metastasis and poor prognosis [39]. In this study, utilizing bioinformatics methods, searching the public databases of TCGA, GTEx, UALCAN, and cBioPortal, we comprehensively demonstrated the expression level of DDX3X and appeal immunological connection to numerous malignancy types.…”

MiR-378a-3p acts as a tumor suppressor in gastric cancer via directly targeting RAB31 and inhibiting the Hedgehog pathway proteins GLI1/2

“…Numerous studies have shown that most miRNAs exert regulatory effects by binding specific target genes [40][41][42] . In addition, miRNAs can be used as new tumor markers, and have applications including early tumor detection, efficacy monitoring and evaluation, and prognostication.…”

A comprehensive analysis of Transcribed Ultra Conserved Regions uncovers important regulatory functions of novel non-coding transcripts in gliomas

“…Next, we performed cell counting assays [20,[37][38][39] to determine the effects of uc.110 knockdown and rescue on cell accumulation. When we reduced uc.110 expression, we reduced cell accumulation in A172 and U251 cells (Figure 4D).…”