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Molecular Neurobiology

, Volume 47, Issue 1, pp 131–144 | Cite as

A Systematic Review of MicroRNA in Glioblastoma Multiforme: Micro-modulators in the Mesenchymal Mode of Migration and Invasion

  • Heidi G. Møller
  • Andreas P. Rasmussen
  • Hjalte H. Andersen
  • Kasper B. Johnsen
  • Michael Henriksen
  • Meg Duroux
Open Access
Article

Abstract

Glioblastoma multiforme (GBM) is an incurable form of brain cancer with a very poor prognosis. Because of its highly invasive nature, it is impossible to remove all tumor cells during surgical resection, making relapse inevitable. Further research into the regulatory mechanism underpinning GBM pathogenesis is therefore warranted, and over the past decade, there has been an increased focus on the functional role of microRNA (miRNA). This systematic review aims to present a comprehensive overview of all the available literature on the expression profiles and function of miRNA in GBM. Here, we have reviewed 163 papers and identified 253 upregulated, 95 downregulated, and 17 disputed miRNAs with respect to expression levels; 85 % of these miRNAs have not yet been functionally characterized. A focus in this study has been 26 interesting miRNAs involved in the mesenchymal mode of migration and invasion, demonstrating the importance of miRNAs in the context of the cellular niche. Both oncogenic and tumor-suppressive miRNAs were found to affect target genes involved in cell migration, cytoskeletal rearrangement, invasiveness, and angiogenesis. Clearly, the distinct functional properties of these miRNAs need further investigation and might hold a great potential in future molecular therapies targeting GBM.

Keywords

MicroRNA Glioblastoma Glioma Migration Invasion Mesenchymal mode of migration and invasion (MMMI) Systematic review EMT 

Introduction

Glioblastoma multiforme (GBM) is a highly prevalent, incurable form of cancer emanating from the brain, accounting for 12–15 % of all brain tumors and approximately 70 % of all diagnosed gliomas [1, 2]. Among the WHO grades of astrocytoma, GBM is classified as being the most progressed and severe (grade IV). It is characterized by an extremely poor prognosis, reflected in a mean survival rate of only 3.3 % at 2 years and 1.2 % at 3 years [3, 4]. While GBM rarely metastasizes, it characteristically grows by infiltrating the surrounding brain tissue [5]. Because of this highly invasive nature, it is impossible to completely remove all tumor cells during surgical resection [6].

Today, treatment of GBM is primarily through tumor resection and subsequent radio- and chemotherapy, typically alkylating agents, e.g., temozolomide [7, 8]. Despite intensive efforts to improve current treatment and explore new therapeutic targets, pivotal clinical improvement has remained absent during the last decade [7, 9]. Other forms of treatment, such as photodynamic therapy, based on photooxidative reactions and accumulation of photo sensitizers in tumor tissue, can be used to facilitate tumor resection and target cell proliferation [10]. Molecular phenotyping of GBM is opening up the potential for molecularly targeted therapies. These can take the form of targeting specific components of oncogenic pathways, e.g., through delivery of a therapeutic gene or microRNA (miRNA) [9, 11, 12, 13]. Several miRNAs are differentially expressed in a variety of malignancies compared to corresponding healthy tissue. Some of these miRNAs have been shown to modulate oncogenes and tumor suppressors, as is the case for GBM. Therefore, miRNAs could hold a great potential in the future treatment of this disease.

Biogenesis of miRNA

In order to understand the context of miRNA in GBM pathology, we highlight here the essential steps in the biogenesis of miRNAs and the effects they exert on their downstream functional targets (Fig. 1). miRNAs are small RNA molecules of approximately 20–23 nucleotides, which have been identified as important regulators of mRNA translation [14]. The biogenesis of miRNA starts with transcription of miRNA genes by RNA polymerase II/III (Pol II/III), generating a primary transcript (pri-miRNA) that is both capped and polyadenylated. The transcript folds into a stem-loop structure via intramolecular base-pairing [14]. The stem-loop structure is cleaved to pre-miRNA by the Drosha/DGCR8 complex and actively transported out of the nucleus by Exportin-5 in the presence of Ran-GTP cofactor [15]. In the cytoplasm, the RNAseIII enzyme Dicer makes the final cleavage to a double-stranded miRNA, of which one strand is incorporated into the RNA-induced silencing complex (RISC), the cytoplasmic effector machine for miRNA. The other strand is degraded [16]. RISC is comprised of Dicer, the double-stranded RNA binding factor (TRBP) and Argonaut protein 2 (Ago2). The posttranscriptional RNA silencing is mediated through complementary binding of miRNA within RISC to the mRNA 3′ untranslated region, resulting in mRNA cleavage, translational inhibition, or mRNA decay [17]. This mRNA interference results in a decreased level of encoded proteins, hereby affecting an array of cellular processes, e.g., proliferation, migration, and apoptosis[18]. A new and less-studied fate of miRNAs is the selective excretion via lipoproteins or microvesicles, possibly functioning as a way of intercellular communication [19, 20].
Fig. 1

The linear biogenesis of miRNA. miRNA biogenesis involves transcription of pri-miRNA by RNA polymerase II/III, cleavage by the Drosha-DGCR8 complex to pre-miRNA, followed by export to the cytoplasm by Exportin-5 in the presence of Ran-GTP cofactor. In the cytoplasm, pre-miRNA is cleaved by the Dicer-TRBP complex to a miRNA duplex, which is unwound to a guide strand that is bound to Ago2 and incorporated into the RISC, and a passenger strand, which is degraded. Ultimately, miRNA binding to target mRNAs results in mRNA target cleavage, translational repression, or mRNA decay. A more novel fate of the miRNAs is the selective secretion via microvesicles or exosomes

Studies of microRNA in Glioblastoma Multiforme

The scope of this paper is to provide the most up-to-date review of the current literature pertaining to miRNA studies in GBM. The first two papers investigating miRNA expression profiles in GBM were published almost simultaneously in 2005 [21, 22]. Ciafrè et al. demonstrated aberrant expression levels of numerous miRNAs when comparing GBM tumor samples to normal brain tissue [22]. While also analyzing miRNA expression levels, Chan et al. [21] were the first to investigate the functional properties of a single miRNA in GBM cell lines. They found that inhibition of miR-21 resulted in significantly increased apoptosis and, therefore, hypothesized that miR-21 could function as a micro-oncogene [21]. Since these early findings, the number of studies published on this subject has steadily increased, elucidating numerous interesting miRNA-mediated mechanisms in the tumorigenesis of GBM.

To obtain a comprehensive overview of the current knowledge on miRNA expression and function in GBM, all available literature on the subject was reviewed. A Medline database search on: “microRNA and Glioblastoma” plus “microRNA and Glioma”1 was performed (date of search entry: April 20, 2012). The results contained a total of 256 papers, of which 163 were found relevant, based on the title and abstract content. The 163 papers were reviewed, 102 of them met the inclusion criteria, which encompassed studies investigating expression levels of miRNAs in GBM tumor samples compared to normal brain tissue, and/or studies exploring the functional properties of selected miRNAs in GBM cell lines. Of the remaining 61 papers, 34 were studies primarily focusing on diagnostics, delivery, and prognostics and were categorized as editor’s notes or generally not the scope of the topic. Twenty-seven papers were reviews and review-like articles, discussing the role of miRNA in GBM. Clearly, none of the 27 reviews were highly systematic in their approach; primarily, they described few well-known and reviewed miRNAs. All relevant material extracted from the 102 papers that were reviewed has been presented in the form of a supplementary table (Supplementary Table 1). The content of this supplementary table provides the foundation for the material discussed in the following sections of the paper. Each section attempts to highlight the population of upregulated, downregulated, and novel miRNAs. Emphasis on the promising therapeutic potential of specific miRNAs is presented with a focus on the mesenchymal mode of migration and invasion (MMMI) in GBM.

MicroRNAs Upregulated in Glioblastoma Multiforme

Based solely on the literature contained in this review, it appears that the most common dysregulation of miRNA in GBM is overexpression, thus, 256 miRNAs were found significantly overexpressed (Supplementary Table 1). Few of these, for example miR-17, miR-21, miR-93, and miR-221/222, have been intensively investigated with respect to both expression and functionality, but the functional properties of the vast majority remains completely unknown. Table 1 display all miRNAs that were found upregulated in greater than or equal to five studies and/or functionally investigated, with emphasis on luciferase-validated targets, in at least one study. In the following sections, miRNAs that are particularly interesting, extensively investigated, or novel are discussed.
Table 1

Upregulated miRNAs and their functional role in GBM

miRNA

Targets

Functional role when 1: overexpressed, 2: underexpressed

Reference

Hsa-mir-9

CAMTA1

 

[23, 24, 30, 31, 32]

Hsa-mir-9*

CAMTA1

2: Proliferation↓, Stemness↓

[25, 32]

Hsa-mir-10ba

HOXD10d

1:Invasiveness↑

[22, 23, 24, 25, 26, 27, 28, 29]

2: Invasiveness↓

Hsa-mir-15b

CCNE1

1:Proliferation↑

[23, 24, 25, 31, 35, 100]

2: Proliferation↓

Hsa-mir-16

  

[24, 25, 30, 31, 36]

Hsa-mir-17a

POLD2, TGFβ-RIIb, CTGF, CAMTA1

1:Angiogenesis↑, Growth↑

[24, 25, 26, 30, 31, 32, 33, 34]

2: Viability↓, Apoptosis↑, Proliferation↓

Hsa-mir-18aa

Smad4, CTGF

1:Angiogenesis↑, Growth↑

[25, 33, 34]

2: Viability↓, Apoptosis↑, Proliferation↓

Hsa-mir-20aa

TGFβ-RIIb, CTGF

1:Angiogenesis↑, Growth↑

[25, 26, 30, 31, 33]

2: Viability↓, Proliferation↓

Hsa-mir-21ac

RECKd,TIMP3d, APAF1, ANP32Ad, SMARCA4, Caspases, PTEN, Cdc25A, HNRPK, TAp63, Spry2d, LRRFIP1, PDCD4

1:Invasiveness↑

[21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55]

2: Invasiveness↓, Apoptosis↑, Viability↓, Proliferation↓, In vivo tumor volume↓, Chemosensitivity↑

