Identification of a novel set of genes reflecting different in vivo invasive patterns of human GBM cells

Monticone, Massimiliano; Daga, Antonio; Candiani, Simona; Romeo, Francesco; Mirisola, Valentina; Viaggi, Silvia; Melloni, Ilaria; Pedemonte, Simona; Zona, Gianluigi; Giaretti, Walter; Pfeffer, Ulrich; Castagnola, Patrizio

doi:10.1186/1471-2407-12-358

Cited by 12 publications

(13 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Second, putative targets of miR-323 and miR-329 incorporated a family of molecules associated with cell migration and adhesion as shown in Figure 4A. Furthermore, the recurrence of GBM is related with these migration and adhesion genes [37]. Herein, miR-323/miR-329 may be involved in migration inhibition in non-recurrent patients through elevation of their expression levels.…”

Section: Discussionmentioning

confidence: 99%

Interactions of miR-323/miR-326/miR-329 and miR-130a/miR-155/miR-210 as prognostic indicators for clinical outcome of glioblastoma patients

et al. 2013

View full text Add to dashboard Cite

BackgroundGlioblastoma multiforme (GBM) is the most common and aggressive brain tumor with poor clinical outcome. Identification and development of new markers could be beneficial for the diagnosis and prognosis of GBM patients. Deregulation of microRNAs (miRNAs or miRs) is involved in GBM. Therefore, we attempted to identify and develop specific miRNAs as prognostic and predictive markers for GBM patient survival.MethodsExpression profiles of miRNAs and genes and the corresponding clinical information of 480 GBM samples from The Cancer Genome Atlas (TCGA) dataset were downloaded and interested miRNAs were identified. Patients’ overall survival (OS) and progression-free survival (PFS) associated with interested miRNAs and miRNA-interactions were performed by Kaplan-Meier survival analysis. The impacts of miRNA expressions and miRNA-interactions on survival were evaluated by Cox proportional hazard regression model. Biological processes and network of putative and validated targets of miRNAs were analyzed by bioinformatics.ResultsIn this study, 6 interested miRNAs were identified. Survival analysis showed that high levels of miR-326/miR-130a and low levels of miR-323/miR-329/miR-155/miR-210 were significantly associated with long OS of GBM patients, and also showed that high miR-326/miR-130a and low miR-155/miR-210 were related with extended PFS. Moreover, miRNA-323 and miRNA-329 were found to be increased in patients with no-recurrence or long time to progression (TTP). More notably, our analysis revealed miRNA-interactions were more specific and accurate to discriminate and predict OS and PFS. This interaction stratified OS and PFS related with different miRNA levels more detailed, and could obtain longer span of mean survival in comparison to that of one single miRNA. Moreover, miR-326, miR-130a, miR-155, miR-210 and 4 miRNA-interactions were confirmed for the first time as independent predictors for survival by Cox regression model together with clinicopathological factors: Age, Gender and Recurrence. Plus, the availability and rationality of the miRNA-interaction as predictors for survival were further supported by analysis of network, biological processes, KEGG pathway and correlation analysis with gene markers.ConclusionsOur results demonstrates that miR-326, miR-130a, miR-155, miR-210 and the 4 miRNA-interactions could serve as prognostic and predictive markers for survival of GBM patients, suggesting a potential application in improvement of prognostic tools and treatments.

show abstract

Section: Discussionmentioning

confidence: 99%

Interactions of miR-323/miR-326/miR-329 and miR-130a/miR-155/miR-210 as prognostic indicators for clinical outcome of glioblastoma patients

et al. 2013

View full text Add to dashboard Cite

show abstract

“…This effect was most pronounced in MYCN non-amplified tumors ( Figure 2C), suggesting that in the context of MYCN amplification, reduced MEGF10 expression does not have a significant effect on neuroblastoma survival, presumably because the multiple biological pathways related to neuroblastoma aggressiveness that are targeted by MYCN predominate [66]. Interestingly, altered expression of MEGF10 has now been reported in several cancers [67][68][69], with prognostic significance in ovarian cancer [68] and glioblastoma [69].…”

Section: Functional Consequences Of Megf10 Repressionmentioning

confidence: 94%

Genome‐wide DNA methylation analysis identifies MEGF10 as a novel epigenetically repressed candidate tumor suppressor gene in neuroblastoma

