• Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
REVIEW
Year : 2015  |  Volume : 1  |  Issue : 2  |  Page : 50-66

Systematic Review of MicroRNAs and its Therapeutic Potential in Glioma


1 Department of Experimental Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China
2 Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

Date of Submission09-Mar-2015
Date of Acceptance31-Mar-2015
Date of Web Publication28-Apr-2015

Correspondence Address:
Prof. Yanyang Tu
Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
USA
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2395-3977.155924

Rights and Permissions
  Abstract 

MicroRNAs (miRNAs) are short noncoding RNAs. The discovery of miRNA has provided a novel tool to the research of tumor pathogenesis, and a new strategy to the diagnosis and prognosis of human cancers. Currently, numerous studies have indicated that the deregulation of miRNAs in glioma is closely related to glioma pathogenesis and progress. miRNAs function as key regulators of glioma through negative control of the target gene expression, by targeting the 3'-untranslated region of its messenger RNA which regulate the cell proliferation, apoptosis and prognosis of glioma. Moreover, radiation and chemotherapy resistance in glioma therapy is also caused by deregulation of miRNAs. It has been suggested that miRNAs act as tumor suppressors or oncogenes in glioma. Not only can miRNAs be used as biomarkers of glioma diagnosis and therapy, but also as novel targets of glioma gene therapy.

Keywords: Glioma, microRNAs, molecular therapy


How to cite this article:
Liu N, Tu Y. Systematic Review of MicroRNAs and its Therapeutic Potential in Glioma. Cancer Transl Med 2015;1:50-66

How to cite this URL:
Liu N, Tu Y. Systematic Review of MicroRNAs and its Therapeutic Potential in Glioma. Cancer Transl Med [serial online] 2015 [cited 2019 Jul 23];1:50-66. Available from: http://www.cancertm.com/text.asp?2015/1/2/50/155924


  Introduction Top


Glioma is the most frequent and malignant brain tumor, accounting for 78% of intracranial primary tumors. [1] It originates from neural mesenchymal cells (i.e., glial cells, ependyma, and choroid plexus epithelial cells) and neural parenchymal cells (neurons); it can be classified as astrocytoma, glioblastoma, medulloblastoma (MB), ependymoma, and oligodendroglioma according to its origin. [2] Glioma is classified into five grades (I-IV) according to the World Health Organization (WHO), and each grade includes a variety of pathological subtypes. [3] Due to its invasive nature, rich blood supply and infiltrating growth, traditional treatments such as surgical techniques and radiotherapy, still obtain a poor prognosis. [4],[5],[6],[7],[8]

Although there are a series of comprehensive treatment measures for glioma, the mortality of malignant glioma remains high; median survival since diagnosis is < 14 months. [9],[10] Astrocytoma is divided into low-grade glioma (WHO I-II) and high-grade glioma (WHO III-IV). [11] The average survival of the low-grade glioma reaches 6-10 years, but for high-grade glioma, the average survival has been reported to reach only 12-15 months to 30-36 months. [12],[13] The situation of glioblastoma multiforme (GBM) is extremely serious, and the prognosis is prominently poor. Due to its highly invasive nature, surgery is often not effective, and because of its resistance to radiation and chemotherapy, GBM has a high relapse rate and is difficult to cure. [14],[15],[16] At present, treatment of GMB includes radiotherapy after surgical resection, followed by temozolomide (TMZ) as adjunctive therapy, then synchronous chemotherapy, again followed by TMZ cycles of chemotherapy. [17],[18] Because of GBM's high radiation and chemotherapy resistance, the 2-year survival rate is only 30% and 5-year survival rate is 9.8%. [19]

Today, the application of MicroRNAs (miRNAs) treatment for glioma has attracted researchers' attention. Theoretically, miRNA can prevent the occurrence of glioma at the molecular level, and greatly improve survival. For example, a knock down study of miR-21 in glioblastoma cell lines led to decreased cell growth, reduced invasiveness, enhanced cell apoptosis, and suppressed tumorgenicity. The research showed that after decreasing the expression of miR-21, the tumor cell activity clearly decreased, and could partially inhibit U373 malignant gliomas (MG) cells tolerance to VM-26. [20],[21],[22] This experiment also suggested that miR-21 down regulation could increase chemotherapy sensitivity of cancer cells, which provides a novel tool to develop a new antitumor therapies.

Although the research of miRNAs in gliomas is still at the initial stage, with the establishment and improvement of the specific miRNA expression profiles of glioma, researchers will be able to provide a new direction for the diagnosis and treatment of human glioma. In this review, we summarize the current finding of miRNAs, which are deregulated in glioma, and discuss the molecular diagnostic and therapeutic potential of miRNAs in glioma.

Introduction of microRNAs

With the further development of the Human Genome Project, scientists have elucidated more of the function of the noncoding sequences which account for 99% of the human genome, the most striking of which is miRNA function. miRNA is a class of single-stranded small RNA, approximately 19-25 nucleotides, and is produced by a former transcript stem-loop structure. [23] Although they do not have an open reading frame and even encode proteins, they play a vital role in variety of important physiological and pathological processes in organisms. [16] They can bind to the 3'- untranslated region (UTR) of their target messenger RNA (mRNA) via imperfect complementary base-pairing, acting as important regulators of diverse biological processes at the posttranscriptional level. [24] This induces mRNA cleavage that could result in silencing of specific genes, which regulates the ontogenesis, cell apoptosis, proliferation, differentiation, and any other processes that play a vital role in many diseases, especially in cancer. [25] There are numerous studies that demonstrate that miRNA could function as oncogenes or as tumor suppressors in glioma. [24],[26],[27],[28] The discovery of miRNA has provided a novel tool to research tumor pathogenesis, and a new strategy for the diagnosis and prognosis of human cancers.

Lin-4 and let-7 are the first two miRNAs that have been discovered in nematode Caenorhabditis elegans. [29],[30] Using experiments and bioinformatics, researchers have found hundreds of miRNAs in the organism. Presumably, about one-third of human encoding genes are negative regulated by miRNAs, [31],[32] leading to increased study in areas such as molecular biology, genetics, and clinical medicine.

Biogenesis of microRNA

In order to understand the context of miRNA in gliomas pathology, we highlight the essential steps of the biogenesis of miRNA [Figure 1]. miRNA is a stem-loop structure encoded by an endogenous gene. Biogenesis starts with the transcription of the genome by RNA polymerase II/III, producing a primary transcript called pri-miRNA, which shows one or more stem-loop structures by intramolecular base-pairing. [33] The transcript is then cleaved into an approximately 60-110 length sequence called pre-miRNA by the complex of Drosha/DGCR8. It is transported into cytoplasm with the assistance of the exportin-5/Ran-GTP cofactor. [34] In the cytoplasm, the stem-loop structure is cleaved into an approximately 19-25 nucleotide double-stranded miRNA by the transactivating response RNA binding protein-Dicer complex. Subsequently, one strand participates in forming the RNA-induced silencing complex which complementary pairs with the 3'- UTR of the target mRNA, leading to translation repression, [35],[36] and has been implicated in numerous pathological processes. [37]
Figure 1. Biogenesis of microRNAs (miRNAs). The miRNA gene is transcribed by RNA polymerase II/III. The transcript is called Pri-miRNA, which is cleaved by Drosha-DGCR8 complex and forms pre-miRNA. This is transported to cytoplasm from nucleus by the exportin-5 and RanGTP cofactor. Pre-miRNA is processed by the transactivating response RNA binding protein-Dicer complex into a miRNA duplex, which is unwound to form mature miRNA. The guide stand binds to Ago to form RNA-induced silencing complex (RISC). RISC complementary pairs with the target messenger RNA (mRNA) 3'-untranslated region, leading to mRNA cleavage and translation repression. The passenger stand is degraded, and the surplus miRNAs are exported to extracellular matrix by exosomes

Click here to view


Relationship between microRNAs and tumo

At least one-third of coding genes are regulated by miRNAs. [38],[39] Research has shown that miRNA expression profiles are different between tumor tissue and normal tissue. miRNA expressed in different kinds of tumor tissue is inordinately up or down-regulated. [40] In other words, one specific miRNA up-regulated in certain types of cancer maybe decreased in others. [41] The deregulation of miRNA influences the cell signal pathways significantly, resulting in out of control cell proliferation and differentiation. [42]

In recent years, a large body of literature has reported that miRNAs are of significance to tumor biology. [43],[44],[45] miRNAs are involved in tumorigenicity, especially, in malignancy. [46] Calin et al.[47] first reported in 2002 that miRNAs were involved in tumorigenicity. Since then, hundreds of miRNAs have been associated with tumorigenicity. Due to radiotherapy and chemotherapy resistance, the treatment of glioma has remained a huge challenge, so finding prognostic factors is the key. [48] For example, researchers showed that the down regulation of two miRNAs miR-181a and miR-181c resulted in TMZ chemotherapy resistance and in the poor prognosis of glioma. [49]

MicroRNA deregulation has become a new characteristic of malignant tumor, so some specific miRNAs are potentially novel biomarkers of cancer diagnosis and prognosis. [50],[51],[52] More than 50% of miRNA genes are located in the fragile site of chromosomes, and in the process of tumorigenesis. Genetic alterations such as deletion, amplification, and translocation often occur in these regions. [53],[54] For specific cancers, miRNAs expression profiles can easily be identified for their distinctive characteristics, and could be used as biomarkers for tumor classification. [55],[56] Quantitative detection of miRNAs levels in plasma of tumor patients can be used in human cancer diagnosis, [57] and blood screening of miRNAs could predict tumor metastasis. [58] For example, down regulation of miR-221 or methylation of miR-9-1 have been shown to be biomarkers of colorectal tumor metastasis. [59],[60] Therefore, miRNA expression profiles can not only be used as tumor diagnostic biomarker, but also can be used for prognosis. [61]

Studies in chronic B cell lymphoma, [62] ovarian carcinoma, [63] glioma, [64] lung cancer, [65],[66] liver cancer, [67] and colon cancer [68],[69] have demonstrated that miRNA expression profile is different between tumor tissue and normal tissue. Thus, the deregulation of miRNA in tumor tissues may contribute to tumorigenicity and progression. Research of miRNAs deregulation in tumor may reveal tumorigenesis mechanisms, novel diagnostic and prognostic biomarkers, and new targets of gene therapy

MicroRNAs in glioma

Deregulation of miRNAs can affect the proliferation, apoptosis, invasion, migration, and drug resistance of glioma cells. miR-21 was the first miRNA investigated in glioma. In 2005, Chan et al. [70] demonstrated that miR-21 was distinctly up-regulated in glioma. Overexpression of miR-21 suppressed apoptotic gene expression and induced tumor progression. Similarly, other studies indicated that various other miRNAs were deregulated in glioma. [49],[71] Ciafrè et al. [72] have quantitatively analyzed hundreds of miRNA expression through microarray, and found that there are 13 kinds of miRNAs deregulated in glioma: 9 were up-regulated such as miR-21, miR-9-2, miR-10b, miR-25, miR-123, miR-125b-1, miR-125b-2, miR-221, miR-130a, while miR-128-1, miR-181a, miR-181b, miR-181c were down-regulated.