Hsa-mir-23a

  

[22, 23, 24, 25, 35, 37, 52]

Hsa-mir-25c

Mdm2, TSC1

1:In vivo tumor volume↓

[22, 23, 24, 25, 26, 30, 101]

Hsa-mir-26ac

PTEN

1:In vivo tumor volume↑

[23, 25, 37]

Hsa-mir-27a

WEE1

 

[23, 25, 52]

Hsa-mir-30ec

IκBαd

1:Invasiveness↑, Proliferation↑, Angiogenesis↑, In vivo tumor volume↑

[25, 96]

2: Invasiveness↓, Proliferation↓, Angiogenesis↓, In vivo tumor volume↓

Hsa-mir-92 a

CTGF

2: Viability↓, Proliferation↓

[25, 26, 33, 34]

Hsa-mir-93ac

Integrin-β8d

1:Angiogenesis↑, Proliferation↑, In vivo tumor volume↑

[23, 24, 26, 56]

Hsa-mir-106b

  

[23, 24, 25, 26, 28, 52]

Hsa-mir-125b

Bmf

1:Invasiveness↑, Apoptosis↓, Proliferation↑

[25, 97, 102, 103]

Hsa-mir-146ac

Notch1

1:Proliferation↓, In vivo tumor volume↓, Migration↓

[24, 25, 104]

Hsa-mir-155

 

2: Viability↓, Apoptosis↑, Chemosensitivity↑

[24, 25, 26, 31, 36, 105]

Hsa-mir-182

  

[23, 24, 25, 26, 37, 106]

Hsa-mir-183

  

[23, 25, 26, 106, 107]

Hsa-mir-210

  

[25, 26, 30, 31, 36]

Hsa-mir-221c

P27, Aktd, PUMA, P57, PTPμd

1:Proliferation↑, Invasiveness↑, in vivo tumor volume↑, Apoptosis↓, Migration↑

[22, 35, 52, 53, 98, 108, 109, 110, 111, 112, 113]

2: Proliferation↓, Apoptosis↑, in vivo tumor volume↓

Hsa-mir-222c

Akt, PUMA, P57, PTPμd

1:Proliferation↑, Invasiveness↑, In vivo tumor volume↑, Apoptosis↓, Migration↑

[22, 35, 52, 98, 109, 110, 111, 112, 113]

2: Proliferation↓, Apoptosis↑, in vivo tumor volume↓

Hsa-mir-335bc

Daam1d

1:Viability↑, Invasiveness↑

[25, 59]

2: Apoptosis↑, Invasiveness↓, In vivo tumor volume↓

Hsa-mir-381bc

LRRC4

1:Proliferation↑, In vivo tumor volume↑

[60]

2: Proliferation↓

miRNAs consistently upregulated in glioblastoma. The table presents miRNAs with observed effects upon their downregulation and their validated targets. The cell lines in which the studies have been performed are presented. Only miRNAs that have been investigated in greater than or equal to five studies and/or have a validated target are included in this table. The cell lines applied in the annotated studies can be found in Supplementary Table 1

aMentioned in the section “MicroRNAs Upregulated in Glioblastoma Multiforme”

bMentioned in the section “MicroRNAs Upregulated in Glioblastoma Multiforme with Limited Functional Characterization”

cMicroRNAs whose down regulation is shown to inhibit tumour growth in vivo

dTargets involved in the mesenchymal mode of migration and invasion

miR-10b

Since its first investigation by Ciafrè et al., overexpression of miR-10b in GBM has been confirmed in eight studies [22, 23, 24, 25, 26, 27, 28, 29]. A significant WHO grade specific correlation of its overexpression has been observed, thus implying the pertinent role of miR-10b in GBM grade progression [28, 29]. Expression levels of urokinase receptor (uPAR) and Ras homolog gene family member C (RhoC) were found to be directly proportional to that of miR-10b, thereby enhancing the invasive capabilities of high-grade glioma [28]. Recently, a negative regulator of uPAR and RhoC, HOXD10, was confirmed as a direct target of miR-10b [29].

miR-17 ~ 92-cluster

The expression of the miR-17 ∼ 92-cluster (comprising miR-17-3p, miR-17-5p, miR-18a, miR-19a, miR-19b, miR-20a, and miR-92a) is upregulated in GBM tumor samples and cell lines [24, 25, 26, 30, 31, 32, 33, 34]. The miR-17 ∼ 92-cluster has been shown to possess a variety of tumorigenic properties, mediated through direct targeting of antiproliferative genes (TGFBRII, SMAD4, and CAMTA1) and regulators of angiogenesis and DNA-repair (CTGF, and POLD2). Hence, inhibition of specific miR-17 ∼ 92-cluster members decreases viability and increases apoptosis in vitro [30, 33, 34].

miR-21

Until now, the most extensively investigated miRNA is miR-21, which is consistently reported to be overexpressed in GBM in a WHO-grade specific manner [21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55]. Forced downregulation of miR-21 reduces the oncogenic potential of GBM cell lines through inhibition of several cellular processes involved in malignancy maintenance. Proliferation is significantly reduced by cessation of miR-21 inhibition on the target genes ANP32A, SMARCA4, PTEN, SPRY2, and LRRFIP1 [35, 39, 46, 50]. This reduction is also associated with a decrease in the protein levels of key components of proliferation-linked signaling pathways, e.g., NF-κB and Ras [46]. These results were further substantiated by decreased tumor growth in immunodeficient mice [35, 43, 51]. miR-21 inhibition does also result in significantly increased levels of caspases, leading to an increase in apoptosis, mediated by decreased targeting of HNRPK, TAp63, and PDCD4 [40, 42, 51]. miR-21 affects invasion by decreasing the expression levels of RECK and TIMP3, which normally retains the levels of MMPs [38, 40]. Furthermore, transfection with antisense-miR-21 has been shown to significantly increase GBM cell line sensitivity to both radio- and chemotherapy [41, 44, 47, 48]. This aspect of its function makes miR-21 of particular interest for exploitation in molecular therapy [47].

miR-93

While several studies have proven that miR-93 is upregulated in GBM [23, 24, 26], only one study has investigated its functional properties [56]. Fang et al. [57] used in vitro and in vivo studies to emphasize the functional role of this miRNA in angiogenesis. Using transfection, they further upregulated miR-93 in the model cell line U87. Following co-culture with endothelial cells, they observed increased endothelial cell proliferation and tube formation. Integrin-β8, which inhibits close association between tumor cells and endothelial cells, was found to be a direct target of miR-93. These results were then substantiated with in vivo assays, showing highly increased blood vessel formation in GBM xenograft tumors in mice, strongly validating miR-93 as an angiogenic inducer [56].

MicroRNAs Upregulated in Glioblastoma Multiforme with Limited Functional Characterization

The case with many studies is that trends are followed around well-studied target genes in order to substantiate and validate results. To date, the center of attention has been pivotal around relatively few, well-investigated miRNAs, such as miR-15b, miR-21, miR-221, and miR-222 [58]. However, research on novel miRNAs, e.g., miR-335 and miR-381, has recently been published [59, 60]. miR-335 was upregulated in GBM and shown to increase proliferation and invasion in malignant astrocytoma, through direct targeting of DAAM1. These effects were reversed by miR-335 silencing [59, 61]. Another upregulated, novel miRNA, miR-381, was shown to increase the level of proliferation both in vitro and in xenograft mouse models. Through direct targeting of leucine-rich repeat C4 (LRRC4), miR-381 caused increased levels of phosphorylated MEK, ERK, and AKT, thus, impacting several important components of mitogenic signaling pathways [60]. Additionally, miR-16, miR-23a, miR-106b, miR-182, miR-183, and miR-210 were found to be consistently upregulated in greater than or equal to five studies but remain completely uninvestigated with respect to functional properties (Table 1).

MicroRNAs Downregulated in Glioblastoma Multiforme

Throughout the reviewed literature, 95 miRNAs were reported as downregulated in GBM, compared to normal brain tissue (Supplementary Table 1). Of these, 28 were reported as downregulated in greater than or equal to five studies and/or functionally investigated, with emphasis on luciferase-validated targets, in at least one study (shown in Table 2). Interestingly, what one can infer is that miRNAs that are consistently downregulated in GBM often appear to possess anti-tumorigenic abilities (Table 2). Therefore, further investigation of these miRNAs could generate knowledge on valuable therapeutic targets. In the following section, downregulated, well-investigated miRNAs are highlighted. In conjunction with this, the novel miRNAs are discussed.
Table 2

Downregulated miRNA and their functional role in GBM

miRNA

Target

Functional role when overexpressed

Reference

Hsa-mir-7

FAK, EGFR, IRS2

Viability↓, Migration↓, Invasiveness↓, Proliferation↓, In vivo tumor volume↓, Radiosensitivity↓

[25, 27, 31, 62, 63, 64, 65]

Hsa-mir-29b

PDPNd

Invasiveness↓ Proliferation↓ Apoptosis↑

[25, 36, 45, 114]

Hsa-mir-32bc

Mdm2, TSC1

In vivo tumor volume↓

[24, 45, 78]

Hsa-mir-34aac

SIRT1d, c-Met, Notch1/2, PDGFRAd, Msi1

Viability↓, Proliferation↓, Apoptosis↑, Invasiveness↓, In vivo tumor volume↓, Differentiation↑

[67, 68, 69, 70, 71]

Hsa-mir-100

ATM

Radiosensitivity↑

[115]

Hsa-mir-101b

EZH2 Msi1

Angiogenesis↓, Migration↓, Viability↓, Proliferation↓

[71, 79]

Hsa-mir-124

SNAI2d

Proliferation↓, Migration↓, Invasiveness↓, Stemness↓

[12, 24, 25, 26, 27, 35, 36, 37, 45, 52, 116, 117]

Hsa-mir-125a

 

Invasiveness↓

[45, 114]

Hsa-mir-128ac

WEE1, p70S6K1, Msi1, E2F3a, Bmi-1, EGFRd, PDGFRAd

Angiogenesis↓, Proliferation↓, In vivo tumor volume↓

[22, 24, 25, 26, 31, 35, 37, 52, 55, 71, 72, 73, 74, 75]

