miR-181d: a predictive glioblastoma biomarker that downregulates MGMT expression

Abstract

Genome-wide microRNA (miRNA) profiling of 82 glioblastomas demonstrated that miR-181d was inversely associated with patient overall survival after correcting for age, Karnofsky performance status, extent of resection, and temozolomide (TMZ) treatment. This association was validated using the Cancer Genome Atlas (TCGA) dataset (n= 424) and an independent cohort (n= 35). In these independent cohorts, an association of miR-181d with survival was evident in patients who underwent TMZ treatment but was not observed in patients without TMZ therapy. Bioinformatic analysis of potential genes regulated by miR-181d revealed methyl-guanine-methyl-transferase (MGMT) as a downstream target. Indeed, transfection of miR-181d downregulated MGMT mRNA and protein expression. Furthermore, luciferase reporter assays and coprecipitation studies showed a direct interaction between miR-181d and MGMT 3'UTR. The suppressive effect of miR-181d on MGMT expression was rescued by the introduction of an MGMT cDNA. Finally, MGMT expression inversely correlated with miR-181d expression in independent glioblastoma cohorts. Together, these results suggest that miR-181d is a predictive biomarker for TMZ response and that its role is mediated, in part, by posttranscriptional regulation of MGMT.

MGMT testing—the challenges for biomarker-based glioma treatment

“…Recent studies addressed a further level of MGMT regulation through direct binding of specific miRNAs to the 3'-UTR of MGMT transcripts, which may lead to decreased mRNA stability and/or reduced protein translation [47]. Distinct miRNAs that have been implicated as direct regulators of MGMT expression include miR-181b [48,49], miR-181d [49], mir221/222 [50], as well as miR-767-3p and miR-648 [47]. Thus, also aberrant expression of miRNAs may contribute to the variable MGMT expression values observed in MGMTunmethylated tumors (Fig.…”

Epigenetic silencing of KAZALD1 confers a better prognosis and is associated with malignant transformation/progression in glioma

“…Despite recent advances in treatment by a combination of surgery and chemotherapy and/ or radiotherapy, the prognosis of malignant glioma remains extremely poor. Glioblastoma (GBM) is the most common and malignant glioma, and has a median survival time of approximately one year (1)(2)(3)(4)(5)(6)(7). In the United States, 75% of glioma patients die within 5 years of diagnosis (8).…”

Genetic Profiling: Searching for Novel Genetic Aberrations in Glioblastoma

“…MiR-181b and miR-181c were significantly down-regulated in glioblastoma tissue of patients who responded to RT/TMZ in comparison to patients with progressive disease [183,185]. In a recent study by Zhang et al [186] genome-wide miRNA profiling of 82 glioblastomas demonstrated that miR-181d was inversely associated with patient overall survival and temozolomide (TMZ) treatment. Bioinformatics analysis of potential genes regulated by miR-181d revealed methyl-guanine-methyl-transferase (MGMT) as a downstream target.…”

“…Finally, there is still lack of miRNA delivery system with enough specificity and efficacy [183]. Telomerase ac va on by c-MYC over-expression [50] VEGFA over-expression [156] P53 inac va ng muta on AKT over-expression BAX dele on [34,65,74] Muta on: IDH1/2 LDHA silencing [120] MGMT down regula on by miR181d [186] IL10 NFKB dysregula on: NFKBIA dele on [62] PTEN regula on of IL10 and B7H1 expression [60,74] Ac va ng invasion…”