Recently, a large number of miRNAs were detected in mammalian brain tissue and involved in regulating the development of brain tissue, neuronal differentiation and higher neural function (such as learning, memory, etc.). In addition, mirRNAs are correlated with diseases such as neurodegenerative disease, psychosis and brain tumor. [73] Research showed that there were a group of cells in glioma, called glioma stem cells (GSCs), which can proliferate and unlimitedly self-renew, and have multi-directional differentiation potential, compared with normal tumor cells. The GSCs are more active in proliferation and tumorigenicity, and may play a vital role in the occurrence, development and relapse of glioma because their biological characteristics are similar with neural stem cells. [74] With further investigation of miRNA biological function, researchers found that there were complicated regulatory networks between miRNA and its target genes, and miRNA impact tumorigenesis through deregulating vital molecules in signaling pathways such as transforming growth factor beta (TGF-β), Wnt, Notch and the epidermal growth factor receptor (EGFR) pathways.

There are many signaling pathway involved in cancer stem cells, for example, receptor tyrosine kinase (RTK)-Akt, Notch, bone morphogenetic proteins/TGF-β, Hedgehog-Gli, Wnt-b-catenin, signal transducer and activator of transcription 3 (STAT3), and glycogen synthase kinase-3-e. They interact and supplement each other, resulting in deregulation of the G1/S phase checkpoint, eventually causing disordered cell cycle regulation, aberrant proliferation and tumorigenesis.

The RTK-Akt signaling pathway plays a crucial role in cancer stem cells, research showed that miR-7 could block cell cycle progress by suppressing insulin receptor substrate-2 in ATK pathway. miR-7 can also suppress EGFR expression, and by blocking the RTK-Akt signaling pathway can reduce invasiveness and viability of glioma cells. [75] GSCs are more dependent on the ATK pathway than glioma cells. Therefore, suppressing the AKT pathway could inhibit the growth of GSCs. [76],[74] The Notch signaling pathway is important to maintain stem cell self-renewal and inhibit cell differentiation. [77] A study showed that miR-326 could induce apoptosis of glioma cells and GSCs through the Notch signaling pathway. [78] Another study demonstrated that miR-107 could inhibit proliferation and invasiveness of GSCs by suppressing Notch levels. [79] Li et al.[80] first found that premiR-34a is down-regulated in glioma, indicating that miR-34a could suppress the expression of Notch-1, Notch-2, cyclin-dependent protein kinases-6 (CDK6) and c-Met in glioma simultaneously, and that low Notch levels could inhibit the formation of tumor spheres. [81] In addition, aberrant expression of Notch is associated with GSCs radiotherapy resistance. [82] TGF-β could induce angiogenesis and promote invasiveness as a key molecule of TGF-β signaling pathway and oncogene, [83] and it has been investigated that it also promotes tumor progression and invasiveness in high-grade gliomas. [84] miR-34a is a novel regulator of TGF-β signaling pathway in GBM, miR-34a regulates the TGF-β signaling pathway through a Smad4 transcriptional network, and its direct target is Smad4. [85] TGF-β pathway has been deemed as an oncogenic factor in GBM: [86] mediated by Id1 and Id3, TGF-β signaling pathway could enhance self-renewal of tumor-derived spheroids in vitro. [87] Recently, research demonstrated that overexpression of miR-146a suppressed TGF-β1 mediated U87 proliferation and migration, and miR-146a could suppress the Smad4 level, miR-146a was deemed as a novel regulator of TGF-β signaling pathways in GBM. [88] Hedgehog-Gli signaling pathways also play a vital role in adult stem cells self-renewal, including neural stem cells. [89] Research has indicated that the Hedgehog-Gli signaling pathway was involved in tumorigenicity and self-renewal of the GSCs. Therefore, blocking Hedgehog-Gli signaling pathway could inhibit the growth of GSCs and promote apoptosis. [90],[91],[92],[93] Notch pathway also affects Gli transcript in mammalian skin cells; Notchl knockdown could induce GliZ to be unregulated and lead to basal cell carcinoma. [93] Gu et al.[94] have found 17 kinds of miRNAs deregulated in GBMs through microarray analysis which targets the Hedgehog-Gli pathway; they indicated that miR-144 was up-regulated in GBMs with a high Gli1 level, while miR-125b-1 was down-regulated. In MBs, miR-125b has been reported as a suppressor of Hedgehog-Gli pathway, the authors also demonstrated that miR-125b, miR-326 and miR-324-5p were regulators of Hedgehog-Gli signaling pathway as well, which means that these miRNAs are involved in the tumorigenic potential of Hedgehog-Gli pathway. [95] Moreover, STAT3 signaling pathway also played a crucial role in the maintenance of GSCs proliferation; knockdown STAT3 can inhibit the growth of GSCs, and thus STAT3 act as oncogene in GSCs. [96],[97] Research demonstrated that miR-124 could inhibit STAT3 signaling to enhance T cell-mediated immune clearance of glioma, and miR-124 was identified to modulate the STAT3 signaling pathway, which is a key pathway mediating immune suppression in tumor microenvironment. [98] miR-21 modulates hTERT expression by STAT3 in GBM, the author indicated that STAT3 was a crucial mediator between miR-21 and hTERT. [99]

In other words, miRNAs have played a vital role in the following aspects of the mechanism of occurrence and development of glioma. First, they can regulate the tumor suppressor gene expression. For instance, miR-21 could inhibit apoptosis related gene expression, [100] and miR-221 and miR-222 could decrease the level of anti-oncogene p27. [101] Second, they could act on signaling pathways involved in glioma occurrence and development. For example, miR-7 could suppress tumorigenicity through blocking the AKT pathway. [75] miR-7 was down-regulated in glioma, and the glioma cell lines in which miR-7 is up-regulated have lower viability and invasiveness. [102] Third, miRNA could induce differentiation of GSCs, and overexpression of miR-124 and miR-137 could induce GSCs differentiation to form glioma cells. There are 6 kinds of miRNA up-regulated in CD133 negative cell lines (miR-16, miR-107, miR-185, miR-425, miR-451, and miR-486), while they are down-regulated in CD133 positive cell lines. [103]


  Micrornas Deregulated in Glioma Top


MicroRNAs uegulated in glioma

Many literatures have indicated that the common deregulation of miRNAs in glioma is over expression. We summarize three kinds of miRNAs in detail, which have been investigated incisively and comprehensively, and they are miR-21, miR-93 and miR-221/222. Although both expression profile and function of a series of miRNAs have been intensively investigated, the target and mechanism of vast majority miRNAs remain unknown, and need further investigation [Table 1].
Table 1: Up-regulated miRNAs and their function in glioma


Click here to view


miR-21

miR-21 was the first miRNA which was investigated in glioma in 2005. Research showed that miR-21 was over expressed in glioma compared with normal brain tissue, [70] and the investigator also indicated that knockdown miR-21 in glioma cell lines could activate caspase involved in apoptosis, suggesting that miR-21 function as an oncogene in tumorigenicity. The up regulation of miR-21 was extreme in grade IV astrocytomas, [21] and functional studies indicated that miR-21 knockdown in GBM cells could reduce invasiveness, enhance apoptosis, decrease cell growth, and suppress tumorigenicity. [20],[21],[70]

Research demonstrated that insulin-like growth factor-binding protein-3 (IGFBP3) was a novel target of miR-21 in GBM and suggested that miR-21 down regulates the expression of IGFBP3, which acts as a tumor suppressor in human GBM. [105] miR-21 has played a vital role in apoptosis and proliferation of GBM GSCs. Shang et al.[106] have found that miR-21 down regulation affects apoptosis and proliferation of GSCs, partly by directly down regulating FASLG, which revealed that FASLG is also a novel target of miR-21. Han et al.[107] demonstrated that miR-21 was regulated by β-catenin/STAT3 pathway that could induce cell proliferation and invasion via STAT3 factor in glioma cells by targeting RECK. Papagiannakopoulos et al. [22] reported that miR-21 was involved in three tumor suppressive pathways, namely p53, TGF-β, and mitochondrial apoptotic pathways, by targeting heterogeneous nuclear ribonucleoprotein K, TAp63, and programmed cell death 4, which are key factors in cell cycle regulations and apoptosis. In addition, a study showed that knockdown miR-21 contributed to the radio-sensitization of glioma cell lines through inhibiting phosphoinositide 3-kinase/ATK pathway and enhanced irradiation-induced autophagy, suggesting that miR-21 played an important role in radio-resistance of malignant glioma. [108]

Drug resistance is considered a multifactorial phenomenon in cancer, and leads to poor prognosis. Ren et al.[109] demonstrated that knockdown of miR-21 contributed to sensitizing human GBM cells U251 (PTEN-mutant) and LN229 (PTEN-wild type) to the anticancer drug taxol, suggested that PTEN maybe another target of miR-21 in glioma. Qian et al.[110] also reported that miR-21 was involved in TMZ resistance and concomitant treatment with miR-21 inhibitor and TMZ gained the best antitumor effect in LN229 cells. miR-21 level is also involved in poor prognosis of glioma patients. Numerous papers indicated that miR-21 level in high-grade (III-IV) gliomas was higher than in low-grade (I-II) gliomas, [21],[70],[105],[106],[107] Hermansen et al.[111] showed that miR-21 was located in both tumor cells and tumor blood vessels and its presence in the tumor cell compartment is an unfavorable prognostic in gliomas. Furthermore, co-inhibition of miR-10b and miR-21 exerts a synergistic inhibition on the proliferation and invasion of human glioma cells. [112]

The investigation of the mechanism of miR-21 up-regulated in gliomas is helpful to understanding the pathogenesis of gliomas. DNA demethylation is considered a mechanism for the transcriptional activation of miR-21 in ovarian tumor cells. [113] Global hypomethylation is common in human cancer. DNA demethylation can activate oncogenes in GBM and other human cancers. [114] However, the exact epigenetic role of miR-21 in gliomas needs further investigation.

