A five-miRNA signature with prognostic and predictive value for <i>MGMT</i> promoter-methylated glioblastoma patients

Cheng, Wen; Ren, Xiufang; Cai, Jinquan; Zhang, Chuanbao; Li, Mingyang; Wang, Kuanyu; Liu, Yang; Han, Sheng; Wu, Anhua

doi:10.18632/oncotarget.4978

Cited by 54 publications

(44 citation statements)

References 37 publications

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“…miRNAs can certainly function as oncogenes and tumour suppressors in GBM as well, as has been reported in many studies. There are umpteen studies that have depicted the deregulation of miRNAs in GBM, which in addition to displaying the distorted landscape of miRNome have also proven useful in terms of diagnosis as well as prognosis [25, 26]. Variations in the expression of miRNAs have been associated with almost every facet of tumour biology like, cell proliferation, migration, angiogenesis and chemo-resistance [7, 22].…”

Section: Discussionmentioning

confidence: 99%

PI3 kinase pathway regulated miRNome in glioblastoma: identification of miR-326 as a tumour suppressor miRNA

et al. 2016

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BackgroundGlioblastomas (GBM) continue to remain one of the most dreaded tumours that are highly infiltrative in nature and easily preclude comprehensive surgical resection. GBMs pose an intricate etiology as they are being associated with a plethora of genetic and epigenetic lesions. Misregulation of the PI3 kinase pathway is one of the most familiar events in GBM. While the PI3 kinase signalling regulated pathways and genes have been comprehensively studied, its impact on the miRNome is yet to be explored. The objective of this study was to elucidate the PI3 kinase pathway regulated miRNAs in GBM.MethodsmiRNA expression profiling was conducted to monitor the differentially regulated miRNAs upon PI3 kinase pathway abrogation. qRT-PCR was used to measure the abundance of miR-326 and its host gene encoded transcript. Proliferation assay, colony suppression assay and wound healing assay were carried out in pre-miR transfected cells to investigate its role in malignant transformation. Potential targets of miR-326 were identified by transcriptome analysis of miR-326 overexpressing cells by whole RNA sequencing and selected targets were validated. Several publically available data sets were used for various investigations described above.ResultsWe identified several miRNA that were regulated by PI3 kinase pathway. miR-326, a GBM downregulated miRNA, was validated as one of the miRNAs whose expression was alleviated upon abrogation of the PI3 kinase pathway. Overexpression of miR-326 resulted in reduced proliferation, colony suppression and hindered the migration capacity of glioma cells. Arrestin, Beta 1 (ARRB1), the host gene of miR-326, was also downregulated in GBM and interestingly, the expression of ARRB1 was also alleviated upon inhibition of the PI3 kinase pathway, indicating similar regulation pattern. More importantly, miR-326 exhibited a significant positive correlation with ARRB1 in terms of its expression. Transcriptome analysis upon miR-326 overexpression coupled with integrative bioinformatics approach identified several putative targets of miR-326. Selected targets were validated and interestingly found to be upregulated in GBM.ConclusionsTaken together, our study uncovered the PI3 kinase regulated miRNome in GBM. miR-326, a PI3 kinase pathway inhibited miRNA, was demonstrated as a tumour suppressor miRNA in GBM.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0557-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

PI3 kinase pathway regulated miRNome in glioblastoma: identification of miR-326 as a tumour suppressor miRNA

et al. 2016

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“…This approach enabled the identification of miRNAs whose expression levels were significantly altered in tumor tissue compared to peripheral brain tissue of the same patient, including miR-221, which was strongly up-regulated in GBM, and a set of brain-enriched miRNAs (miR-128, miR-181a, miR-181b, and miR-181c), which were down-regulated in GBM [32]. Very recently, a number of prognostic miRNA signatures have been reported for GBM [33–35, 15, 36, 37, 18–20, 38, 39]. We compared these signatures with our signature in terms of complexity, independent validation, and the approach used for identification of the signature.…”

