miRNA array screening reveals cooperative MGMT-regulation between miR-181d-5p and miR-409-3p in glioblastoma

Khalil, Susanna; Fabbri, Enrica; Santangelo, A; Bezzerri, Valentino; Cantù, Cinzia; Gennaro, Gianfranco Di; Finotti, Alessia; Ghimenton, Claudio; Eccher, Albino; Dechecchi, Maria Cristina; Scarpa, Aldo; Hirshman, Brian R.; Chen, Clark C.; Ferracin, Manuela; Negrini, Massimo; Gambari, Roberto; Cabrini, Giulio

doi:10.18632/oncotarget.8618

Cited by 36 publications

(31 citation statements)

References 33 publications

(55 reference statements)

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“…In addition to the findings of W. Zhang et al, our study showed a noticeable tendency of prolonged survival time in GBM patients with methylated MGMT promoter and higher miR-181d tumoral expression levels. These results strengthen the suggestion that miR-181d is activated during MGMT promoter methylation processes, in order to suppress MGMT oncogenic activity in GBM patients [ 25 ].…”

Section: Discussionsupporting

confidence: 89%

Unique Interplay between Molecular miR-181b/d Biomarkers and Health Related Quality of Life Score in the Predictive Glioma Models

Stakaitis

Pranckevičienė

Steponaitis

et al. 2020

IJMS

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In the last decade, an increasing amount of research has been conducted analyzing microRNA expression changes in glioma tissue and its expressed exosomes, but there is still sparse information on microRNAs or other biomarkers and their association with patients’ functional/psychological outcomes. In this study, we performed a combinational analysis measuring miR-181b and miR-181d expression levels by quantitative polymerase chain reaction (qPCR), evaluating isocitrate dehydrogenase 1 (IDH1) single nucleotide polymorphism (SNP), and O-6-methylguanine methyltransferase (MGMT) promoter methylation status in 92 post-surgical glioma samples and 64 serum exosomes, including patients’ quality of life evaluation applying European Organization for Research and Treatment of Cancer (EORTC) questionnaire for cancer patients (QLQ-30), EORTC the Brain Cancer-Specific Quality of Life Questionnaire (QLQ-BN20), and the Karnofsky performance status (KPS). The tumoral expression of miR-181b was lower in grade III and glioblastoma, compared to grade II glioma patients (p < 0.05). Additionally, for the first time, we demonstrated the association between miR-181 expression levels and patients’ quality of life. A positive correlation was observed between tumoral miR-181d levels and glioma patients’ functional parameters (p < 0.05), whereas increased exosomal miR-181b levels indicated a worse functional outcome (p < 0.05). Moreover, elevated miR-181b exosomal expression can indicate a significantly shorter post-surgical survival time for glioblastoma multiforme (GBM) patients. In addition, both tumoral and exosomal miR-181 expression levels were related to patients’ functioning and tumor-related symptoms. Our study adds to previous findings by demonstrating the unique interplay between molecular miR-181b/d biomarkers and health related quality of life (HRQOL) score as both variables remained significant in the predictive glioma models.

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Section: Discussionsupporting

confidence: 89%

Unique Interplay between Molecular miR-181b/d Biomarkers and Health Related Quality of Life Score in the Predictive Glioma Models

Stakaitis

Pranckevičienė

Steponaitis

et al. 2020

IJMS

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“…In the present study, we observed a dose-dependent decrease in MGMT expression by T98G cells following treatment with 250–500 µM TMZ for 48 hours (Figure 3D ). There are numerous possible explanations for this discrepancy, as MGMT is regulated by several factors, including mutant p53 [ 9 ], MEK-ERK [ 56 ], mTOR [ 44 ], hypoxia [ 15 , 57 ], and microRNAs [ 58 , 59 ]. Further, the TMZ dose-dependent MGMT decrease we observed is enhanced with GLI1 silencing (Figure 3D ).…”