miR-93

Numerous studies have found that miR-93 is over expressed in GBM. [115],[116],[117] miR-93 is a member of miR-106b-25 cluster, which is a paralog of the miR-17-92 cluster, both of which possess carcinogenic activities. [118],[119],[120],[121] Dong et al. [122] have illustrated the functional properties of miR-93, and they found that miR-93 could promote tumor formation and angiogenesis by targeting integrin-β8 which is associated with apoptosis in GBM. The authors also indicated that miR-93 could induce angiogenesis and promote tumor growth via a series of in vivo and in vitro experiments. They confirmed this with a co-culture with a U87 cell line which was transfected with exogenous miR-93, enhanced the proliferation, migration, and tube formation of endothelial cells. Moreover, the up regulation of miR-93 increased blood vessel formation prominently in mice, which have GBM xenograft tumors, which suggested that miR-93 is an angiogenic inducer indeed and propose a novel therapy for human GBM. [123]

miR-221/222

miR-221 and miR-222 are located on chromosome Xp11.3, belong to the same cluster, and have the same target specificity. [124] These two miRNAs are often overexpressed in high-grade astrocytomas (WHO grade III and IV) and primary GBM. [72],[125],[126] Research indicated that they played a vital role in cell cycle progression. [127],[128] miR-221/222 could also suppress the expression of p27kip1 (cyclin-dependent kinase inhibitor 1B), [127] which is a negative cell cycle regulator and often down-regulated in high-grade astrocytomas. [129] p27kip1 is an CDK inhibitor; it binds to CDK with a cyclin and leads to cell cycle arrest in G1 phase. Research showed that p27kip1 was a direct target of miR-221/222. [127] According to bioinformatics analysis, CDK4 may serve as an activator of miR-221, and the expression of p27kip1 will be enhanced when CDK4 was suppressed, [130] inhibiting the transcription of miR-221 can achieve the same goal. [127] According to an analysis of miRNA expression profile during cell cycle progression of GBM cells, the author found that miR-221/222 was overexpressed during G1/S phase; they also indicated that CDKN1C/p57 was also a target of miR-221/222 besides p27kip1. [56] Zhang et al. [131] found 16 kinds of miR-221/22 target which can interact with ATK by bioinformatics analysis, suggested that miR-221/22 may also regulate the AKT pathway in glioma. In addition, the study also indicated that up-regulation of miR-221/222 can enhance proliferation and invasiveness of glioma cell in vitro, and can induce glioma growth in a subcutaneous xenograft mouse model.

Other microRNAs up-regulated in glioma

There are many other miRNAs, which are substantially upregulated in glioma cell lines and tissue compared with normal tissue [Table 1]. Similar to miR-21, miR-93 and miR-221/222, their down regulation also induced cell growth, invasiveness, migration, and proliferation of glioma by binding to their target. Moreover, they may serve as a potential noninvasive biomarker for the diagnosis and prognosis of glioma. miR-372 was confirmed up-regulated in glioma cell lines and tissues, decreasing the miR-372 level would prominently reduce cell proliferation, invasiveness, and enhance apoptosis by targeting PHLPP2. [132],[133] Guo et al.[134] indicated that miR-454-3p would act as a potential prognostic indicator in human glioma. miR-17 expression significantly predicts poor prognosis in human glioma, [135] and down regulation of miR-23b causes growth inhibition, suppresses invasion of glioma in vitro, and induces apoptosis by targeting von Hippel-Lindau. [136] Wang et al.[137] indicated that miR-92b is also up-regulated in glioma, and down regulation leads to proliferation and invasion inhibition by targeting nemo-like kinase. In addition, down regulation of miR-146a could block TGF-β signaling pathways in GBM. [138] There are also many other miRNAs reported up-regulated in glioma such as miR-10b, miR-15b, miR-18a, miR-33a, miR-155, miR-182, miR-183, miR-210, miR-335, and miR-381 [Table 1]; these miRNAs reported in at least one research study, act as oncogenes in glioma, and can be used as therapeutic target of glioma therapy.{Table 1}

MicroRNAs down-regulated in glioma

In addition, in this paper, we review 22 kinds of miRNAs, which were confirmed as down-regulated in glioma [Table 2], and may act as tumor suppressors in glioma by regulating the expression of their target. Here, we summarized four kinds of miRNAs, miR-128, miR-7, miR-218, and miR-181, which have been reported by multiple publications.
Table 2: Down-regulated miRNAs and their function in glioma


Click here to view


miR-128

microR-128 is considered a brain specific miRNA, [151] and several studies have reported that miR-128 is down-regulated in GBM, but it has less decreased levels in low-grade glioma. [152] It can suppress tumor growth via several direct targets in gliomas. Bmi-1 is the first target of miR-128 which could promote stem cell self-renewal, and was confirmed as oncogene, [153] Bmi-1 was also considered as the first neural stem cell self-renewal factor which is regulated by miR-218. The authors indicated that miR-128 overexpression not only reduced glioma cell proliferation in vitro significantly, but also suppressed glioma xenograft growth in vivo.

Another direct target of miR-128 is E2F3a. [152] A study indicated that miR-128 could inhibit glioma cells proliferation by targeting transcription factor E2F3a; the authors showed that the levels of E2F3a were negatively correlated to the levels of miR-128 whether in gliomas and normal brain tissues. Furthermore, the levels of E2F3a in T98G cells were reduced by over expression of miR-128.

Moreover, research showed that miR-128 could repress glioma-initiating neural stem cells growth by enhancing neuronal differentiation, via targeting oncogenic RTKs such as EGFR and platelet-derived growth facto receptor-α (PDGFRα). The author indicated that decreased expression of miR-128 correlates with aggressive human glioma subtypes, and they confirmed miR-128 is a tumor suppressor in vivo. [154] Peruzzi et al.[155] illustrated that miR-128 was confirmed as an important suppressor of polycomb repressor complex (PRC), which is oncogenic in GBM, miR-128 inhibited PRC activity by directly targeting its key component SUZ12 of PRC2. The authors also indicated that the absence of miR-128 is an early event in glioma genesis. Another study revealed EphB1 and EphB2 are novel miR-128 targets in glioma; [156] miR-128 could promote cell-cell adhesion in U87 cells by targeting EphB1 and EphB2, and the authors indicated that miR-128 significantly inhibited cell migration through down regulating of EphB2 in glioma. WEE1 and Msi1 have also confirmed as the direct targets of miR-128 involved in proliferation of glioma. [141] Shi et al.[157] identified that p70S6K1 was a novel direct target of miR-128; overexpression of miR-128 suppressed p70S6K1 and its downstream signaling molecules such as hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor expression, which were involved in angiogenesis in glioma. Thus, miR-128 can be regarded as a tumor suppressor of glioma. Recently, a study showed that the SNAI1/miR-128/SP1 axis played a vital role in glioma progression, and SP1 was confirmed as another target of miR-128, [158] suggested that this axis is a potential candidate molecular target for clinical diagnosis and treatment.

miR-7

miR-7 is also down-regulated in glioma targeting critical cancer signaling pathway. Disruption of the EGFR and ATK signaling pathways are the most common genetic alterations in GBM. [159],[160] Kefas et al.[75] indicated that miR-7 could deregulate these two vital signaling pathways in GBM. miR-7 decreased the expression of EGFR prominently in GBM, and it also blocked the ATK signaling pathway by targeting its upstream regulators ISR1 and ISR2, the authors also demonstrated that the viability and invasiveness of GBM cells were prominently decreased through transfected miR-7.

In line with this study, Liu et al.[161] reported that miR-7 suppressed the PI3K/ATK and Raf/MEK/ERK pathways simultaneously through targeting the two transcription factors PI3K and Raf-1, which are both located in downstream of EGFR. Moreover, transfection with miR-7 could induce GBM cell apoptosis, inhibit proliferation, suppress migration in vitro, and reduce tumorigenicity in vivo.

Another miR-7 target identified in GBM is focal adhesion kinase (FAK). Wu et al.[162] illustrated that miR-7 directly suppressed GBM cell invasion via targeting FAK; they indicated that overexpression of miR-7 decreased the invasion and migration of U87 and U251 cells, and the level of endogenous miR-7 and FAK showed negative correlation. The authors also reported that miR-7 repressed the expression of invasion factors p-ERK1/2, matrix metalloproteinase 2 (MMP-2) and MMP-9 in GBM. [162] Recently, a study showed that miR-7 could inhibit glucose metabolism and cellular growth in gliomas by directly targeting IGF 1 receptor. [163] Interestingly, miR-7-5p was also regulated in GBM microvasculature and suppressed vascular endothelial cell proliferation through targeting RAF1, confirmed as oncogene. [164] Babae et al.[165] reported that GBM angiogenesis and growth was suppressed by transfecting with miR-7, transfection of miR-7 in endothelial cells reduced cell viability, tube formation, sprouting and migration, similar to anti-angiogenic drug sunitinib. All of these studies confirm that miR-7 is down-regulated in gliomas. A functional analysis indicated that miR-7 is a tumor suppressor of gliomas suggesting that miR-7 is a novel molecular drug for glioma treatment.

miR-218

MicroR-218 was confirmed down-regulated in tumor tissue, and numerous evidence indicated that miR-218 acts as a tumor suppressor in human glioma. [166],[167],[168],[169],[170],[171] The research reported that the level of miR-218 was prominently down-regulated in glioma cell lines and over expression of miR-218 could enhance apoptosis and inhibit invasion of glioma cells. The author also indicated that this was mediated by inactivating the nuclear factor kappa β (NF-kβ)/MMP-9 pathway via down-regulating IKK-β, which is the upstream regulator of NF-kβ, and it has proven a bona fide target of miR-218. [166] Moreover, NF-kβ is a vital member of NF-kβ pathway and the level of numerous NF-kβ-regulated genes were elevated. [167] In addition, EGFR-coamplified and overexpressed protein (ECOP) was confirmed as a key regulator of NF-kβ signal, [168] and research demonstrated that transfection with miR-218 could induce apoptosis in glioma cells and inhibit tumorigenicity by targeting ECOP, and not only inhibit NF-kβ activity but also suppress the expression of its downstream target genes such as B cell lymphoma (BcL)-xL, MYC, and CCND1. [167]

In addition, oncogenic transcription factor lymphoid enhancer-binding factor 1 (LEF1) was another target of miR-218. Liu et al. [169] showed that miR-218 was down-regulated in glioma tissues, and its level was especially low in GBM, and miR-218 could reverse high invasiveness of GBM cells by targeting the oncogenic transcription factor LEF1 and blocking the invasive axis, miR-218-LEF1-MMPs. The MMP family is downstream effectors of the Wnt/LEF1 pathway.