Hsa-mir-128b

WEE1

 

[12, 22, 25, 26, 35, 37, 52]

Hsa-mir-129

  

[24, 25, 26, 27, 101]

Hsa-mir-132

  

[12, 24, 25, 26, 31, 35, 52]

Hsa-mir-135ac

STAT6, Smad5, BMPR2

Inhibition causes: In vivo tumor volume↓, Apoptosis↑

[118]

Hsa-mir-137ac

CDK6, Msi1, Cox-2

Proliferation↓, Invasiveness↓, Migration↓, In vivo tumor volume↓

[25, 26, 27, 35, 45, 52, 71, 77]

Hsa-mir-138

Msi1

Proliferation↓

[24, 37, 71]

Hsa-mir-139-5p

  

[12, 25, 26, 27, 31]

Hsa-mir-146b-5pc

EGFRd

Invasiveness↓, Migration↓, Proliferation↓, In vivo tumor volume↓

[119]

Hsa-mir-149

RAP1B, Wnt-pathway

Proliferation↓, Migration↓

[31, 37]

Hsa-mir-153

Bcl-2, Mcl-1, Irs-2

Proliferation↓, Viability↓, Apoptosis↑

[26, 120]

Hsa-mir-181a

Bcl-2

Proliferation↓, Apoptosis↑, Invasiveness↓, Radiosensitivity↑

[22, 37, 121, 122]

Hsa-mir-181b

 

Proliferation↓, Apoptosis↑, Invasiveness↓

[22, 37, 45, 53, 121]

Hsa-mir-181dc

Bcl-2, K-Rasd

Proliferation↓, Apoptosis↑, In vivo tumor volume↓

[123]

Hsa-mir-184

Akt2d

Apoptosis↑, Invasiveness↓

[30]

Hsa-mir-185

DNMT1

DNA methylation↓

[124]

Hsa-mir-218

IKK-βd

Invasiveness↓

[25, 26, 27, 125]

Hsa-mir-326bc

Notch-1/2, PKM2d

Proliferation↓, Apoptosis↑, Viability↓, Invasiveness↓, In vivo tumor volume↓

[80, 81]

Hsa-mir-483-5pb

ERK1d

Proliferation↓

[24, 83]

Hsa-mir-491-5pb

MMP9d

Invasiveness↓

[37, 82]

miRNAs consistently downregulated in glioblastoma. The table presents miRNAs with observed effects upon their upregulation and their validated targets. The cell lines in which the studies have been performed are presented. Only miRNAs that are investigated in greater than or equal to five studies and/or have a validated target are included in this table. The cell lines applied in the annotated studies can be found in Supplementary Table 1

aMentioned in the section “MicroRNAs downregulated in Glioblastoma Multiforme”

bMentioned in the section “MicroRNAs Downregulated in Glioblastoma Multiforme with Limited Functional Characterization”

cMicroRNAs whose upregulation is shown to inhibit tumor growth in vivo

dTargets involved in the mesenchymal mode of migration and invasion

miR-7

Seven studies published within the last 4 years have established miR-7 as being downregulated in GBM [25, 27, 31, 62, 63, 64, 65]. A study by Lages et al. found a decrease in miR-7 expression of 0.11 and 0.09 fold in GBM and oligodendroglioma, respectively, suggesting that miR-7 also has a key role in tumors of non-astrocytic origin [31]. The first paper to functionally characterize miR-7 in GBM was published in 2008 by Kefas et al. and utilized a luciferase reporter assay to establish EGFR, frequently amplified in GBM [66], and IRS-2 as a direct targets of miR-7 [65]. Interestingly, the same paper found that transfection with miR-7 led to a decrease in phosphorylated Akt in a non EGFR-dependent manner and reduced invasiveness in several GBM cell lines [65]. More recently, it was shown that Focal Adhesion Kinase (FAK) is also a direct target of miR-7 and that overexpression of miR-7 resulted in decreased rates of both migration and invasion, possibly in part mediated by lowered levels MMP-2 and MMP-9 [63]. It is evident that miR-7 is an important suppressor of the MMMI, and future research could reveal further promising therapeutic characteristics.

miR-34a

The first interesting study investigating miR-34a utilized both CD133+ and CD133− GBM cells, thus also examining the connection between the cancer stem cell hypothesis and miRNA. Here, Li et al. [50] found that forced overexpression of miR-34a resulted in inhibited proliferation and invasion both in vitro and in immunodeficient mice. It was found that these growth inhibitory effects on both CD133+ and CD133− cells were mediated by targeting the Notch signaling pathway via Notch1/2 and via c-Met [67]. Later, the group showed that miR-34a overexpression led to an increase in cell differentiation and apoptosis in a glioma stem cell culture [68]. The tumor-suppressive role of miR-34a was confirmed by Luan et al. who also found that miR-34a levels reflect the status of tumor suppressor p53, and that miR-34a could activate the p53 signaling cascade of p53 expression independently, possibly through targeting of SIRT1 [69]. Recently, two new targets of miR-34a were determined: Musashi1 and platelet-derived growth factor receptor-α (PDGFRA), last mentioned known to be amplified in GBM [70, 71]. Interestingly, a negative feedback mechanism between PDGFRA and miR-34a was discovered, implying that the underlying cause of miR-34a downregulation in GBM might be a result of increased PDGF-signaling [70]. Despite an obvious potential, intracranial delivery of miR-34a in the treatment of GBM has yet to be attempted.

miR-128

Several papers have reported significant miR-128 repression in GBM cell lines and tumor samples [22, 24, 25, 26, 31, 35, 37, 52, 55, 71, 72, 73, 74, 75]. It is capable of suppressing tumor growth, mediated through numerous direct gene targets in a number of different cell lines. The first target investigated, Bmi-1, which normally drives stem cell renewal and glioma growth, was found to be downregulated upon miR-128 induction [75]. Adding to the antiproliferative effect of miR-128 is the fact that it mediates the silencing of the transcription factor E2F3a, an effect that was shown to be reversible by E2F3a restoration [73, 74]. Papagiannakopoulos et al. found the two growth factor receptors EGFR and PDGFRA, both typically overexpressed in GBM, to be repressed by miR-128 [76]. Other direct targets of miR-128 include WEE1 [25] and Msi1, involved in proliferation, and p70S6K1, involved in angiogenesis [72]. Based on the above-mentioned experimental evidence, it appears that miR-128 is a good candidate for repressing GBM growth and invasion.

miR-137

Since its first description in relation to the pathology of GBM in 2008, miR-137 has been consistently reported as downregulated and has often been investigated in combination with other miRNAs, e.g., miR-124 [25, 26, 27, 35, 45, 52, 71, 77]. Studies have revealed antiproliferative and anti-invasive effects upon forced miR-137 overexpression, mediated through CDK6 [27], Msi1 [71], and Cox-2 [77]. Of significant interest here is the inhibition of Cox-2, as this enzyme is shown to play a role in cell proliferation [77].

MicroRNAs Upregulated in Glioblastoma Multiforme with Limited Functional Characterization

As for the upregulated miRNAs, several specific downregulated miRNAs have been intensively investigated, while others, e.g., miR-32, miR-101, miR-326, and miR-491-5p, have received limited attention. Furthermore, mir-181b, mir-139-5p, mir-132, and mir-129 were found to be consistently downregulated in greater than or equal to five studies but remains uninvestigated with respect to functional role in GBM. miR-32 was found to be downregulated in three studies and shown to suppress intracranial xenograft tumor growth, thus improving overall survival rate of mice. Furthermore, two important p53 inhibitors, MDM2 and TSC1, were validated as direct targets of this miRNA [24, 45, 78]. Two studies found that miR-101 was able to decrease levels of angiogenesis, proliferation, migration, and viability by targeting part of the Polycomb-group family EZH2 and Msi1 [71, 79]. Lowered expression of EZH2 results in a reduction of histone methylation, affecting the expression of several genes involved in tumor suppression [71, 79].

Until now, only Kefas et al. [80, 81] have investigated miR-326 expression and function in GBM. In their two publications, they found that by targeting Notch1/2 and pyruvate kinase M2 (PKM2), miR-326 was able to decrease proliferation and invasiveness in a subset of different cell lines. In addition, they proposed that miR-326 and Notch1 regulate each other in a negative feedback manner [80, 81]. Another miRNA with anti-invasive properties is miR-491-5p, which is found to inhibit MMP9, a key component in the degradation of extracellular matrix [82].

The most recently published study on miR-483-5p has shown that it is decreased in both tumor samples and cell lines. Induction of miR-483-5p inhibited proliferation of GBM cells by arrest in the G0/G1 transition. Further verifying these results, was the interesting finding that miR-483-5p caused silencing of ERK1, known to be an important factor in several major mitogenic signaling pathways [83]. Clearly, the function of miR-483-5p is interesting with respect to its involvement in cell cycle arrest and its role in gene silencing of key regulatory pathways in tumorigenesis.