Section: Discussionmentioning

confidence: 99%

“…With a high degree of promiscuity miRNAs target and regulate several mRNA species encoding for proteins involved in various signaling pathways [14]. Accumulating evidence indicates that miRNA expression signatures can serve as biomarkers for diagnosis and risk assessment of diverse malignancies, including GBM [15–20]. Given that the available prognostic markers can segregate GBM patients only to a limited extent, additional markers and/or signatures have to be defined.…”

Section: Introductionmentioning

confidence: 99%

A 4-miRNA signature predicts the therapeutic outcome of glioblastoma

et al. 2016

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Multimodal therapy of glioblastoma (GBM) reveals inter-individual variability in terms of treatment outcome. Here, we examined whether a miRNA signature can be defined for the a priori identification of patients with particularly poor prognosis.FFPE sections from 36 GBM patients along with overall survival follow-up were collected retrospectively and subjected to miRNA signature identification from microarray data. A risk score based on the expression of the signature miRNAs and cox-proportional hazard coefficients was calculated for each patient followed by validation in a matched GBM subset of TCGA. Genes potentially regulated by the signature miRNAs were identified by a correlation approach followed by pathway analysis.A prognostic 4-miRNA signature, independent of MGMT promoter methylation, age, and sex, was identified and a risk score was assigned to each patient that allowed defining two groups significantly differing in prognosis (p-value: 0.0001, median survival: 10.6 months and 15.1 months, hazard ratio = 3.8). The signature was technically validated by qRT-PCR and independently validated in an age- and sex-matched subset of standard-of-care treated patients of the TCGA GBM cohort (n=58). Pathway analysis suggested tumorigenesis-associated processes such as immune response, extracellular matrix organization, axon guidance, signalling by NGF, GPCR and Wnt. Here, we describe the identification and independent validation of a 4-miRNA signature that allows stratification of GBM patients into different prognostic groups in combination with one defined threshold and set of coefficients that could be utilized as diagnostic tool to identify GBM patients for improved and/or alternative treatment approaches.

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“…[34] Even now, the association of miRNAs with the methylation of the MGMT promoter is still controversial since miRNAs are not considered as direct epigenetic regulators. [21,35] However, overexpression of miR-222, -145 and -132 is related with TMZ resistance coupled with MGMT promoter methylation. [35] Additionally, miR-181b and -181c are downregulated in patients that responded to radiotherapy and concomitant TMZ.…”

Section: Molecular Approach Against Multi-resistant Gliomasmentioning

confidence: 99%

“…[21,35] However, overexpression of miR-222, -145 and -132 is related with TMZ resistance coupled with MGMT promoter methylation. [35] Additionally, miR-181b and -181c are downregulated in patients that responded to radiotherapy and concomitant TMZ. [36] However, sensibility to chemotherapy is not only dependent of the presence of MGMT.…”

Section: Molecular Approach Against Multi-resistant Gliomasmentioning

confidence: 99%

Effects of Gas1 on gliomas: a review on current preclinical studies

Segovia¹,

Bautista²,

Lara-Lozano³

2016

JCMT

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Glioblastoma multiforme (GBM) is the most common and lethal brain tumor. Its prognosis remains very poor, despite the use of combined treatments such as surgical resection, radiation and chemotherapy. The major limitations for the treatment of GBM are its high invasiveness, tumor recurrence and resistance to treatments. Therefore, gene therapy appears as a relevant strategy for its treatment. Thus, we have investigated the use of growth-arrest-specific 1 (Gas1) for the treatment of GBM. Gas1 is a tumor suppressor protein that inhibits glioma growth by inducing arrest and apoptosis of tumor cells. Moreover, we have shown that a soluble form of Gas1 acting in both autocrine and paracrine manners is also effective inhibiting tumor growth in animal models, indicating its potential as an adjuvant for the treatment of GBM.

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A five-miRNA signature with prognostic and predictive value for MGMT promoter-methylated glioblastoma patients

Cited by 54 publications

References 37 publications

PI3 kinase pathway regulated miRNome in glioblastoma: identification of miR-326 as a tumour suppressor miRNA

PI3 kinase pathway regulated miRNome in glioblastoma: identification of miR-326 as a tumour suppressor miRNA

A 4-miRNA signature predicts the therapeutic outcome of glioblastoma

Effects of Gas1 on gliomas: a review on current preclinical studies

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