Our previous study has found that miR-218 could inhibit glioma invasiveness, migration, proliferation, and cancer stem-like cell self-renewal by targeting the polycomb group gene Bmi1. [170] Recent research indicated that GBM, especially the mesenchymal GBM, is a highly malignant tumor which frequently exhibits regions of severe hypoxia and necrosis, and tumor hypoxia that has been associated with chemoresistance. MiR-218 up-regulated in mice harboring intracranial tumors could reduce tumor burden observably, and also increase survival when treated with the chemotherapeutic agent TMZ. Furthermore, down-regulated miR-218 increases the expression of multiple components of RTK signaling pathway, which enhances the activation of HIF, HIF2α in particular, suggesting that an miR-218-RTK-HIF2α signal axis could promote GBM cell survival and tumor angiogenesis. [171]

miR-181 cluster

The miR-181 family, including miR-181a, miR-181b and miR-181c, was reported down-regulated in human gliomas, [72],[125] suggesting that these miRNAs may act as tumor suppressors in gliomas. Research demonstrated that the level of miR-181a was inversely related to the tumor grade, but down-regulated miR-181b was only detected in grade II-IV astrocytomas, [172] and the level of miR-181c in gliomas seems to be similar to normal brain tissue. [125] Numerous studies revealed that GBM transected with miR-181a and miR-181b, could inhibit cell growth and invasion, induce apoptosis and lose the ability of anchorage-independent growth. [125],[172]

The radiation and chemotherapy resistance are two knotty problems in glioma treatment and contribute to the poor prognosis of gliomas. Chen et al.[173] illustrated that transiently overexpression of miR-181a could notably elevate the sensitivity of malignant glioma U87 MG cells to radiation treatment concurrent with the down regulation of protein Bcl-2/leukemia-2, which suggested that Bcl-2 could act as a target of miR-181a in gliomas. TMZ resistance is also a troublesome problem in glioma therapy. Research showed that up regulation of miR-181 family could enhance the chemo-sensitivity of TMZ in glioblastoma cells by targeting Rap1B-mediated cytoskeleton remodeling, and overexpression of these miRNAs could suppress invasive proliferation of glioblastoma cells. [174] Gong et al.[175] also demonstrated that aplysin could enhance TMZ sensitivity in glioma cells by increasing miR-181 level, which exhibit antitumor activity via inducing apoptosis and cell cycle arrest. Recently, a study indicated that miR-181 could inhibit glioma cell proliferation by targeting cyclin B1, which is a positive cell - cycle regulator, the authors illustrated that transfection with miR-181 could inhibit cell proliferation in U251 and SHG-44 cells. [176]

Other microRNAs down-regulated in glioma

Furthermore, targets and functions of novel miRNAs such as miR-326, miR-214, miR-31, miR-142-3p, miR-205, miR-297, miR-326, miR-622, and miR-708, are reported in at least in one study [Table 2]. There are two studies reported that miR-326 was down-regulated in human glioma, and overexpression of miR-326 could act as a suppressor of Hedgehog signaling pathway, and reduce cell proliferation, viability and invasiveness in glioma by targeting SMO. [177],[178] miR-214 has been reported down-regulated in gliomas, and it played a vital role in tumor cell proliferation, migration, invasion, and tumor angiogenesis by targeting ubiquitin-conjugating enzyme 9. [179] Zhang et al. [180] found that miR-622 is significantly down-regulated in glioma tissues and cell lines; overexpression of miR-622 could suppress proliferation, invasion, and migration by directly targeting activating transcription factor 2. A study also showed that miR-203 down regulation was associated with unfavorable prognosis in human glioma. [181] miR-297 could inhibit invasiveness and tumorigenicity of GBM by targeting diacylglycerol kinase alpha, [182] and miR-708 would also act as tumor suppressor in human glioblastoma cells. [134] All of these studies have indicated that these miRNAs could act as tumor suppressors of glioma.{Table 2}

MicroRNAs with disputed levels of expression in glioma

In addition to the series of miRNAs up or down-regulated in glioma, which have been confirmed by multiple studies mentioned above, there are still miRNAs with unclear levels and obscure function in glioma. Here, we will discuss two kinds of these disputed miRNAs in detail.

miR-184

miR-184 is known to play a key role in neurological development and apoptosis, but whether the level of miR-184 is up or down-regulated in glioma remains disputed. MiR-184 was reported to be down-regulated by Emdad et al. [199] who demonstrated that the level of miR-184 was decreased in malignant glioma compared with normal brain tissue. SND1 is known to be over-expressed in human glioma tissue, and its level exhibited a negative correlation with miR-184. Transfecting with miR-184 or knockdown of SND1 could inhibit invasiveness of glioma cells and suppress colony formation, reduce anchorage-independent growth in soft agar, and significantly improved survival of tumor-bearing mice. Finally, the authors indicated that miR-184 acted as a tumor suppressor in glioma by targeting SND1. In keeping with this study, Malzkorn et al.[144] also indicated that up regulation of miR-184 in A172 and T98G glioma cells significantly decreased (P < 0.05) cell viability and proliferation. miR-184 also reduced invasiveness in matrigel assays of T98G cells. Remarkably, overexpression of miR-184 could increase apoptotic activity in A172 cells, but decrease apoptotic activity in T98G cells. In addition, another two research studies showed that miR-184 could inhibit neuroblastoma cell survival by targeting the serine/threonine kinase AKT2, which is a major downstream effector of the PI3K pathway. [200],[201]

Nevertheless, contradictory to these studies, Foley et al.[202] indicated that up regulation of miR-184 could enhance the malignant biological behavior of human glioma cell line A172 by targeting FIH-1. They showed that miR-184 was significantly up-regulated in human glioma by HIF-1α. They verified that down regulation of miR-184 could inhibit cell viability and increase the HEB cell apoptotic rate by targeting FIH-1, which was confirmed as a negative regulator of HIF-1α. In line with this study, there is also a study which showed that overexpression of miR-184 could promote the cell proliferation capacity of glioma cell U87 and T98G by regulated FOXO3. [203] Moreover, miR-184 level was significantly high in hepatocellular carcinoma (HCC), where it acted as an oncogenic regulator in HCC, [204],[205] and it played the same role in squamous cell carcinoma of tongue. [206] Whether the level of miR-184 is up- or down-regulated in human glioma needs further investigation, and how miR-184 participates in the regulatory network in glioma needs in-depth research.

miR-145

MicroR-145 is another miRNA which has been confirmed disputed level in glioma. [27],[207],[208],[209] There are two studies which indicated that miR-145 was down-regulated in glioma. [27],[207] Lee et al.[27] showed that overexpression of miR-145 could decrease proliferation and invasion in glioma. They also found when inserting miR-145 expression cassette into herpes simplex virus tk-expressing adenoviral vector, and transfected that recombinant vector into mice, the survival of the mice was improved. In line with these studies, another research study indicated that up regulating miR-145 could increase the sensibility of radiotherapy and chemotherapy by targeting Oct4 and Sox 2. [216] To strengthen this observation, Rani et al.[207] demonstrated that miR-145 could act as a tumor suppressor by targeting Sox 9 in human glioma cells. On the contrary, Koo et al.[209] indicated that miR-145 was up-regulated in highly invasive GBM cell lines, and decrease miR-145 expression could inhibit invasiveness of GBM cell. Therefore, whether miR-145 is down- or up-regulated in glioma also needs further investigation, and to illuminate the mechanism of how miR-145 works in glioma could be significant in the treatment of gliomas.


  Therapeutic Potential of Micrornas in Glioma Top


The study demonstrated that the expression profile of miRNAs is prominently different between glioma tissue and normal brain tissue, which suggests a novel biomarker for diagnosis and therapy of glioma. Moreover, the specific deregulation of miRNAs in tumor cell lines compared with normal cells indicates that these specific miRNAs can act as candidates of tumor diagnostic biomarkers and in human glioma. Through analyzing the miRNA expression profile in colon cancer, liver cancer, pancreatic cancer, and stomach cancer specimens, researchers found these tumor miRNA expression profiles are markers of tumor grade. [210]

Recent studies have shown that miRNAs have significant value for diagnosis, prognosis and therapy. For instance, up regulation of miR-21 is closely related to the high level of Ki-67 and metastasis of liver cancer. [211] In pancreatic adenocarcinoma, patients with high level of miR-196-a-2 whose median survival was only 14.3 months, had far higher levels than patients with low miR-196-a-2 level whose median survival was up to 26.5 months, [212] suggesting that miR-196-a-2 can predict survival rate. MiR-15b overexpression is closely involved in tumorigenicity and poor prognosis of melanoma, [213] low levels of miR-26 is associated with shorter overall survival in liver cancer patients. [214] There are numerous studies showing that miRNAs expression profile not only plays a crucial role in diagnosis, but also can estimate the prognosis. [61] Nevertheless, it is certain that miRNA can be a molecular target for therapy. [33],[43],[44],[45],[215],[216] Wong et al.[217] have reported that concomitant treatment with miR-21 inhibitor and TMZ results in a significant higher apoptotic rate than TMZ treatment alone, and thus transfection with anti-miR-21 oligonucleotide could decrease TMZ-resistance in GBM. Griveau et al.[218] indicated that locked nucleic acid-lipid nanocapsule complexes (LNA-LNCs) could sensitize human glioblastoma cells to radiation-induced cell death by silencing miR-21, and showed newly developed LNCs represented an interesting tool to convey LNAs within GBM cells to silence well-defined miRNA pathways. This will trigger beneficial synergistic effects to overcome radio-resistance.

Molecular therapy is developing rapidly in oncotherapy because of its lower toxicity and adaptability to personalization. [219] This kind of therapy still needs detailed study of the mechanism of action. miRNAs could block the biological signaling pathway by inhibiting the expression of its key molecular targets, which participate in vital metabolism regulation in organism. The molecular therapy of glioma is divided into molecular diagnosis and therapy. [220] A number of miRNAs play a crucial role in new strategies for tumor molecular therapy. Nevertheless, delivery of miRNAs to the central nervous system is a big challenge due to a multitude factors such as the blood-brain barrier, blood components and the reticular endothelial tissue uptake (reticuloendothelial system), the extracellular matrix, and intracellular obstacles. In spite of these problems, many improved cellular delivery strategies are developing rapidly. For instance, delivering oligonucleotides directionally via lipid capsule, [221],[222] the recombinant adeno-associated virus can penetrate the blood-brain barrier when transferring endogenous miRNAs. [222] The method to transfer miRNAs which serve as tumor suppressors in glioma still needs further investigation. Success will relieve the suffering of the patients and improve poor prognosis.

In conclusion, glioma is the most frequent and malignant brain tumor, and recently, researchers found that miRNAs play a crucial role in glioma pathogenesis. However, whether the occurrence and development of cancers have caused the deregulation of miRNAs or the aberration of miRNA gives rise to tumor and deterioration still needs further investigation. miRNA is a negative regulator, which could decrease gene levels at the posttranscriptional level and function as a tumor suppressors or oncogenes in human glioma. In this paper, we reviewed 43 kinds of miRNAs deregulated in glioma, which could regulate the key molecules participating in the occurrence and development of glioma, are involved in glioma cell proliferation, invasiveness, migration, apoptosis, and prognosis, and affect the radiation and chemotherapy resistance of glioma. miRNAs could be a new biomarker in pathology, which suggests a novel strategy for diagnosis and therapy of glioma.