Charlet

Tomari

Dallosso

et al. 2016

Molecular Carcinogenesis

View full text Add to dashboard Cite

Neuroblastoma is a childhood cancer in which many children still have poor outcomes, emphasising the need to better understand its pathogenesis. Despite recent genome‐wide mutation analyses, many primary neuroblastomas do not contain recognizable driver mutations, implicating alternate molecular pathologies such as epigenetic alterations. To discover genes that become epigenetically deregulated during neuroblastoma tumorigenesis, we took the novel approach of comparing neuroblastomas to neural crest precursor cells, using genome‐wide DNA methylation analysis. We identified 93 genes that were significantly differentially methylated of which 26 (28%) were hypermethylated and 67 (72%) were hypomethylated. Concentrating on hypermethylated genes to identify candidate tumor suppressor loci, we found the cell engulfment and adhesion factor gene MEGF10 to be epigenetically repressed by DNA hypermethylation or by H3K27/K9 methylation in neuroblastoma cell lines. MEGF10 showed significantly down‐regulated expression in neuroblastoma tumor samples; furthermore patients with the lowest‐expressing tumors had reduced relapse‐free survival. Our functional studies showed that knock‐down of MEGF10 expression in neuroblastoma cell lines promoted cell growth, consistent with MEGF10 acting as a clinically relevant, epigenetically deregulated neuroblastoma tumor suppressor gene. © 2016 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc.

show abstract

“…Data were analyzed with the Coffalyser software (MRC-Holland). For each GBM, gains and losses were assigned by comparing the peaks between the patient and the reference samples (DNA from normal human astrocytes), as previously described ( Monticone et al, 2012 , 2014 ).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Chloride Intracellular Channel 1 (CLIC1) as Biguanide Class-Effect to Impair Human Glioblastoma Stem Cell Viability

et al. 2018

Self Cite

View full text Add to dashboard Cite

The antidiabetic biguanide metformin exerts antiproliferative effects in different solid tumors. However, during preclinical studies, metformin concentrations required to induce cell growth arrest were invariably within the mM range, thus difficult to translate in a clinical setting. Consequently, the search for more potent metformin derivatives is a current goal for new drug development. Although several cell-specific intracellular mechanisms contribute to the anti-tumor activity of metformin, the inhibition of the chloride intracellular channel 1 activity (CLIC1) at G1/S transition is a key events in metformin antiproliferative effect in glioblastoma stem cells (GSCs). Here we tested several known biguanide-related drugs for the ability to affect glioblastoma (but not normal) stem cell viability, and in particular: phenformin, a withdrawn antidiabetic drug; moroxydine, a former antiviral agent; and proguanil, an antimalarial compound, all of them possessing a linear biguanide structure as metformin; moreover, we evaluated cycloguanil, the active form of proguanil, characterized by a cyclized biguanide moiety. All these drugs caused a significant impairment of GSC proliferation, invasiveness, and self-renewal reaching IC50 values significantly lower than metformin, (range 0.054–0.53 mM vs. 9.4 mM of metformin). All biguanides inhibited CLIC1-mediated ion current, showing the same potency observed in the antiproliferative effects, with the exception of proguanil which was ineffective. These effects were specific for GSCs, since no (or little) cytotoxicity was observed in normal umbilical cord mesenchymal stem cells, whose viability was not affected by metformin and moroxydine, while cycloguanil and phenformin induced toxicity only at much higher concentrations than required to reduce GSC proliferation or invasiveness. Conversely, proguanil was highly cytotoxic also for normal mesenchymal stem cells. In conclusion, the inhibition of CLIC1 activity represents a biguanide class-effect to impair GSC viability, invasiveness, and self-renewal, although dissimilarities among different drugs were observed as far as potency, efficacy and selectivity as CLIC1 inhibitors. Being CLIC1 constitutively active in GSCs, this feature is relevant to grant the molecules with high specificity toward GSCs while sparing normal cells. These results could represent the basis for the development of novel biguanide-structured molecules, characterized by high antitumor efficacy and safe toxicological profile.

show abstract

Identification of a novel set of genes reflecting different in vivo invasive patterns of human GBM cells

Cited by 12 publications

References 36 publications

Interactions of miR-323/miR-326/miR-329 and miR-130a/miR-155/miR-210 as prognostic indicators for clinical outcome of glioblastoma patients

Interactions of miR-323/miR-326/miR-329 and miR-130a/miR-155/miR-210 as prognostic indicators for clinical outcome of glioblastoma patients

Genome‐wide DNA methylation analysis identifies MEGF10 as a novel epigenetically repressed candidate tumor suppressor gene in neuroblastoma

Inhibition of Chloride Intracellular Channel 1 (CLIC1) as Biguanide Class-Effect to Impair Human Glioblastoma Stem Cell Viability

Contact Info

Product

Resources

About