MicroRNAs with Disputed Levels of Expression in Glioblastoma Multiforme

Besides the long list of up- and downregulated miRNAs are a group of conflicting experimental findings that need further resolution in order to define the key regulatory determinants. Throughout the literature review process, a number of studies could be identified where the expression levels of miRNAs were disputed (Table 3). In total, 17 miRNAs were found to be both up- and downregulated. Much of this could be attributed to the experimental framework of the studies, different models, and the well-known fact that the tumor niche is a governing factor with respect to gene regulation and expression [84, 85]. In the following section, a number of these disputed miRNAs will be discussed.
Table 3

miRNAs with disputed expression levels and their functional role in GBM

miRNA

Target

Functional role when overexpressed

Functional role when underexpressed

References

Overexpression in GBM

Underexpression in GBM

Hsa-mir-19a

CTGF

 

Viability↓, Apoptosis↑, Proliferation↓

[24, 25, 26, 30]

[34]

Hsa-mir-26b

EphA2a

Proliferation↓, Invasiveness↓, Angiogenesis↓

 

[31]

[26, 107]

Hsa-mir-27b

WEE1

 

Proliferation↓, Apoptosis↑, Invasiveness↓

[126]

[25]

Hsa-mir-106a

E2F1

Proliferation↓, Apoptosis↑

 

[24, 26, 35]

[45, 127]

Hsa-mir-143

  

Invasiveness↓

[6]

[26]

Hsa-mir-145bc

Oct4, SOX2

In vivo tumor volume↓, Migration↓, Stemness↓, Chemosensitivity↑, Radiosensitivity↑

Invasiveness↓

[6, 86]

[11]

Hsa-mir-205

VEGF-Aa

Proliferation↓, Apoptosis↑, Invasiveness↓

 

[26]

[99]

Hsa-mir-451b

PI3K/Akt-pathway, CAB39a

Proliferation↓, Invasion↓, Stemness↓, Neurosphere formation↓, Proliferation↑

Migration↑

[23, 87, 89]

[35, 52, 88, 89]

miRNAs found to be both up- and downregulated in GBM and their functional role. The table presents miRNAs, which have been reported with differential expression levels in GBM between different research groups. Only miRNAs that are investigated in greater than or equal to five studies and/or have a validated target are included in this table. The effects of upregulation or downregulation and validated targets are presented. The cell lines applied in the annotated studies can be found in Supplementary Table 1

aTargets involved in the mesenchymal mode of migration and invasion

bMentioned in the section “miRNAs with disputed expression levels”

cmiRNAs whose upregulation is shown to inhibit tumor growth in vivo

miR-145

One of the miRNAs with disputed findings in expression levels between nonmalignant brain tissue and GBM tumor samples/cell lines was miR-145 [6, 11, 86]. miR-145 was reported to be downregulated by Lee et al. [11] who also found a decrease in proliferation and invasion when inducing overexpression of miR-145. Furthermore, when inserting a miR-145 expression cassette into a HSVtk-expressing adenoviral vector, an increase in survival was observed following transmission to mice [11]. These observations were strengthened by Yang et al. [86] who showed increased radio- and chemosensitivity accompanied by a decrease in migration, stemness, and xenograft tumor growth upon miR-145 overexpression. These effects were found to be mediated through direct targeting of the two stemness transcription factors Oct4 and Sox2 [86]. However, contradictory to these two studies, Koo et al. [6] reported miR-145 to be upregulated in a number of highly invasive GBM cell lines, and that downregulation of miR-145 decreased the invasive abilities of GBM cells. Interestingly, the group also found miR-145 to be most upregulated in highly invasive regions of freshly resected human GBM tumor samples [6].

miR-451

Generating another discrepancy in the literature are two papers exploring expression levels of miR-451 in GBM cell lines, finding dissimilar results [87, 88]. Gal et al. found that miR-451 was overexpressed in CD133− GBM cells, while Nan et al. found a downregulation of miR-451 in three GBM cell lines [87, 88]. However, both papers agreed that transfection with miR-451-mimics significantly decreased proliferation and viability, thus implying that miR-451 has tumor-suppressive effects in vitro. A possible explanation for these contradictory results might exist as presented by Godlewski et al. [89]. In two key papers, they investigated the relationship between metabolic stress in GBM cell lines and the expression of miR-451. Interestingly, they discovered that the cell migratory ability varies, dependent on glucose availability. Thus, when glucose levels are low, miR-451 is underexpressed, leading to increased migration via the AMPK/MAPK-pathway, mediated by direct targeting of calcium-binding protein 39 (CAB39) [90, 91].

MicroRNAs and the Mesenchymal Mode of Migration and Invasion

Epithelial to mesenchymal transition (EMT) is a phenomenon during which epithelial cells lose many of their epithelial characteristics and acquire markers and phenotypes of mesenchymal cells. EMT facilitates metastasis through increased migration, invasion, intravasation and/or extravasation [92, 93]. Due to the astrocytic origin of GBM, a complementary concept called MMMI is proposed as a valuable notion in the malignant progression of glioblastoma (inspired by Zhong et al. [5]).

EMT encompasses many known pathways such as the EGFR, TGF-β, and Wnt-signaling that promote the continuous acquisition of malignant biological features by cancer cells and contributes to the highly invasive nature of certain cancers [94]. Essential transcription factors in EMT include ZEBs (delta-crystalline enhancer binding factors) which, together with the EMT-promoting transcription factor TWIST, regulate several of the EMT-associated pathways and enhance cellular invasion [95]. The ZEB and Twist proteins are implicated in EMT in several tumor types and regulate, or are under the regulation of miRNAs, underpinning that miRNAs are important regulators of malignancy development [93].

MMMI encompasses interaction between GBM cells and their surrounding extracellular matrix (ECM), through integrin-attachment and detachment resulting in FAK-signaling. This prompts several intracellular changes such as actin filamentation and myosin phosphorylation, which ultimately enables cell locomotion. Invasive GBM cells infiltrate the brain parenchyma and escape surgical resection and other local therapeutic modalities, and are considered a principle reason for tumor recurrence [5]. In the following section, the concept of MMMI is broadened to include all cellular processes, related to miRNAs, facilitating invasion and migration of GBM cells.

It is clear from the literature that a number of miRNAs, both oncogenic and tumor suppressive, are involved in MMMI, thus affecting cell migration, cytoskeletal rearrangement, invasiveness, and angiogenesis (Fig. 2). This emphasizes the function of miRNAs as modulators of the ECM and tumor niche. miR-21, the most investigated miRNA in the literature, has been shown to be involved in many aspects regarding MMMI [22, 38, 93]. It is able to increase the expression and activity levels of a number of MMPs, facilitate Ras/Raf binding, and induce ERK phosphorylation through targeting of known tumor suppressors, like RECK, TIMP3, ANP32A, and SPRY2, thereby enhancing the invasive potential of the GBM cells [38, 39, 46, 48].
Fig. 2

Schematic overview of miRNAs involved in the mesenchymal mode of migration and invasion in glioma. The inhibition of validated targets (yellow boxes) by specific miRNAs results in either pro-invasive (red box) or anti-invasive (green box) effects. Red ovals depict upregulated, oncogenic miRNAs, e.g., miR-10b targets HOXD10, resulting in increased MMP14 expression and invasion. Blue ovals depict downregulated tumor suppressor miRNAs in GBM, e.g., miR-26b targets EphA2, resulting in decreased levels of angiogenesis

By inhibiting DAAM1, miR-335 is able to initiate cytoskeletal rearrangement and decrease the level of myosin light chain phosphorylation, which ultimately results in increased invasion [59]. Similar results have been obtained when exploring the effects of other known oncogenic miRNAs, such as miR-10b, miR-30e*, miR-125b, and miR-221 [29, 96, 97, 98].

In addition, 16 tumor-suppressive miRNAs (Fig. 2) are shown to play a role in the inhibition of invasion. For example, overexpression of miR-7, which targets EGFR and FAK, reduces the level of invasion in GBM, and diminishes the expressional levels of MMPs and phosphorylation of Akt and Erk [63, 64, 65]. miR-326 targets PKM2 with a resulting decrease in ATP levels, which is associated with less mTOR signaling and less invasion [81]. Furthermore, interesting results have been obtained regarding miR-491-5p, which directly targets MMP9 and, therefore, inhibits migration of GBM cells [82].

Another factor associated with invasion is angiogenesis, which is also under regulation of miRNAs. In addition to bringing nutrients to the tumor mass, angiogenesis is also required for facilitating tumor cell migration [93]. miRNAs, such as miR-93 and miR-205, have been shown to regulate the level of angiogenesis; miR-93 inhibits integrin-β8 with a resultant increase in angiogenesis [56], while miR-205, which targets VEGF-A, has the opposite effect [99]. Given the broad and very profound involvement of miRNAs in the regulation of gene expression and extracellular signaling, a focus on the miRNAs involved in MMMI and ECM dynamics as future agents, or targets for therapy, would be promising.

Conclusion

In this comprehensive review of 102 papers, we have attempted to highlight the expression profile of miRNAs significantly up- or downregulated in GBM and subsequently focused on a group defined as more novel with respect to functional characterization. 253 miRNAs were found to be significantly upregulated, 95 significantly downregulated, and 17 were disputed with respect to expression levels###; 313 of these miRNAs have yet to be functionally characterized, prompting the need for further investigations. The function of miRNAs encompasses modulation of the ECM dynamics (Fig. 2) and likewise the miRNA expression can be influenced by the tumor niche [85]. Hence, the assembly of a group of miRNAs with disputed results in the levels of expression highlights the importance of tissue isolation/processing, choice of control tissue, and the tumor microenvironment; all of which are factors that could contribute to these differences in expression. Even though 365 miRNAs have been studied with respect to their expression in glioma, only 21 of them have been investigated with respect to their function in vivo (Supplementary Table 1). Furthermore, the 15 most studied miRNAs (miR-7, miR-10b, miR-15b, miR-17, miR-21, miR-23a, miR-25, miR-124, miR-128a, miR-128b, miR-132, miR-137, miR-195, miR-221, and miR-222) in GBM were investigated in 62 out of the 102 papers. The popularity per se of this cohort of well-investigated miRNAs sets a bias in the literature with respect to the importance of these miRNAs in glioma initiation, progression, and invasion. This leaves a large number of miRNAs that could hold a similar or greater potential in future therapeutics than the highly studied cohort.

Footnotes

  1. 1.

    Search typed: “(microRNA AND Glioblastoma) OR (microRNA AND Glioma)”

Notes

Acknowledgments

This research was supported by the Department of Health Science and Technology, Aalborg University. Further thanks to Spar Nord Fonden, Det Obelske Familiefond, and Harboe Fonden.