 
  References Top

1.
Miller CR, Perry A. Glioblastoma. Arch Pathol Lab Med 2007; 131(3): 397 -0 406.  Back to cited text no. 1
    
2.
Buckner JC1, Brown PD, O'Neill BP, Meyer FB, Wetmore CJ, Uhm JH. Central nervous system tumors. Mayo Clin Proc 2007; 82(10): 1271-86.  Back to cited text no. 2
    
3.
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P. The 2007 WHO classification of tumours of the central nervous system. Aeta Neuropathol 2007; 114(2): 97-109.  Back to cited text no. 3
    
4.
Mason WP,Caimcross JG. Drug Insight: temozolomide as a treatment for malignant glioma - impact of a recent trial. Nat Clin Pract Neurol 2005; 1(2): 88-95.  Back to cited text no. 4
    
5.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352(10): 987-96.  Back to cited text no. 5
    
6.
Kleber S, Sancho-Martinez I, Wiestler B, Beisel A, Gieffers C, Hill O, Thiemann M, Mueller W, Sykora J, Kuhn A, Schreglmann N, Letellier E, Zuliani C, Klussmann S, Teodorczyk M, Gröne HJ, Ganten TM, Sültmann H, Tüttenberg J, von Deimling A, Regnier-Vigouroux A, Herold-Mende C, Martin-Villalba A. Yes and PI3K bind CD95 to signal invasion of glioblastoma. Cancer Cell 2008; 13(3): 235-48.  Back to cited text no. 6
    
7.
Ohgaki H, Kleihues P. Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 2005; 64(6): 479-89.  Back to cited text no. 7
    
8.
Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, Burkhard C, Schüler D, Probst-Hensch NM, Maiorka PC, Baeza N, Pisani P, Yonekawa Y, Yasargil MG, Lütolf UM, Kleihues P. Genetic pathways to glioblastoma: a population-based study. Cancer Res 2004; 64(19): 6892-9.  Back to cited text no. 8
    
9.
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. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 2007; 21(21): 2683-710.  Back to cited text no. 9
    
10.
Novakova J, Slaby O, Vyzula R, Michalek J. MicroRNA involvement in glioblastoma pathogenesis. Biochem Biophys Res Commun 2009; 386(1): 1-5.  Back to cited text no. 10
    
11.
Burnet NG, Lynch AG, Jefferies SJ, Price SJ, Jones PH, Antoun NM, Xuereb JH, Pohl U. High grade glioma: imaging combined with pathological grade defines management and predicts prognosis. Radiother Oncol 2007; 85(3): 371-8.  Back to cited text no. 11
    
12.
Ohgaki H, Kleihues P. Epidemiology and etiology of gliomas. Acta Neuropathol 2005; 109(1): 93-  Back to cited text no. 12
    
13.
Cho DY, Lin SZ, Yang WK, Hsu DM, Lin HL, Lee HC, Lee WY, Chiu SC. The role of cancer stem cells (CD133(+)) in malignant gliomas. Cell Transplant 2011; 20(1): 121-5.  Back to cited text no. 13
    
14.
Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003; 63(18): 5821-8.  Back to cited text no. 14
    
15.
Singh SKnone , Hawkins Cnone , Clarke IDnone , Squire JAnone , Bayani Jnone , Hide Tnone , Henkelman RMnone , Cusimano MDnone , Dirks PBnone . Identification of human brain tumour initiating cells. Nature 2004; 432(7015): 396-401.  Back to cited text no. 15
    
16.
Bao Snone , Wu Qnone , McLendon REnone , Hao Ynone , Shi Qnone , Hjelmeland ABnone , Dewhirst MWnone , Bigner DDnone , Rich JNnone . Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006; 444(7120): 756-60.  Back to cited text no. 16
    
17.
Hong Bnone , Wiese Bnone , Bremer Mnone , Heissler HEnone , Heidenreich Fnone , Krauss JKnone , Nakamura Mnone . Multiple microsurgical resections for repeated recurrence of glioblastoma multiforme. Am J Clin Oncol 2013; 36(3): 261-8.  Back to cited text no. 17
    
18.
Becker KP, Yu J. Status quo-standard-of-care medical and radiation therapy for glioblastoma. Cancer J 2012; 18(1): 12-9.  Back to cited text no. 18
    
19.
Yaman Enone , Coskun Unone , Ozturk Bnone , Buyukberber Snone , Kaya AOnone , Coskun Onone , Buyukberber Nnone , Yildiz Rnone , Benekli Mnone . Opportunistic cytomegalovirus infection in a patientreceiving temozolomide for treatment of malignant glioma. J Clin Neurosci 2009; 16(4): 591-2.  Back to cited text no. 19
    
20.
Corsten MFnone , Miranda Rnone , Kasmieh Rnone , Krichevsky AMnone , Weissleder Rnone , Shah Knone . MicroRNA-21 knockdown disrupts glioma growth in vivo and displays synergistic cytotoxicity with neural precursor cell delivered S-TRAIL in human gliomas. Cancer Res 2007; 67(19): 8994-9000.  Back to cited text no. 20
    
21.
Gabriely Gnone , Wurdinger Tnone , Kesari Snone , Esau CCnone , Burchard Jnone , Linsley PSnone , Krichevsky AMnone . MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators. Mol Cell Biol 2008; 28(17): 5369-80.   Back to cited text no. 21
    
22.
Papagiannakopoulos T, Shapiro A, Kosik KS. MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Res 2008; 68(19): 8164-72.  Back to cited text no. 22
    
23.
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116(2): 281-97.   Back to cited text no. 23
    
24.
Liu X, Fortin K, Mourelatos Z. MicroRNAs: biogenesis and molecular functions. Brain Pathol 2008; 18(1): 113-21.   Back to cited text no. 24
    
25.
Tavallaie R, De Almeida SR, Gooding JJ. Toward biosensors for the detection of circulating microRNA as a cancer biomarker: an overview of the challenges and successes. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2DOI:10.1002/wnan.1324  Back to cited text no. 25
    
26.
Mohyeldin A, Chiocca EA. Gene and viral therapy for glioblastoma: a review of clinical trials and future directions. Cancer J 2012; 18(1): 82-8.  Back to cited text no. 26
    
27.
Lee SJnone , Kim SJnone , Seo HHnone , Shin SPnone , Kim Dnone , Park CSnone , Kim KTnone , Kim YHnone , Jeong JSnone , Kim IHnone . Over-expression of miR-145 enhances the effectiveness of HSVtk gene therapy for malignant glioma. Cancer Lett 2012; 320(1): 72-80.  Back to cited text no. 27
    
28.
Skalsky RL, Cullen BR. Reduced expression of brainenriched microRNAs in glioblastomas permits targeted regulation of a cell death gene. PLoS One 2011; 6(9): e24248.  Back to cited text no. 28
    
29.
Reinhart BJnone , Slack FJnone , Basson Mnone , Pasquinelli AEnone , Bettinger JCnone , Rougvie AEnone , Horvitz HRnone , Ruvkun Gnone . The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 2000; 403(6772): 901-6.  Back to cited text no. 29
    
30.
Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993; 75(5): 843-54.  Back to cited text no. 30
    
31.
Harfe BD. MicroRNAs in vertebrate development. Curr Opin Genet Dev 2005; 15(4): 410-5.  Back to cited text no. 31
    
32.
Xi Ynone , Shalgi Rnone , Fodstad Onone , Pilpel Ynone , Ju Jnone . Differentially regulated micro-RNAs and actively translated messenger RNA transcripts by tumor suppressor p53 in colon cancer. Clin Cancer Res 2006; 12 (7 Pt 1): 2014-24.  Back to cited text no. 32
    
33.
Winter Jnone , Jung Snone , Keller Snone , Gregory RInone , Diederichs Snone . Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol 2009; 11(3): 228-34.  Back to cited text no. 33
    
34.
Yi R, Qin Y, Macara IG, Cullen BR. Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev 2003; 17(24): 3011-6.  Back to cited text no. 34
    
35.
Kawamata T, Yoda M, Tomari Y. Multilayer checkpoints for microRNA authenticity during RISC assembly. EMBO Rep 2011; 12(9): 944-9.  Back to cited text no. 35
    
36.
Winter J, Diederichs S. MicroRNA biogenesis and cancer. Methods Mol Biol 2011; 676: 3-22.  Back to cited text no. 36
    
37.
Rana TM. Illuminating the silence: understanding the structure and function of small RNAs. Nat Rev Mol Cell Biol 2007; 8(1): 23-36.  Back to cited text no. 37
    
38.
Gartel AL, Kandel ES. miRNAs: little known mediators of oncogenesis. Semin Cancer Biol 2008; 18(2): 103-10.  Back to cited text no. 38
    
39.
Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005; 120(1): 15-20.  Back to cited text no. 39
    
40.
Avraham R, Yarden Y. Regulation of signalling by microRNAs. Biochem Soc Trans 2012; 40(1): 26-30.  Back to cited text no. 40
    
41.
Volinia Snone , Calin GAnone , Liu CGnone , Ambs Snone , Cimmino Anone , Petrocca Fnone , Visone Rnone , Iorio Mnone , Roldo Cnone , Ferracin Mnone , Prueitt RLnone , Yanaihara Nnone , Lanza Gnone , Scarpa Anone , Vecchione Anone ,Negrini Mnone , Harris CCnone , Croce CMnone . A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 2006; 103(7): 2257-61.  Back to cited text no. 41
    
42.
Inui M, Martello G, Piccolo S. MicroRNA control of signal transduction. Nat Rev Mol Cell Biol 2010; 11(4): 252-63.  Back to cited text no. 42
    
43.
Brown BD, Naldini L. Exploiting and antagonizing microRNA regulation for therapeutic and experimental applications. Nat Rev Genet 2009; 10(8): 578-85.  Back to cited text no. 43
    
44.
Garzon R, Calin GA, Croce CM. MicroRNAs in Cancer. Annu Rev Med 2009; 60: 167-79.  Back to cited text no. 44
    
45.
Petri A, Lindow M, Kauppinen S. MicroRNA silencing in primates: towards development of novel therapeutics. Cancer Res 2009; 69(2): 393-5.   Back to cited text no. 45
    
46.
Gao H, Zhao H, Xiang W. Expression level of human miR-34a correlates with glioma grade and prognosis. J Neurooncol 2013; 113(2): 221-8.  Back to cited text no. 46
    
47.
Calin GAnone , Dumitru CDnone , Shimizu Mnone , Bichi Rnone , Zupo Snone , Noch Enone , Aldler Hnone , Rattan Snone , Keating Mnone , Rai Knone , Rassenti Lnone , Kipps Tnone , Negrini Mnone , Bullrich Fnone , Croce CMnone . Proc Natl Acad Sci USA 2002; 99(24): 15524-9.  Back to cited text no. 47
    