Section: Discussionmentioning

confidence: 99%

Investigating the role of Hedgehog/GLI1 signaling in glioblastoma cell response to temozolomide

et al. 2018

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Resistance to chemotherapy substantially hinders successful glioblastoma (GBM) treatment, contributing to an almost 100% mortality rate. Resistance to the frontline chemotherapy, temozolomide (TMZ), arises from numerous signaling pathways that are deregulated in GBM, including Hedgehog (Hh) signaling. Here, we investigate suppression of Hh signaling as an adjuvant to TMZ using U87-MG and T98G cell lines as in vitro models of GBM. We found that silencing GLI1 with siRNA reduces cell metabolic activity by up to 30% in combination with TMZ and reduces multidrug efflux activity by 2.5-fold. Additionally, pharmacological GLI inhibition modulates nuclear p53 levels and decreases MGMT expression in combination with TMZ. While we surprisingly found that silencing GLI1 does not induce apoptosis in the absence of TMZ co-treatment, we discovered silencing GLI1 without TMZ co-treatment induces senescence as evidenced by a significant 2.3-fold increase in senescence associated β-galactosidase staining, and this occurs in a loss of PTEN-dependent manner. Finally, we show that GLI inhibition increases apoptosis in glioma stem-like cells by up to 6.8-fold in combination with TMZ, and this reduces the size and number of neurospheres grown from glioma stem-like cells. In aggregate, our data warrant the continued investigation of Hh pathway inhibitors as adjuvants to TMZ chemotherapy and highlight the importance of identifying signaling pathways that determine whether co-treatment will be successful.

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“… 36 Interestingly, two miRNAs, miR-181d-5p and miR-409-3p, have been shown cooperatively to suppress MGMT expression, augmenting each other’s effect. 37 Therefore, in spite of the apparent noncanonical mode of interaction of miR-142-3p with MGMT 3′-UTR, it may exert its effect by cooperating with other miRNAs. In a recent study, it was shown that miR-603 directly regulated MGMT expression and targeted MGMT mRNA on five 3′-UTR sites.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-142-3p is involved in regulation of <em>MGMT</em> expression in glioblastoma cells

Lee

Yarmishyn

Wang

et al. 2018

CMAR

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BackgroundGlioblastoma multiforme (GBM) is the most malignant brain tumor, and there is no effective treatment strategy. Patients with GBM have a median overall survival of only 14.6 months. Current treatment consists of safe and maximal surgical excision, followed by concurrent chemoradiotherapy and maintenance chemotherapy. There are several obstacles that hinder the effectiveness of this aggressive treatment. Temozolomide (TMZ) is an oral alkylating drug that acts through alkylating the O6 position of guanine in DNA that leads to cell death. However, the expression and enzymatic activity of the DNA repair protein MGMT limits the therapeutic benefit from treatment with TMZ. MGMT reduces the efficacy of alkylating drugs by removing the methyl or alkyl group from damaged O6-methylguanine. Expression levels of MGMT play an important role in the outcome of GBM patients. miRNAs are a group of small regulatory RNAs that control target gene expression by binding to mRNAs. miR-142-3p has been found to be an important factor in the development and maintenance of the oncogenic state.ResultsIn this study, we sought to investigate whether miR-142-3p can regulate MGMT gene expression in GBM cells. Here, we show that miR-142-3p downregulates MGMT expression through binding to the 3′-UTR of MGMT mRNA, thus affecting protein translation. Responsiveness to TMZ was significantly enhanced after transfection with miR-142-3p. Overexpression of miR-142-3p also sensitized GBM cells to alkylating drugs.ConclusionAbove all, our findings demonstrate that miR-142-3p plays a critical role in regulating MGMT expression, has great potential for future clinical applications, and acts as a new diagnostic marker for this intractable disease.

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miRNA array screening reveals cooperative MGMT-regulation between miR-181d-5p and miR-409-3p in glioblastoma

Cited by 36 publications

References 33 publications

Unique Interplay between Molecular miR-181b/d Biomarkers and Health Related Quality of Life Score in the Predictive Glioma Models

Unique Interplay between Molecular miR-181b/d Biomarkers and Health Related Quality of Life Score in the Predictive Glioma Models

Investigating the role of Hedgehog/GLI1 signaling in glioblastoma cell response to temozolomide

MicroRNA-142-3p is involved in regulation of <em>MGMT</em> expression in glioblastoma cells

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