Open Access

This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

Supplementary material

12035_2012_8349_MOESM1_ESM.docx (312 kb)
ESM 1 (DOCX 478 kb)

References

  1. 1.
    Ohgaki H, Kleihues P (2007) Genetic pathways to primary and secondary glioblastoma. Am J Pathol 170(5):1445–1453PubMedCrossRefGoogle Scholar
  2. 2.
    Ohgaki H, Kleihues P (2005) Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 64(6):479–489PubMedGoogle Scholar
  3. 3.
    Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre P-L, Burkhard C, Schüler D, Probst-Hensch NM, Maiorka PC, Baeza N, Pisani P, Yonekawa Y, Yasargil MG, Lütolf UM, Kleihues P (2004) Genetic pathways to glioblastoma: a population-based study. Cancer Res 64(19):6892–6899PubMedCrossRefGoogle Scholar
  4. 4.
    Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, Hahn WC, Ligon KL, Louis DN, Brennan C, Chin L, DePinho RA, Cavenee WK (2007) Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 21(21):2683–2710PubMedCrossRefGoogle Scholar
  5. 5.
    Zhong J, Paul A, Kellie SJ, O’Neill GM (2010) Mesenchymal migration as a therapeutic target in glioblastoma. J Oncol 2010:430142. doi: 10.1155/2010/430142 CrossRefGoogle Scholar
  6. 6.
    Koo S, Martin GS, Schulz KJ, Ronck M, Toussaint LG (2012) Serial selection for invasiveness increases expression of miR-143/miR-145 in glioblastoma cell lines. BMC Cancer 12(1):143PubMedCrossRefGoogle Scholar
  7. 7.
    Hong B, Wiese B, Bremer M, Heissler HE, Heidenreich F, Krauss JK and Nakamura M (2012) Multiple microsurgical resections for repeated recurrence of glioblastoma multiforme. Am J Clin OncolGoogle Scholar
  8. 8.
    Becker KP, Yu J (2012) Status quo–standard-of-care medical and radiation therapy for glioblastoma. Cancer J 18(1):12–19PubMedCrossRefGoogle Scholar
  9. 9.
    Mohyeldin A, Chiocca EA (2012) Gene and viral therapy for glioblastoma: a review of clinical trials and future directions. Cancer J 18(1):82–88PubMedCrossRefGoogle Scholar
  10. 10.
    Kostron H (2010) Photodynamic diagnosis and therapy and the brain. Methods Mol Biol 635:261–280PubMedCrossRefGoogle Scholar
  11. 11.
    Lee S-J, Kim S-J, Seo H-H, Shin S-P, Kim D, Park C-S, Kim K-T, Kim Y-H, Jeong J-S, Kim I-H (2012) Over-expression of miR-145 enhances the effectiveness of HSVtk gene therapy for malignant glioma. Cancer Lett 320(1):72–80PubMedCrossRefGoogle Scholar
  12. 12.
    Skalsky RL, Cullen BR (2011) Reduced expression of brain-enriched microRNAs in glioblastomas permits targeted regulation of a cell death gene. PLoS One 6(9):e24248PubMedCrossRefGoogle Scholar
  13. 13.
    Ohka F, Natsume A, Wakabayashi T (2012) Current trends in targeted therapies for glioblastoma multiforme. Neurol Res Int 2012:878425. doi: 10.1155/2012/878425 PubMedGoogle Scholar
  14. 14.
    Winter J, Jung S, Keller S, Gregory RI, Diederichs S (2009) Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol 11(3):228–234PubMedCrossRefGoogle Scholar
  15. 15.
    Yi R, Qin Y, Macara IG, Cullen BR (2003) Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev 17(24):3011–3016PubMedCrossRefGoogle Scholar
  16. 16.
    Kawamata T, Yoda M, Tomari Y (2011) Multilayer checkpoints for microRNA authenticity during RISC assembly. EMBO Rep 12(9):944–949PubMedCrossRefGoogle Scholar
  17. 17.
    Winter J, Diederichs S (2011) MicroRNA biogenesis and cancer. Methods Mol Biol 676:3–22PubMedCrossRefGoogle Scholar
  18. 18.
    Rana TM (2007) Illuminating the silence: understanding the structure and function of small RNAs. Nat Rev Mol Cell Biol 8(1):23–36PubMedCrossRefGoogle Scholar
  19. 19.
    Stoorvogel W (2012) Functional transfer of microRNA by exosomes. Blood 119(3):646–648PubMedCrossRefGoogle Scholar
  20. 20.
    Chen X, Liang H, Zhang J, Zen K, Zhang C-Y (2012) Horizontal transfer of microRNAs: molecular mechanisms and clinical applications. Protein Cell 3(1):28–37PubMedCrossRefGoogle Scholar
  21. 21.
    Chan JA, Krichevsky AM, Kosik KS (2005) MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res 65(14):6029–6033PubMedCrossRefGoogle Scholar
  22. 22.
    Ciafrè SA, Galardi S, Mangiola A, Ferracin M, Liu CG, Sabatino G, Negrini M, Maira G, Croce CM, Farace MG (2005) Extensive modulation of a set of microRNAs in primary glioblastoma. Biochem Biophys Res Commun 334(4):1351–1358PubMedCrossRefGoogle Scholar
  23. 23.
    Huse JT, Brennan C, Hambardzumyan D, Wee B, Pena J, Rouhanifard SH, Sohn-Lee C, le Sage C, Agami R, Tuschl T, Holland EC (2009) The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo. Genes Dev 23(11):1327–1337PubMedCrossRefGoogle Scholar
  24. 24.
    Rao SAM, Santosh V, Somasundaram K (2010) Genome-wide expression profiling identifies deregulated miRNAs in malignant astrocytoma. Mod Pathol 23(10):1404–1417PubMedCrossRefGoogle Scholar
  25. 25.
    Wuchty S, Arjona D, Li A, Kotliarov Y, Walling J, Ahn S, Zhang A, Maric D, Anolik R, Zenklusen JC, Fine HA (2011) Prediction of associations between microRNAs and gene expression in glioma biology. PLoS One 6(2):e14681PubMedCrossRefGoogle Scholar
  26. 26.
    Lavon I, Zrihan D, Granit A, Einstein O, Fainstein N, Cohen MA, Cohen MA, Zelikovitch B, Shoshan Y, Spektor S, Reubinoff BE, Felig Y, Gerlitz O, Ben-Hur T, Smith Y, Siegal T (2010) Gliomas display a microRNA expression profile reminiscent of neural precursor cells. Neuro-Oncology 12(5):422–433PubMedGoogle Scholar
  27. 27.
    Silber J, Lim DA, Petritsch C, Persson AI, Maunakea AK, Yu M, Vandenberg SR, Ginzinger DG, James CD, Costello JF, Bergers G, Weiss WA, Alvarez-Buylla A, Hodgson JG (2008) miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med 6:14PubMedCrossRefGoogle Scholar
  28. 28.
    Sasayama T, Nishihara M, Kondoh T, Hosoda K, Kohmura E (2009) MicroRNA-10b is overexpressed in malignant glioma and associated with tumor invasive factors, uPAR and RhoC. Int J Cancer 125(6):1407–1413PubMedCrossRefGoogle Scholar
  29. 29.
    Sun L, Yan W, Wang Y, Sun G, Luo H, Zhang J, Wang X, You Y, Yang Z, Liu N (2011) MicroRNA-10b induces glioma cell invasion by modulating MMP-14 and uPAR expression via HOXD10. Brain Res 1389:9–18PubMedCrossRefGoogle Scholar
  30. 30.
    Malzkorn B, Wolter M, Liesenberg F, Grzendowski M, Stühler K, Meyer HE, Reifenberger G (2010) Identification and functional characterization of microRNAs involved in the malignant progression of gliomas. Brain Pathol 20(3):539–550PubMedCrossRefGoogle Scholar
  31. 31.
    Lages E, Guttin A, Atifi El M, Ramus C, Ipas H, Dupré I, Rolland D, Salon C, Godfraind C, deFraipont F, Dhobb M, Pelletier L, Wion D, Gay E, Berger F, Issartel J-P (2011) MicroRNA and target protein patterns reveal physiopathological features of glioma subtypes. PLoS One 6(5):e20600PubMedCrossRefGoogle Scholar
  32. 32.
    Schraivogel D, Weinmann L, Beier D, Tabatabai G, Eichner A, Zhu JY, Anton M, Sixt M, Weller M, Beier CP, Meister G (2011) CAMTA1 is a novel tumour suppressor regulated by miR-9/9* in glioblastoma stem cells. EMBO J 30(20):4309–4322PubMedCrossRefGoogle Scholar
  33. 33.
    Dews M, Fox JL, Hultine S, Sundaram P, Wang W, Liu YY, Furth E, Enders GH, El-Deiry W, Schelter JM, Cleary MA, Thomas-Tikhonenko A (2010) The myc-miR-17 92 axis blunts TGF{beta} signaling and production of multiple TGF{beta}-dependent antiangiogenic factors. Cancer Res 70(20):8233–8246PubMedCrossRefGoogle Scholar
  34. 34.
    Ernst A, Campos B, Meier J, Devens F, Liesenberg F, Wolter M, Reifenberger G, Herold-Mende C, Lichter P, Radlwimmer B (2010) De-repression of CTGF via the miR-17-92 cluster upon differentiation of human glioblastoma spheroid cultures. Oncogene 29(23):3411–3422PubMedCrossRefGoogle Scholar
  35. 35.
    Zhou X, Ren Y, Moore L, Mei M, You Y, Xu P, Wang B, Wang G, Jia Z, Pu P, Zhang W, Kang C (2010) Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status. Lab Invest 90(2):144–155PubMedCrossRefGoogle Scholar
  36. 36.