48.
Ziegler DSnone , Wright RDnone , Kesari Snone , Lemieux MEnone , Tran MAnone , Jain Mnone , Zawel Lnone , Kung ALnone . Resistance of human glioblastoma multiforme cells to growth factor inhibitors is overcome by blockade of inhibitor of apoptosisproteins. J Clin Invest 2008; 118(9): 3109-22.  Back to cited text no. 48
    
49.
Slaby Onone , Lakomy Rnone , Fadrus Pnone , Hrstka Rnone , Kren Lnone , Lzicarova Enone , Smrcka Mnone , Svoboda Mnone , Dolezalova Hnone , Novakova Jnone , Valik Dnone , Vyzula Rnone , Michalek Jnone . MicroRNA-181 family predicts response to concomitant chemoradiotherapy with temozolomide in glioblastoma patients. Neoplasma 2010; 57(3): 264-9.  Back to cited text no. 49
    
50.
Yu SLnone , Chen HYnone , Chang GCnone , Chen CYnone , Chen HWnone , Singh Snone , Cheng CLnone , Yu CJnone , Lee YCnone , Chen HSnone , Su TJnone , Chiang CCnone , Li HNnone , Hong QSnone , Su HYnone , Chen CCnone , Chen WJnone , Liu CCnone , Chan WKnone , Chen WJnone , Li KCnone , Chen JJnone , Yang PCnone . MicroRNA signature predicts survival and relapse in lung cancer. Cancer Cell 2008; 13(1): 48-57.  Back to cited text no. 50
    
51.
Shenouda SK, Alahari SK. MicroRNA function in cancer: oncogene or a tumor suppressor. Cancer Metastasis Rev 2009; 28(3-4): 369-78.  Back to cited text no. 51
    
52.
Cho WC. MicroRNAs: potential biomarkers for cancer diagnosis, prognosis and targets for therapy. Int J Biochem Cell Biol 2010; 42(8): 1273-81.  Back to cited text no. 52
    
53.
Calin GAnone , Sevignani Cnone , Dumitru CDnone , Hyslop Tnone , Noch Enone , Yendamuri Snone , Shimizu Mnone , Rattan Snone , Bullrich Fnone , Negrini Mnone , Croce CMnone . Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA 2004; 101(9): 2999-3004.  Back to cited text no. 53
    
54.
Zhang B, Pan X, Cobb GP, Anderson TA. microRNAs as oncogenes and tumor suppressors. Dev Biol 2007; 302(1): 1-12.  Back to cited text no. 54
    
55.
Calin GAnone , Croce CMnone . MicroRNA signatures in human cancers. Nat Rev Cancer 2006; 6(11): 857-66.  Back to cited text no. 55
    
56.
Cho WC. MicroRNAs in cancer - from research to therapy. Biochim Biophys Acta 2010; 1805(2): 209-17.  Back to cited text no. 56
    
57.
Kosaka N, Iguchi H, Ochiya T. Circulating microRNA in body fluid: a new potential biomarker for cancer diagnosis and prognosis. Cancer Sci 2010; 101(10): 2087-92.  Back to cited text no. 57
    
58.
Corcoran Cnone , Friel AMnone , Duffy MJnone , Crown Jnone , O'Driscoll Lnone . Intracellular and extracellular microRNAs in breast cancer. Clin Chem 2011; 57(1): 18-32.  Back to cited text no. 58
    
59.
Bandres Enone , Agirre Xnone , Bitarte Nnone , Ramirez Nnone , Zarate Rnone , Roman-Gomez Jnone , Prosper Fnone , Garcia-Foncillas Jnone . Epigenetic regulation of microRNA expression in colorectal cancer. Int J Cancer 2009; 125(11): 2737-43.  Back to cited text no. 59
    
60.
Spahn Mnone , Kneitz Snone , Scholz CJnone , Stenger Nnone , Rüdiger Tnone , Ströbel Pnone , Riedmiller Hnone , Kneitz Bnone . Expression of microRNA-221 is progressively reduced in aggressive prostate cancer and metastasis and predicts clinical recurrence. Int J Cancer 2010; 127(2): 394-403.  Back to cited text no. 60
    
61.
Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet 2009; 10(10): 704-14.  Back to cited text no. 61
    
62.
Mraz M, Kipps TJ. MicroRNAs and B cell receptor signaling in chronic lymphocytic leukemia. Leuk Lymphoma 2013; 54(8): 1836-9.  Back to cited text no. 62
    
63.
Nam EJnone , Yoon Hnone , Kim SWnone , Kim Hnone , Kim YTnone , Kim JHnone , Kim JWnone , Kim Snone . MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res 2008; 14(9): 2690-5.  Back to cited text no. 63
    
64.
Turner JDnone , Williamson Rnone , Almefty KKnone , Nakaji Pnone , Porter Rnone , Tse Vnone , Kalani MYnone . The many roles of microRNAs in brain tumor biology. Neurosurg Focus 2010; 28(1): E3.  Back to cited text no. 64
    
65.
Zhu Dnone , Chen Hnone , Yang Xnone , Chen Wnone , Wang Lnone , Xu Jnone , Yu Lnone . Decreased microRNA-224 and its clinical significance in non-small cell lung cancer patients. Diagn Pathol 2014; 9(1): 198.  Back to cited text no. 65
    
66.
Yang Ynone , Meng Hnone , Peng Qnone , Yang Xnone , Gan Rnone , Zhao Lnone , Chen Znone , Lu Jnone , Meng QHnone . Downregulation of microRNA-21 expression restrains non-small cell lung cancer cell proliferation and migration through upregulation of programmed cell death. Cancer Gene Ther 2015; 22(1): 23-9.  Back to cited text no. 66
    
67.
Yang N, Ekanem NR, Sakyi CA, Ray SD. Hepatocellular carcinoma and microRNA: new perspectives on therapeutics and diagnostics. Adv Drug Deliv Rev 2015; 81: 62-74.  Back to cited text no. 67
    
68.
Chen P, Wang BL, Pan BS, Guo W. MiR-1297 Regulates the growth, migration and invasion of colorectal cancer cells by targeting cyclo-oxygenase-2. Asian Pac J Cancer Prev 2014; 15(21): 9185-90.  Back to cited text no. 68
    
69.
Zhou MK, Liu XJ, Zhao ZG, Cheng YM. MicroRNA-100 functions as a tumor suppressor by inhibiting Lgr5 expression in colon cancer cells. Mol Med Rep 2015; 11(4): 2947-52.  Back to cited text no. 69
    
70.
Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res 2005; 65(14): 6029-33.  Back to cited text no. 70
    
71.
Hummel R, Maurer J, Haier J. MicroRNAs in Brain Tumors. Mol Neurobiol 2011; 44(3): 223-34.  Back to cited text no. 71
    
72.
Ciafrè SA, Galardi S, Mangiola A, Ferracin M, Liu CG, Sabatino G, Negrini M, Maira G, Croce CM, Farace MG. Extensive modula tion of a set of microRNAs in primary glioblastoma. Biochem Biophys Res Commun 2005; 334(4): 1351-8.  Back to cited text no. 72
    
73.
J Pang JC, Kwok WK, Chen Z, Ng HK. Oncogenic role of microRNAs in brain tumors. Acta Neuropathol 2009; 117(6): 599-611.  Back to cited text no. 73
    
74.
Gallia GL, Tyler BM, Hann CL, Siu IM, Giranda VL, Vescovi AL, Brem H, Riggins GJ. Inhibition of Akt inhibits growth of glioblastoma and glioblastoma stem-like cells. Mol Cancer Ther 2009; 8(2): 386-93.  Back to cited text no. 74
    
75.
Kefas B, Godlewski J, Comeau L, Li Y, Abounader R, Hawkinson M, Lee J, Fine H, Chiocca EA, Lawler S, Purow B. MicroRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma. Cancer Res 2008; 68(10): 3566-72.  Back to cited text no. 75
    
76.
Eyler CE, Foo WC, LaFiura KM, McLendon RE, Hjelmeland AB, Rich JN. Brain cancer stem cells display preferential sensitivity to Akt inhibition. Stem Cells 2008; 26(12): 3027-36.   Back to cited text no. 76
    
77.
Fan X, Khaki L, Zhu TS, Soules ME, Talsma CE, Gul N, Koh C, Zhang J, Li YM, Maciaczyk J, Nikkhah G, Dimeco F, Piccirillo S, Vescovi AL, Eberhart CG. Eberhart CG: NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells 2010; 28(1): 5-16.   Back to cited text no. 77
    
78.
Kefas B, Comeau L, Erdle N, Montgomery E, Amos S, Purow B. Pyruvate kinase M2 is a target of the tumor-suppressive microRNA-326 and regulates the survival of glioma cells. Neuro Oncol 2010; 12(11): 1102-12.   Back to cited text no. 78
    
79.
Chen L, Chen XR, Zhang R, Li P, Liu Y, Yan K, Jiang XD. MicroRNA-107 inhibits glioma cell migration and invasion by modulating Notch2 expression. J Neurooncol 2013; 112(1): 59-66.  Back to cited text no. 79
    
80.
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. MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Res 2009; 69(19): 7569-76.  Back to cited text no. 80
    
81.
Lathia JD, Mattson MP, Cheng A. Notch: from neural development to neurological disorders. J Neurochem 2008; 107(6): 1471-81.  Back to cited text no. 81
    
82.
Wang J, Wakeman TP, Lathia JD, Hjelmeland AB, Wang XF, White RR, Rich JN, Sullenger BA. Notch promotes radioresistance of glioma stem cells. Stem Cells 2010; 28(1): 17-28.  Back to cited text no. 82
    
83.
Wick W, Naumann U, Weller M. Transforming growth factor-beta; a molecular target for the future therapy of glioblastoma. Curr Pharm Des 2006; 12(3): 341-9.  Back to cited text no. 83
    
84.
Kjellman C, Olofsson SP, Hansson O, Von Schantz T, Lindvall M, Nilsson I, Salford LG, Sjögren HO, Widegren B. Expression of TGF-beta isoforms, TGF-beta receptors, and SMAD molecules at different stages of human glioma. Int J Cancer 2000; 89(3): 251-8.  Back to cited text no. 84
    
85.
Genovese G, Ergun A, Shukla SA, Campos B, Hanna J, Ghosh P, Quayle SN, Rai K, Colla S, Ying H, Wu CJ, Sarkar S, Xiao Y, Zhang J, Zhang H, Kwong L, Dunn K, Wiedemeyer WR, Brennan C, Zheng H, Rimm DL, Collins JJ, Chin L. microRNA regulatory network inference identifies miR-34a as a novel regulator of TGFâ signaling in GBM. Cancer Discov 2012; 2(8): 736-49.   Back to cited text no. 85
    