    Dong H, Luo L, Hong S, Siu H, Xiao Y, Jin L, Chen R, Xiong M (2010) Integrated analysis of mutations, miRNA and mRNA expression in glioblastoma. BMC Syst Biol 4:163PubMedCrossRefGoogle Scholar
  37. 37.
    Li D, Chen P, Li X-Y, Zhang L-Y, Xiong W, Zhou M, Xiao L, Zeng F, Li X-L, Wu M-H, Li G-Y (2011) Grade-specific expression profiles of miRNAs/mRNAs and docking study in human grade I-III astrocytomas. OMICS 15(10):673–682PubMedCrossRefGoogle Scholar
  38. 38.
    Gabriely G, Würdinger T, Kesari S, Esau CC, Burchard J, Linsley PS, Krichevsky AM (2008) MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators. Mol Cell Biol 28(17):5369–5380PubMedCrossRefGoogle Scholar
  39. 39.
    Schramedei K, Mörbt N, Pfeifer G, Läuter J, Rosolowski M, Tomm JM, von Bergen M, Horn F, Brocke-Heidrich K (2011) MicroRNA-21 targets tumor suppressor genes ANP32A and SMARCA4. Oncogene 30(26):2975–2985PubMedCrossRefGoogle Scholar
  40. 40.
    Zhou X, Zhang J, Jia Q, Ren Y, Wang Y, Shi L, Liu N, Wang G, Pu P, You Y, Kang C (2010) Reduction of miR-21 induces glioma cell apoptosis via activating caspase 9 and 3. Oncol Rep 24(1):195–201PubMedGoogle Scholar
  41. 41.
    Li Y, Zhao S, Zhen Y, Li Q, Teng L, Asai A, Kawamoto K (2011) A miR-21 inhibitor enhances apoptosis and reduces G(2)-M accumulation induced by ionizing radiation in human glioblastoma U251 cells. Brain Tumor Pathol 28(3):209–214PubMedCrossRefGoogle Scholar
  42. 42.
    Papagiannakopoulos T, Shapiro A, Kosik KS (2008) MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Res 68(19):8164–8172PubMedCrossRefGoogle Scholar
  43. 43.
    Corsten MF, Miranda R, Kasmieh R, Krichevsky AM, Weissleder R, Shah K (2007) MicroRNA-21 knockdown disrupts glioma growth in vivo and displays synergistic cytotoxicity with neural precursor cell delivered S-TRAIL in human gliomas. Cancer Res 67(19):8994–9000PubMedCrossRefGoogle Scholar
  44. 44.
    Shi L, Chen J, Yang J, Pan T, Zhang S, Wang Z (2010) MiR-21 protected human glioblastoma U87MG cells from chemotherapeutic drug temozolomide induced apoptosis by decreasing Bax/Bcl-2 ratio and caspase-3 activity. Brain Res 1352:255–264PubMedCrossRefGoogle Scholar
  45. 45.
    Zhi F, Chen X, Wang S, Xia X, Shi Y, Guan W, Shao N, Qu H, Yang C, Zhang Y, Wang Q, Wang R, Zen K, Zhang C-Y, Zhang J, Yang Y (2010) The use of hsa-miR-21, hsa-miR-181b and hsa-miR-106a as prognostic indicators of astrocytoma. Eur J Cancer 46(9):1640–1649PubMedCrossRefGoogle Scholar
  46. 46.
    Kwak H-J, Kim Y-J, Chun K-R, Woo YM, Park S-J, Jeong J-A, Jo SH, Kim TH, Min HS, Chae JS, Choi E-J, Kim G, Shin S-H, Gwak H-S, Kim S-K, Hong E-K, Lee G-K, Choi K-H, Kim JH, Yoo H, Park JB, Lee S-H (2011) Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas. Oncogene 30(21):2433–2442PubMedCrossRefGoogle Scholar
  47. 47.
    Ren Y, Zhou X, Mei M, Yuan X-B, Han L, Wang GX, Jia Z-F, Xu P, Pu P-Y, Kang C-S (2010) MicroRNA-21 inhibitor sensitizes human glioblastoma cells U251 (PTEN-mutant) and LN229 (PTEN-wild type) to taxol. BMC Cancer 10:27PubMedCrossRefGoogle Scholar
  48. 48.
    Ren Y, Kang C-S, Yuan X-B, Zhou X, Xu P, Han L, Wang GX, Jia Z, Zhong Y, Yu S, Sheng J, Pu P-Y (2010) Co-delivery of as-miR-21 and 5-FU by poly(amidoamine) dendrimer attenuates human glioma cell growth in vitro. J Biomater Sci Polym Ed 21(3):303–314PubMedCrossRefGoogle Scholar
  49. 49.
    Chaudhry MA, Sachdeva H, Omaruddin RA (2010) Radiation-induced micro-RNA modulation in glioblastoma cells differing in DNA-repair pathways. DNA Cell Biol 29(9):553–561PubMedCrossRefGoogle Scholar
  50. 50.
    Li Y, Li W, Yang Y, Lu Y, He C, Hu G, Liu H, Chen J, He J, Yu H (2009) MicroRNA-21 targets LRRFIP1 and contributes to VM-26 resistance in glioblastoma multiforme. Brain Res 1286:13–18PubMedCrossRefGoogle Scholar
  51. 51.
    Gaur AB, Holbeck SL, Colburn NH, Israel MA (2011) Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo. Neuro-Oncology 13(6):580–590PubMedCrossRefGoogle Scholar
  52. 52.
    Zhang C, Han L, Zhang A, Yang W, Zhou X, Pu P, Du Y, Zeng H, Kang C (2010) Global changes of mRNA expression reveals an increased activity of the interferon-induced signal transducer and activator of transcription (STAT) pathway by repression of miR-221/222 in glioblastoma U251 cells. Int J Oncol 36(6):1503–1512PubMedGoogle Scholar
  53. 53.
    Conti A, Aguennouz M, La Torre D, Tomasello C, Cardali S, Angileri FF, Maio F, Cama A, Germanò A, Vita G, Tomasello F (2009) miR-21 and 221 upregulation and miR-181b downregulation in human grade II-IV astrocytic tumors. J Neurooncol 93(3):325–332PubMedCrossRefGoogle Scholar
  54. 54.
    Guan Y, Mizoguchi M, Yoshimoto K, Hata N, Shono T, Suzuki SO, Araki Y, Kuga D, Nakamizo A, Amano T, Ma X, Hayashi K, Sasaki T (2010) MiRNA-196 is upregulated in glioblastoma but not in anaplastic astrocytoma and has prognostic significance. Clin Cancer Res 16(16):4289–4297PubMedCrossRefGoogle Scholar
  55. 55.
    Lakomy R, Sana J, Hankeova S, Fadrus P, Kren L, Lzicarova E, Svoboda M, Dolezelova H, Smrcka M, Vyzula R, Michalek J, Hajduch M, Slaby O (2011) MiR-195, miR-196b, miR-181c, miR-21 expression levels and O-6-methylguanine-DNA methyltransferase methylation status are associated with clinical outcome in glioblastoma patients. Cancer Sci 102(12):2186–2190PubMedCrossRefGoogle Scholar
  56. 56.
    Fang L, Deng Z, Shatseva T, Yang J, Peng C, Du WW, Yee AJ, Ang LC, He C, Shan SW, Yang BB (2011) MicroRNA miR-93 promotes tumor growth and angiogenesis by targeting integrin-β8. Oncogene 30(7):806–821PubMedCrossRefGoogle Scholar
  57. 57.
    Dong H, Siu H, Luo L, Fang X, Jin L, Xiong M (2010) Investigation gene and microRNA expression in glioblastoma. BMC Genomics 11(Suppl 3):S16PubMedCrossRefGoogle Scholar
  58. 58.
    Silber J, James CD, Hodgson JG (2009) microRNAs in gliomas: small regulators of a big problem. Neuromol Med 11(3):208–222CrossRefGoogle Scholar
  59. 59.
    Shu M, Zheng X, Wu S, Lu H, Leng T, Zhu W, Zhou Y, Ou Y, Lin X, Lin Y, Xu D, Zhou Y, Yan G (2011) Targeting oncogenic miR-335 inhibits growth and invasion of malignant astrocytoma cells. Mol Cancer 10:59PubMedCrossRefGoogle Scholar
  60. 60.
    Tang H, Liu X, Wang Z, She X, Zeng X, Deng M, Liao Q, Guo X, Wang R, Li X, Zeng F, Wu M, Li G (2011) Interaction of hsa-miR-381 and glioma suppressor LRRC4 is involved in glioma growth. Brain Res 1390:21–32PubMedCrossRefGoogle Scholar
  61. 61.
    Shu M, Zhou Y, Zhu W, Zhang H, Wu S, Chen J, Yan G (2012) MicroRNA 335 is required for differentiation of malignant glioma cells induced by activation of cAMP/protein kinase A pathway. Mol Pharmacol 81(3):292–298PubMedCrossRefGoogle Scholar
  62. 62.
    Leber MF, Bossow S, Leonard VHJ, Zaoui K, Grossardt C, Frenzke M, Miest T, Sawall S, Cattaneo R, von Kalle C, Ungerechts G (2011) MicroRNA-sensitive oncolytic measles viruses for cancer-specific vector tropism. Mol Ther 19(6):1097–1106PubMedCrossRefGoogle Scholar
  63. 63.
    Wu D-G, Wang Y-Y, Fan L-G, Luo H, Han B, Sun L-H, Wang X-F, Zhang J-X, Cao L, Wang X-R, You Y-P, Liu N (2011) MicroRNA-7 regulates glioblastoma cell invasion via targeting focal adhesion kinase expression. Chin Med J 124(17):2616–2621PubMedGoogle Scholar
  64. 64.
    Lu ZJ, Liu SY, Yao YQ, Zhou YJ, Zhang S, Dai L, Tian HW, Zhou Y, Deng HX, Yang JL, Luo F (2011) The effect of miR-7 on behavior and global protein expression in glioma cell lines. Electrophoresis 32(24):3612–3620PubMedCrossRefGoogle Scholar
  65. 65.
    Kefas B, Godlewski J, Comeau L, Li Y, Abounader R, Hawkinson M, Lee J, Fine H, Chiocca EA, Lawler S, Purow B (2008) microRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma. Cancer Res 68(10):3566–3572PubMedCrossRefGoogle Scholar
  66. 66.
    Parsons DW, Jones S, Zhang X, Lin JC-H, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu I-M, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA, Hartigan J, Smith DR, Strausberg RL, Marie SKN, Shinjo SMO, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321(5897):1807–1812PubMedCrossRefGoogle Scholar