86.
Massagué J. TGFbeta in Cancer. Cell 2008; 134(2): 215-30.   Back to cited text no. 86
    
87.
Anido J, Sáez-Borderías A, Gonzàlez-Juncà A, Rodón L, Folch G, Carmona MA, Prieto-Sánchez RM, Barba I, Martínez-Sáez E, Prudkin L, Cuartas I, Raventós C, Martínez-Ricarte F, Poca MA, García-Dorado D, Lahn MM, Yingling JM, Rodón J, Sahuquillo J, Baselga J, Seoane J. TGF-beta Receptor Inhibitors Target the CD44(high)/Id1(high) Glioma-Initiating Cell Population in Human Glioblastoma. Cancer cell 2010; 18(6): 655-68.   Back to cited text no. 87
    
88.
Lv S, Sun B, Dai C, Shi R, Zhou X, Lv W, Zhong X, Wang R, Ma W. The Downregulation of MicroRNA-146a Modulates TGF-â Signaling Pathways Activity in Glioblastoma. Mol Neurobiol 2DOI: 10.1007/s12035-014-8938-8.  Back to cited text no. 88
    
89.
Ruiz i Altaba A, Mas C, Stecca B. The Gli code: an information nexus regulating cell fate, stemness and cancer. Trends Cell Biol 2007; 17(9): 438-47.  Back to cited text no. 89
    
90.
Clement V, Sanchez P, de Tribolet N, Radovanovic I, Ruiz i Altaba A. HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol 2007; 17(2): 165-72.  Back to cited text no. 90
    
91.
Bar EE, Chaudhry A, Lin A, Fan X, Schreck K, Matsui W, Piccirillo S, Vescovi AL, DiMeco F, Olivi A, Eberhart CG. Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells 2007; 25(10): 2524-33.  Back to cited text no. 91
    
92.
Ehtesham M, Sarangi A, Valadez JG, Chanthaphaychith S, Becher MW, Abel TW, Thompson RC, Cooper MK. Ligand-dependent activation of the hedgehog pathway in glioma progenitor cells. Oncogene 2007; 26(39): 5752-61.  Back to cited text no. 92
    
93.
Xu Q, Yuan X, Liu G, Black KL, Yu JS. Hedgehog signaling regulates brain tumor-initiating cell proliferation and portends shorter survival for patients with PTEN-coexpressing glioblastomas. Stem Cells 2008; 26(12): 3018-26.  Back to cited text no. 93
    
94.
Gu W, Shou J, Gu S, Sun B, Che X. Identifying hedgehog signaling specific microRNAs in glioblastomas. Int J Med Sci 2014; 11(5): 488-93.   Back to cited text no. 94
    
95.
Ferretti E, De Smaele E, Miele E, Laneve P, Po A, Pelloni M, Paganelli A, Di Marcotullio L, Caffarelli E, Screpanti I, Bozzoni I, Gulino A. Concerted microRNA control of Hedgehog signalling in cerebellar neuronal progenitor and tumour cells. EMBO J 2008; 27(19): 2616-27.   Back to cited text no. 95
    
96.
Woodward WA, Chen MS, Behbod F, Alfaro MP, Buchholz TA, Rosen JM. WNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells. Proc Natl Acad Sci USA 2007; 104(2): 618-23.  Back to cited text no. 96
    
97.
Cao Y, Lathia JD, Eyler CE, Wu Q, Li Z, Wang H, McLendon RE, Hjelmeland AB, Rich JN. Erythropoietin receptor signaling through STAT3 is required for glioma stem cell maintenance. Genes Cancer 2010; 1(1): 50-61.  Back to cited text no. 97
    
98.
Wei J, Wang F, Kong LY, Xu S, Doucette T, Ferguson SD, Yang Y, McEnery K, Jethwa K, Gjyshi O, Qiao W, Levine NB, Lang FF, Rao G, Fuller GN, Calin GA, Heimberger AB. miR-124 inhibits STAT3 signaling to enhance T cell-mediated immune clearance of glioma. Cancer Res 2013; 73(13): 3913-26.   Back to cited text no. 98
    
99.
Wang YY, Sun G, Luo H, Wang XF, Lan FM, Yue X, Fu LS, Pu PY, Kang CS, Liu N, You YP. MiR-21 Modulates hTERT Through a STA T3-Dependent Manner on Glioblas toma Cell Growth. CNS Neurosci Ther 2012; 18(9): 722-8.   Back to cited text no. 99
    
100.
Zhou X, Ren Y, Moore L, Mei M, You Y, Xu P, Wang B, Wang G, Jia Z, Pu P, Zhang W, Kang C. Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status. Lab Invest 2010; 90(2): 144-55.  Back to cited text no. 100
    
101.
Zhang C, Wang G, Kang C, Du Y, Pu P. Up-regulation of p27(kip1) by miR-221/222 antisense oligonucleotides enhances the radiosensitivity of U251 glioblastoma. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2009; 26(6): 634-8. (in Chinese)  Back to cited text no. 101
    
102.
Webster RJ, Giles KM, Price KJ, Zhang PM, Mattick JS, Leedman PJ. Regulation of epidermal growth factor receptor signaling in human cancer cells by microRNA-7. J Biol Chem 2009; 284(9): 5731-41.  Back to cited text no. 102
    
103.
Gal H, Pandi G, Kanner AA, Ram Z, Lithwick-Yanai G, Amariglio N, Rechavi G, Givol D. MIR-451 and Imatinib mesylate inhibit tumor growth of Glioblastoma stem cells. Biochem Biophys Res Commun 2008; 376(1): 86-90.  Back to cited text no. 103
    
104.
Costa PM, Cardoso AL, Custódia C, Cunha P, Pereira de Almeida L, Pedroso de Lima MC. MiRNA-21 silencing mediated by tumor-targeted nanoparticles combined with sunitinib: a new multimodal gene therapy approach for glioblastoma. J Control Release 2015; 207: 31-9.  Back to cited text no. 104
    
105.
Yang CH, Yue J, Pfeffer SR, Fan M, Paulus E, Hosni-Ahmed A, Sims M, Qayyum S, Davidoff AM, Handorf CR, Pfeffer LM. MicroRNA-21 Promotes Glioblastoma Tumorigenesis by Down-regulating Insulin-like Growth Factor-binding Protein-3 (IGFBP3). J Biol Chem 2014; 289(36): 25079-87.  Back to cited text no. 105
    
106.
Shang C, Guo Y, Hong Y, Liu YH, Xue YX. MiR-21 up-regulation mediates glioblastoma cancer stem cells apoptosis and proliferation by targeting FASLG. Mol Biol Rep 2015; 42(3): 721-7.   Back to cited text no. 106
    
107.
Han L, Yue X, Zhou X, Lan FM, You G, Zhang W, Zhang KL, Zhang CZ, Cheng JQ, Yu SZ, Pu PY, Jiang T, Kang CS. MicroRNA-21 Expression is regulated by â -catenin/STAT3 Pathway and Promotes Glioma Cell Invasion by Direct Targeting RECK. CNS Neurosci Ther 2012; 18(7): 573-83.   Back to cited text no. 107
    
108.
Gwak HS, Kim TH, Jo GH, Kim YJ, Kwak HJ, Kim JH, Yin J, Yoo H, Lee SH, Park JB. Silencing of microRNA-21 confers radio-sensitivity through inhibition of the PI3K/AKT pathway and enhancing autophagy in malignant glioma cell lines. PLoS One 2012; 7(10): e47449.  Back to cited text no. 108
    
109.
Ren Y, Zhou X, Mei M, Yuan XB, Han L, Wang GX, Jia ZF, Xu P, Pu PY, Kang CS. MicroRNA-21 inhibitor sensitizes human glioblastoma cells U251(PTEN-mutant) and LN229(PTEN- wild type) totaxol. BMC Cancer 2010; 10: 27.  Back to cited text no. 109
    
110.
Qian X, Ren Y, Shi Z, Long L, Pu P, Sheng J, Yuan X, Kang C. Sequence-Dependent Synergistic Inhibition of Human Glioma Cell Lines by Combined Temozolomide and miR-21 Inhibitor Gene Therapy. Mol Pharm 2012; 9(9): 2636-45.  Back to cited text no. 110
    
111.
Hermansen SK, Dahlrot RH, Nielsen BS, Hansen S, Kristensen BW. MiR-21 expression in the tumor cell compartment holds unfavorable prognostic value in gliomas. J Neurooncol 2013; 111(1): 71-81.  Back to cited text no. 111
    
112.
Dong CG, Wu WK, Feng SY, Wang XJ, Shao JF, Qiao J. Co-inhibition of microRNA-10b and microRNA-21 exerts synergistic inhibition on the proliferation and invasion of human glioma cells. Int J Oncol 2012; 41(3): 1005-12.  Back to cited text no. 112
    
113.
Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P, Taccioli C, Volinia S, Liu CG, Alder H, Calin GA, Ménard S, Croce CM. MicroRNA signatures in human ovarian cancer. Cancer Res 2007; 67(18): 8699-707.  Back to cited text no. 113
    
114.
Cadieux B, Ching TT, VandenBerg SR, Costello JF. Genome-wide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation. Cancer Res 2006; 66(17): 8469-76.  Back to cited text no. 114
    
115.
Huse JT, Brennan C, Hambardzumyan D, Wee B, Pena J, Rouhanifard SH, Sohn-Lee C, le Sage C, Agami R, Tuschl T, Holland EC. The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo. Genes Dev 2009; 23(11): 1327-37.  Back to cited text no. 115
    
116.
Rao SA, Santosh V, Somasundaram K. Genome-wide expression profiling identifies deregulated miRNAs in malignant astrocytoma. Mod Pathol 2010; 23(10): 1404-17.  Back to cited text no. 116
    
117.
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. Gliomas display a microRNA expression profile reminiscent of neural precursor cells. Neuro Onco 2010; 12(5): 422-33.  Back to cited text no. 117
    
118.
Aguda BD, Kim Y, Piper-Hunter MG, Friedman A, Marsh CB. MicroRNA regulation of a cancer network: consequences of the feedback loops involving miR-17-92, E2F, and Myc. Proc Natl Acad Sci USA 2008; 105(50): 19678-83.  Back to cited text no. 118
    
119.
Mendell JT. miRiad roles for the miR-17-92 cluster in development and disease. Cell 2008; 133(2): 217-22.  Back to cited text no. 119
    
120.
Petrocca F, Vecchione A, Croce CM. Emerging role of miR-106b-25/miR-17-92 clusters in the control of transforming growth factor beta signaling. Cancer Res 2008; 68(20): 8191-4.  Back to cited text no. 120
    
121.
Uziel T, Karginov FV, Xie S, Parker JS, Wang YD, Gajjar A, He L, Ellison D, Gilbertson RJ, Hannon G, Roussel MF. The miR-17B92 cluster collaborates with the Sonic Hedgehog pathway in medulloblastoma. Proc Natl Acad Sci USA 2009; 106(8): 2812-7.  Back to cited text no. 121
    