  67. 67.
    Li Y, Guessous F, Zhang Y, Dipierro C, Kefas B, Johnson E, Marcinkiewicz L, Jiang J, Yang Y, Schmittgen TD, Lopes B, Schiff D, Purow B, Abounader R (2009) MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Res 69(19):7569–7576PubMedCrossRefGoogle Scholar
  68. 68.
    Guessous F, Zhang Y, Kofman A, Catania A, Li Y, Schiff D, Purow B, Abounader R (2010) microRNA-34a is tumor suppressive in brain tumors and glioma stem cells. Cell Cycle 9(6):1031–1036PubMedCrossRefGoogle Scholar
  69. 69.
    Luan S, Sun L, Huang F (2010) MicroRNA-34a: a novel tumor suppressor in p53-mutant glioma cell line U251. Arch Med Res 41(2):67–74PubMedCrossRefGoogle Scholar
  70. 70.
    Silber J, Jacobsen A, Ozawa T, Harinath G, Pedraza A, Sander C, Holland EC, Huse JT (2012) miR-34a repression in proneural malignant gliomas upregulates expression of its target PDGFRA and Promotes tumorigenesis. PLoS One 7(3):e33844PubMedCrossRefGoogle Scholar
  71. 71.
    Vo DT, Qiao M, Smith AD, Burns SC, Brenner AJ and Penalva LOF (2011) The oncogenic RNA-binding protein Musashi1 is regulated by tumor suppressor miRNAs. RNA Biol 8(5)Google Scholar
  72. 72.
    Shi Z-M, Wang J, Yan Z, You Y-P, Li C-Y, Qian X, Yin Y, Zhao P, Wang Y-Y, Wang X-F, Li M-N, Liu L-Z, Liu N, Jiang B-H (2012) MiR-128 inhibits tumor growth and angiogenesis by targeting p70S6K1. PLoS One 7(3):e32709PubMedCrossRefGoogle Scholar
  73. 73.
    Cui JG, Zhao Y, Sethi P, Li YY, Mahta A, Culicchia F, Lukiw WJ (2010) Micro-RNA-128 (miRNA-128) down-regulation in glioblastoma targets ARP5 (ANGPTL6), Bmi-1 and E2F-3a, key regulators of brain cell proliferation. J Neurooncol 98(3):297–304PubMedCrossRefGoogle Scholar
  74. 74.
    Zhang Y, Chao T, Li R, Liu W, Chen Y, Yan X, Gong Y, Yin B, Liu W, Qiang B, Zhao J, Yuan J, Peng X (2009) MicroRNA-128 inhibits glioma cells proliferation by targeting transcription factor E2F3a. J Mol Med 87(1):43–51PubMedCrossRefGoogle Scholar
  75. 75.
    Godlewski J, Nowicki MO, Bronisz A, Williams S, Otsuki A, Nuovo G, Raychaudhury A, Newton HB, Chiocca EA, Lawler S (2008) Targeting of the Bmi-1 oncogene/stem cell renewal factor by microRNA-128 inhibits glioma proliferation and self-renewal. Cancer Res 68(22):9125–9130PubMedCrossRefGoogle Scholar
  76. 76.
    Papagiannakopoulos T, Friedmann-Morvinski D, Neveu P, Dugas JC, Gill RM, Huillard E, Liu C, Zong H, Rowitch DH, Barres BA, Verma IM, Kosik KS (2012) Pro-neural miR-128 is a glioma tumor suppressor that targets mitogenic kinases. Oncogene 31(15):1884–1895PubMedCrossRefGoogle Scholar
  77. 77.
    Chen L, Wang X, Wang H, Li Y, Yan W, Han L, Zhang K, Zhang J, Wang Y, Feng Y, Pu P, Jiang T, Kang C and Jiang C (2012) miR-137 is frequently down-regulated in glioblastoma and is a negative regulator of Cox-2. Eur J CancerGoogle Scholar
  78. 78.
    Suh S-S, Yoo JY, Nuovo GJ, Jeon Y-J, Kim S, Lee TJ, Kim T, Bakàcs A, Alder H, Kaur B, Aqeilan RI, Pichiorri F, Croce CM (2012) MicroRNAs/TP53 feedback circuitry in glioblastoma multiforme. Proc Natl Acad Sci U S A 109(14):5316–5321PubMedCrossRefGoogle Scholar
  79. 79.
    Smits M, Nilsson J, Mir SE, van der Stoop PM, Hulleman E, Niers JM, de Witt Hamer PC, Marquez VE, Cloos J, Krichevsky AM, Noske DP, Tannous BA, Würdinger T (2010) miR-101 is down-regulated in glioblastoma resulting in EZH2-induced proliferation, migration, and angiogenesis. Oncotarget 1(8):710–720PubMedGoogle Scholar
  80. 80.
    Kefas B, Comeau L, Floyd DH, Seleverstov O, Godlewski J, Schmittgen T, Jiang J, diPierro CG, Li Y, Chiocca EA, Lee J, Fine H, Abounader R, Lawler S, Purow B (2009) The neuronal microRNA miR-326 acts in a feedback loop with notch and has therapeutic potential against brain tumors. J Neurosci 29(48):15161–15168PubMedCrossRefGoogle Scholar
  81. 81.
    Kefas B, Comeau L, Erdle N, Montgomery E, Amos S, Purow B (2010) Pyruvate kinase M2 is a target of the tumor-suppressive microRNA-326 and regulates the survival of glioma cells. Neuro-Oncology 12(11):1102–1112PubMedCrossRefGoogle Scholar
  82. 82.
    Yan W, Zhang W, Sun L, Liu Y, You G, Wang Y, Kang C, You Y, Jiang T (2011) Identification of MMP-9 specific microRNA expression profile as potential targets of anti-invasion therapy in glioblastoma multiforme. Brain Res 1411:108–115PubMedGoogle Scholar
  83. 83.
    Wang L, Shi M, Hou S, Ding B, Liu L, Ji X, Zhang J and Deng Y (2012) MiR-483-5p suppresses the proliferation of glioma cells via directly targeting ERK1. FEBS LettGoogle Scholar
  84. 84.
    Seidel S, Garvalov BK, Wirta V, von Stechow L, Schänzer A, Meletis K, Wolter M, Sommerlad D, Henze A-T, Nistér M, Reifenberger G, Lundeberg J, Frisén J, Acker T (2010) A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha. Brain 133(Pt 4):983–995PubMedCrossRefGoogle Scholar
  85. 85.
    Lu P, Weaver VM, Werb Z (2012) The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol 196(4):395–406PubMedCrossRefGoogle Scholar
  86. 86.
    Yang Y-P, Chien Y, Chiou G-Y, Cherng J-Y, Wang M-L, Lo W-L, Chang Y-L, Huang P-I, Chen Y-W, Shih Y-H, Chen M-T, Chiou S-H (2012) Inhibition of cancer stem cell-like properties and reduced chemoradioresistance of glioblastoma using microRNA145 with cationic polyurethane-short branch PEI. Biomaterials 33(5):1462–1476PubMedCrossRefGoogle Scholar
  87. 87.
    Gal H, Pandi G, Kanner AA, Ram Z, Lithwick-Yanai G, Amariglio N, Rechavi G, Givol D (2008) MIR-451 and Imatinib mesylate inhibit tumor growth of Glioblastoma stem cells. Biochem Biophys Res Commun 376(1):86–90PubMedCrossRefGoogle Scholar
  88. 88.
    Nan Y, Han L, Zhang A, Wang G, Jia Z, Yang Y, Yue X, Pu P, Zhong Y, Kang C (2010) MiRNA-451 plays a role as tumor suppressor in human glioma cells. Brain Res 1359:14–21PubMedCrossRefGoogle Scholar
  89. 89.
    Godlewski J, Nowicki MO, Bronisz A, Nuovo G, Palatini J, De Lay M, Van Brocklyn J, Ostrowski MC, Chiocca EA, Lawler SE (2010) MicroRNA-451 regulates LKB1/AMPK signaling and allows adaptation to metabolic stress in glioma cells. Mol Cell 37(5):620–632PubMedCrossRefGoogle Scholar
  90. 90.
    Godlewski J, Bronisz A, Nowicki MO, Chiocca EA, Lawler S (2010) microRNA-451: A conditional switch controlling glioma cell proliferation and migration. Cell Cycle 9(14):2742–2748PubMedCrossRefGoogle Scholar
  91. 91.
    Godlewski J, Newton HB, Chiocca EA, Lawler SE (2010) MicroRNAs and glioblastoma; the stem cell connection. Cell Death Differ 17(2):221–228PubMedCrossRefGoogle Scholar
  92. 92.
    Nieto MA and Cano A (2012) The epithelial-mesenchymal transition under control: Global programs to regulate epithelial plasticity. Semin Cancer BiolGoogle Scholar
  93. 93.
    Bracken CP, Gregory PA, Khew-Goodall Y, Goodall GJ (2009) The role of microRNAs in metastasis and epithelial-mesenchymal transition. Cell Mol Life Sci 66(10):1682–1699PubMedCrossRefGoogle Scholar
  94. 94.
    Jin X, Jeon H-Y, Joo KM, Kim J-K, Jin J, Kim SH, Kang BG, Beck S, Lee SJ, Kim JK, Park A-K, Park W-Y, Choi Y-J, Nam D-H, Kim H (2011) Frizzled 4 regulates stemness and invasiveness of migrating glioma cells established by serial intracranial transplantation. Cancer Res 71(8):3066–3075PubMedCrossRefGoogle Scholar
  95. 95.
    Mikheeva SA, Mikheev AM, Petit A, Beyer R, Oxford RG, Khorasani L, Maxwell J-P, Glackin CA, Wakimoto H, González-Herrero I, Sánchez-García I, Silber JR, Horner PJ, Rostomily RC (2010) TWIST1 promotes invasion through mesenchymal change in human glioblastoma. Mol Cancer 9:194PubMedCrossRefGoogle Scholar
  96. 96.
    Jiang L, Lin C, Song L, Wu J, Chen B, Ying Z, Fang L, Yan X, He M, Li J, Li M (2012) MicroRNA-30e* promotes human glioma cell invasiveness in an orthotopic xenotransplantation model by disrupting the NF-κB/IκBα negative feedback loop. J Clin Invest 122(1):33–47PubMedCrossRefGoogle Scholar
  97. 97.
    Wan Y, Fei X-F, Wang Z-M, Jiang D-Y, Chen H-C, Yang J, Shi L and Huang Q (2012) Expression of miRNA-125b in the new, highly invasive glioma stem cell and progenitor cell line SU3. Chin J CancerGoogle Scholar
  98. 98.
    Zhang J, Han L, Ge Y, Zhou X, Zhang A, Zhang C, Zhong Y, You Y, Pu P, Kang C (2010) miR-221/222 promote malignant progression of glioma through activation of the Akt pathway. Int J Oncol 36(4):913–920PubMedGoogle Scholar
  99. 99.
    Yue X, Wang P, Xu J, Zhu Y, Sun G, Pang Q, Tao R (2012) MicroRNA-205 functions as a tumor suppressor in human glioblastoma cells by targeting VEGF-A. Oncol Rep 27(4):1200–1206PubMedGoogle Scholar
  100. 100.
    Xia H, Qi Y, Ng SS, Chen X, Chen S, Fang M, Li D, Zhao Y, Ge R, Li G, Chen Y, He M-L, Kung H-F, Lai L, Lin MC (2009) MicroRNA-15b regulates cell cycle progression by targeting cyclins in glioma cells. Biochem Biophys Res Commun 380(2):205–210PubMedCrossRefGoogle Scholar
  101. 101.
    Birks DK, Barton VN, Donson AM, Handler MH, Vibhakar R, Foreman NK (2011) Survey of MicroRNA expression in pediatric brain tumors. Pediatr Blood Cancer 56(2):211–216PubMedCrossRefGoogle Scholar
  102. 102.
    Xia H-F, He T-Z, Liu C-M, Cui Y, Song P-P, Jin X-H, Ma X (2009) MiR-125b expression affects the proliferation and apoptosis of human glioma cells by targeting Bmf. Cell Physiol Biochem 23(4–6):347–358PubMedCrossRefGoogle Scholar
  103. 103.
    Shi L, Zhang J, Pan T, Zhou J, Gong W, Liu N, Fu Z, You Y (2010) MiR-125b is critical for the suppression of human U251 glioma stem cell proliferation. Brain Res 1312:120–126PubMedCrossRefGoogle Scholar
  104. 104.
    Mei J, Bachoo R, Zhang C-L (2011) MicroRNA-146a inhibits glioma development by targeting Notch1. Cell Mol Biol 31(17):3584–3592CrossRefGoogle Scholar
  105. 105.
    Meng W, Jiang L, Lu L, Hu H, Yu H, Ding D, Xiao K, Zheng W, Guo H and Ma W (2012) Anti-miR-155 oligonucleotide enhances chemosensitivity of U251 cell to taxol by inducing apoptosis. Cell Biol IntGoogle Scholar
  106. 106.
    Jiang L, Mao P, Song L, Wu J, Huang J, Lin C, Yuan J, Qu L, Cheng S-Y, Li J (2010) miR-182 as a prognostic marker for glioma progression and patient survival. Am J Pathol 177(1):29–38PubMedCrossRefGoogle Scholar
  107. 107.
    Wu N, Zhao X, Liu M, Liu H, Yao W, Zhang Y, Cao S, Lin X (2011) Role of microRNA-26b in glioma development and its mediated regulation on EphA2. PLoS One 6(1):e16264PubMedCrossRefGoogle Scholar
  108. 108.
    Lu X, Zhao P, Zhang C, Fu Z, Chen Y, Lu A, Liu N, You Y, Pu P, Kang C (2009) Analysis of miR-221 and p27 expression in human gliomas. Mol Med Rep 2(4):651–656Google Scholar
  109. 109.
    Zhang C-Z, Zhang J-X, Zhang A-L, Shi Z-D, Han L, Jia Z-F, Yang W-D, Wang GX, Jiang T, You Y-P, Pu P-Y, Cheng J-Q, Kang C-S (2010) MiR-221 and miR-222 target PUMA to induce cell survival in glioblastoma. Mol Cancer 9:229PubMedCrossRefGoogle Scholar
  110. 110.
    Lukiw WJ, Cui JG, Li YY, Culicchia F (2008) Up-regulation of micro-RNA-221 (miRNA-221; chr Xp11.3) and caspase-3 accompanies down-regulation of the survivin-1 homolog BIRC1 (NAIP) in glioblastoma multiforme (GBM). J Neurooncol 91(1):27–32PubMedCrossRefGoogle Scholar
  111. 111.
    Medina R, Zaidi SK, Liu C-G, Stein JL, van Wijnen AJ, Croce CM, Stein GS (2008) MicroRNAs 221 and 222 bypass quiescence and compromise cell survival. Cancer Res 68(8):2773–2780PubMedCrossRefGoogle Scholar
  112. 112.
    Quintavalle C, Garofalo M, Zanca C, Romano G, Iaboni M, del Basso De Caro M, Martinez-Montero JC, Incoronato M, Nuovo G, Croce CM, Condorelli G (2011) miR-221/222 overexpession in human glioblastoma increases invasiveness by targeting the protein phosphate PTPμ. Oncogene 31(7):858–868PubMedCrossRefGoogle Scholar
  113. 113.
    Wang X, Han L, Zhang A, Wang G, Jia Z, Yang Y, Yue X, Pu P, Shen C, Kang C (2011) Adenovirus-mediated shRNAs for co-repression of miR-221 and miR-222 expression and function in glioblastoma cells. Oncol Rep 25(1):97–105PubMedGoogle Scholar
  114. 114.
    Cortez MA, Nicoloso MS, Shimizu M, Rossi S, Gopisetty G, Molina JR, Carlotti C, Tirapelli D, Neder L, Brassesco MS, Scrideli CA, Tone LG, Georgescu M-M, Zhang W, Puduvalli V, Calin GA (2010) miR-29b and miR-125a regulate podoplanin and suppress invasion in glioblastoma. Genes Chromosom Cancer 49(11):981–990PubMedCrossRefGoogle Scholar
  115. 115.
    Ng WL, Yan D, Zhang X, Mo Y-Y, Wang Y (2010) Over-expression of miR-100 is responsible for the low-expression of ATM in the human glioma cell line: M059J. DNA Repair (Amst) 9(11):1170–1175CrossRefGoogle Scholar
  116. 116.
    Fowler A, Thomson D, Giles K, Maleki S, Mreich E, Wheeler H, Leedman P, Biggs M, Cook R, Little N, Robinson B, McDonald K (2011) miR-124a is frequently down-regulated in glioblastoma and is involved in migration and invasion. Eur J Cancer 47(6):953–963PubMedCrossRefGoogle Scholar
  117. 117.
    Xia H, Cheung WKC, Ng SS, Jiang X, Jiang S, Sze J, Leung GKK, Lu G, Chan DTM, Bian X-W, Kung H-F, Poon WS, Lin MC (2012) Loss of Brain-enriched miR-124 MicroRNA enhances stem-like traits and invasiveness of glioma cells. J Biol Chem 287(13):9962–9971PubMedCrossRefGoogle Scholar
  118. 118.
    Wu S, Lin Y, Xu D, Chen J, Shu M, Zhou Y, Zhu W, Su X, Zhou Y, Qiu P and Yan G (2011) MiR-135a functions as a selective killer of malignant glioma. OncogeneGoogle Scholar
  119. 119.
    Katakowski M, Zheng X, Jiang F, Rogers T, Szalad A, Chopp M (2010) MiR-146b-5p suppresses EGFR expression and reduces in vitro migration and invasion of glioma. Cancer Invest 28(10):1024–1030PubMedCrossRefGoogle Scholar
  120. 120.
    Xu J, Liao X, Wong C (2010) Downregulations of B-cell lymphoma 2 and myeloid cell leukemia sequence 1 by microRNA 153 induce apoptosis in a glioblastoma cell line DBTRG-05MG. Int J Cancer 126(4):1029–1035PubMedGoogle Scholar
  121. 121.
    Slaby O, Lakomy R, Fadrus P, Hrstka R, Kren L, Lzicarova E, Smrcka M, Svoboda M, Dolezalova H, Novakova J, Valik D, Vyzula R, Michalek J (2010) MicroRNA-181 family predicts response to concomitant chemoradiotherapy with temozolomide in glioblastoma patients. Neoplasma 57(3):264–269PubMedCrossRefGoogle Scholar
  122. 122.
    Chen G, Zhu W, Shi D, Lv L, Zhang C, Liu P, Hu W (2010) MicroRNA-181a sensitizes human malignant glioma U87MG cells to radiation by targeting Bcl-2. Oncol Rep 23(4):997–1003PubMedGoogle Scholar
  123. 123.
    Wang X-F, Shi Z-M, Wang X-R, Cao L, Wang Y-Y, Zhang J-X, Yin Y, Luo H, Kang C-S, Liu N, Jiang T, You Y-P (2012) MiR-181d acts as a tumor suppressor in glioma by targeting K-ras and Bcl-2. J Cancer Res Clin Oncol 138(4):573–584PubMedCrossRefGoogle Scholar
  124. 124.
    Zhang Z, Tang H, Wang Z, Zhang B, Liu W, Lu H, Xiao L, Liu X, Wang R, Li X, Wu M, Li G (2011) MiR-185 targets the DNA methyltransferases 1 and regulates global DNA methylation in human glioma. Mol Cancer 10:124PubMedCrossRefGoogle Scholar
  125. 125.
    Song L, Huang Q, Chen K, Liu L, Lin C, Dai T, Yu C, Wu Z, Li J (2010) miR-218 inhibits the invasive ability of glioma cells by direct downregulation of IKK-β. Biochem Biophys Res Commun 402(1):135–140PubMedCrossRefGoogle Scholar
  126. 126.
    Chen L, Li H, Han L, Zhang K, Wang G, Wang Y, Liu Y, Zheng Y, Jiang T, Pu P, Jiang C, Kang C (2011) Expression and function of miR-27b in human glioma. Oncol Rep 26(6):1617–1621PubMedGoogle Scholar
  127. 127.
    Yang G, Zhang R, Chen X, Mu Y, Ai J, Shi C, Liu Y, Shi C, Sun L, Rainov NG, Li H, Yang B, Zhao S (2011) MiR-106a inhibits glioma cell growth by targeting E2F1 independent of p53 status. J Mol Med 89(10):1037–1050PubMedCrossRefGoogle Scholar

Copyright information

© The Author(s) 2012

Authors and Affiliations

  • Heidi G. Møller
    • 1
  • Andreas P. Rasmussen
    • 1
  • Hjalte H. Andersen
    • 1
  • Kasper B. Johnsen
    • 1
  • Michael Henriksen
    • 1
  • Meg Duroux
    • 1
  1. 1.Department of Biomedicine, Institute for Medicine and Health TechnologyAalborg UniversityAalborg ØstDenmark

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