122.
Dong H, Siu H, Luo L, Fang X, Jin L, Xiong M. Investigation gene and microRNA expression in glioblastoma. BMC Genomics 2010; 11(Suppl 3): S16.  Back to cited text no. 122
    
123.
Fang L, Deng Z, Shatseva T, Yang J, Peng C, Du WW, Yee AJ, Ang LC, He C, Shan SW, Yang BB. MicroRNA miR-93 promotes tumor growth and angiogenesis by targeting integrin-â8. Oncogene 2011; 30(7): 806-21.  Back to cited text no. 123
    
124.
Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB. Prediction of mammalian microRNA targets. Cell 2003; 115(7): 787-98.   Back to cited text no. 124
    
125.
Conti A, Aguennouz M, La Torre D, Tomasello C, Cardali S, Angileri FF, Maio F, Cama A, Germanò A, Vita G, Tomasello F. miR-21 and 221 upregulation and miR-181b downregulation in human grade II-IV astrocytic tumors. J. Neurooncol 2009; 93(3): 325-32.   Back to cited text no. 125
    
126.
Lukiw WJ, Cui JG, Li YY, Culicchia F. 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 2009; 91(1): 27-32.  Back to cited text no. 126
    
127.
Gillies JK1, Lorimer IA. Regulation of p27Kip1 by miRNA 221/222 in glioblastoma. Cell Cycle 2007; 6(16): 2005-9.  Back to cited text no. 127
    
128.
Medina R, Zaidi SK, Liu CG, Stein JL, van Wijnen AJ, Croce CM, Stein GS. MicroRNAs 221 and 222 bypass quiescence and compromise cell survival. Cancer Res 2008; 68(8): 2773-80.   Back to cited text no. 128
    
129.
Piva R, Cavalla P, Bortolotto S, Cordera S, Richiardi P, Schiffer D. p27/kip1 expression in human astrocytic gliomas. Neurosci Lett 1997; 234(2-3): 127-30.  Back to cited text no. 129
    
130.
González T, Seoane M, Caamaño P, Viñuela J, Domínguez F, Zalvide J. Inhibition of Cdk4 activity enhances translation of p27kip1 in quiescent Rbnegative cells. J Biol Chem 2003; 278(15): 12688-95.  Back to cited text no. 130
    
131.
Zhang J, Han L, Ge Y, Zhou X, Zhang A, Zhang C, Zhong Y, You Y, Pu P, Kang C. miR-221/222 promote malignant progression of glioma through activation of the Akt pathway. Int J Oncol 2010; 36(4): 913-20.  Back to cited text no. 131
    
132.
Chen X, Hao B, Han G, Liu Y, Dai D, Li Y, Wu X, Zhou X, Yue Z, Wang L, Cao Y, Liu J. MiR- 372 regulates glioma cell proliferation and invasion by directly targeting PHLPP2. J Cell Biochem 2015; 116(2): 225-32.   Back to cited text no. 132
    
133.
Li G, Zhang Z, Tu Y, Jin T, Liang H, Cui G, He S, Gao G. Correlation of microrna-372 upregulation with poor prognosis in human glioma. Diagn Pathol 2013; 8: 1.  Back to cited text no. 133
    
134.
Guo P, Lan J, Ge J, Nie Q, Mao Q, Qiu Y. miR-708 acts as a tumor suppressor in human glioblastoma cells. Oncol Rep 2013; 30(2): 870-6.  Back to cited text no. 134
    
135.
Lu S, Wang S, Geng S, Ma S, Liang Z, Jiao B. Increased Expression of microRNA-17 Predicts Poor Prognosis in Human Glioma. J Biomed Biotechnol 2012; 2012: 970  Back to cited text no. 135
    
136.
Chen L, Han L, Zhang K, Shi Z, Zhang J, Zhang A, Wang Y, Song Y, Li Y, Jiang T, Pu P, Jiang C, Kang C. VHL regulates the effects of miR-23b on glioma survival and invasion via suppression of HIF-1a/VEGF andb-catenin/Tcf-4 signaling. Neuro Oncol 2012; 14(8): 1026-36.   Back to cited text no. 136
    
137.
Wang K, Wang X, Zou J, Zhang A, Wan Y, Pu P, Song Z, Qian C, Chen Y, Yang S, Wang Y. miR-92b controls glioma proliferation and invasion through regulating Wnt/beta-catenin signaling via Nemo-like kinase. Neuro Oncol 2013; 15(5): 578-88.   Back to cited text no. 137
    
138.
Lv S, Sun B, Dai C, Shi R, Zhou X, Lv W, Zhong X, Wang R, Ma W. The Downregulation of MicroRNA-146a Modulates TGF-â Signaling Pathways Activity in Glioblastoma. Mol Neurobio 2doi: 10.1007/s12035-014-8938-8.  Back to cited text no. 138
    
139.
Sun L, Yan W, Wang Y, Sun G, Luo H, Zhang J, Wang X, You Y, Yang Z, Liu N. MicroRNA-10b induces glioma cell invasion by modulating MMP-14 and uPAR expression via HOXD10. Brain Res 2011; 1389: 9-18.  Back to cited text no. 139
    
140.
Sasayama T, Nishihara M, Kondoh T, Hosoda K, Kohmura E. MicroRNA-10b is overexpressed in malignant glioma and associated with tumor invasive factors, uPAR and RhoC. Int J Cancer 2009; 125(6): 1407-13.  Back to cited text no. 140
    
141.
Wuchty S, Arjona D, Li A, Kotliarov Y, Walling J, Ahn S, Zhang A, Maric D, Anolik R, Zenklusen JC, Fine HA. Prediction of associations between microRNAs and gene expression in glioma biology. PLoS One 2011; 6(2): e14681.  Back to cited text no. 141
    
142.
Lages E, Guttin A, El Atifi 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 JP. MicroRNA and target protein patterns reveal physiopathological features of glioma subtypes. PLoS One 2011; 6(5): e20600.  Back to cited text no. 142
    
143.
Xia H, Qi Y, Ng SS, Chen X, Chen S, Fang M, Li D, Zhao Y, Ge R, Li G, Chen Y, He ML, Kung HF, Lai L, Lin MC. MicroRNA-15b regulates cell cycle progression by targeting cyclins in glioma cells. Biochem Biophys Res Commun 2009; 380(2): 205-10.  Back to cited text no. 143
    
144.
Malzkorn B, Wolter M, Liesenberg F, Grzendowski M, Stühler K, Meyer HE, Reifenberger G. Identification and functional characterization of microRNAs involved in the malignant progression of gliomas. Brain Pathol 2010; 20(3): 539-50.  Back to cited text no. 144
    
145.
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. The myc-miR-17-92 axis blunts TGFâ signaling and production of multiple TGFâ-dependent antiangiogenic factors. Cancer Res 2010; 70(20): 8233-46.  Back to cited text no. 145
    
146.
Wang H, Sun T, Hu J, Zhang R, Rao Y, Wang S, Chen R, McLendon RE, Friedman AH, Keir ST, Bigner DD, Li QJ, Wang H, Wang XF. miR-33a promotes glioma-initiating cell self-renewal via PKA and NOTCH pathways. J Clin Invest 2014; 124(10): 4489-502.  Back to cited text no. 146
    
147.
Dong H, Luo L, Hong S, Siu H, Xiao Y, Jin L, Chen R, Xiong M. Integrated analysis of mutations, miRNA and mRNA expression in glioblastoma. BMC Syst Biol 2010; 4: 163.  Back to cited text no. 147
    
148.
Jiang L, Mao P, Song L, Wu J, Huang J, Lin C, Yuan J, Qu L, Cheng SY, Li J. miR-182 as a prognostic marker for glioma progression and patient survival. Am J Pathol 2010; 177(1): 29-38.  Back to cited text no. 148
    
149.
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. Targeting oncogenic miR-335 inhibits growth and invasion of malignant astrocytoma cells. Mol Cancer 2011; 10: 59.  Back to cited text no. 149
    
150.
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. Interaction of hsamiR-381 and glioma suppressor LRRC4 is involved in glioma growth. Brain Res 2011; 1390: 21-32.  Back to cited text no. 150
    
151.
Sempere LF, Freemantle S, Pitha-Rowe I, Moss E, Dmitrovsky E, Ambros V. Expression profiling of mammalian microRNAs uncovers a subset of brainexpressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biol 2004; 5(3): R13.  Back to cited text no. 151
    
152.
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. MicroRNA-128 inhibits glioma cells proliferation by targeting transcription factor E2F3a. J Mol Med 2009; 87(1): 43-51.  Back to cited text no. 152
    
153.
Godlewski J, Nowicki MO, Bronisz A, Williams S, Otsuki A, Nuovo G, Raychaudhury A, Newton HB, Chiocca EA, Lawler S. Targeting of the Bmi-1 oncogene/stem cell renewal factor by microRNA-128 inhibits glioma proliferation and self-renewal. Cancer Res 2008; 68(22): 9125-30.  Back to cited text no. 153
    
154.
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. Pro-neural miR-128 is a glioma tumor suppressor that targets mitogenic kinases. Oncogene 2012; 31(15): 1884-95.  Back to cited text no. 154
    
155.
Peruzzi P, Bronisz A, Nowicki MO, Wang Y, Ogawa D, Price R, Nakano I, Kwon CH, Hayes J, Lawler SE, Ostrowski MC, Chiocca EA, Godlewski J. MicroRNA-128 coordinately targets Polycomb Repressor Complexes in glioma stem cells. Neuro Oncol 2013; 15(9): 1212-24.   Back to cited text no. 155
    
156.
Lin L, Chen X, Peng X, Zhou J, Kung HF, Lin MC, Jiang S. MicroRNA-128 promotes cell-cell adhesion in U87 glioma cells via regulation of EphB2. Oncol Rep 2013; 30(3): 1239-48.   Back to cited text no. 156
    
157.
Shi ZM, Wang J, Yan Z, You YP, Li CY, Qian X, Yin Y, Zhao P, Wang YY, Wang XF, Li MN, Liu LZ, Liu N, Jiang BH. MiR-128 inhibits tumor growth and angiogenesis by targeting p70S6K1. PLoS One 2012; 7(3): e32709.  Back to cited text no. 157
    
158.
Dong Q, Cai N, Tao T, Zhang R, Yan W, Li R, Zhang J, Luo H, Shi Y, Luan W, Zhang Y, You Y, Wang Y, Liu N. An xis Involving SNAI1, microRN A-128 and SP1 Modulates Glioma Progression. PLoS One 2014; 9(6): e98  Back to cited text no. 158
    
159.
Haas-Kogan D, Shalev N, Wong M, Mills G, Yount G, Stokoe D. Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC. Curr Biol 1998; 8(21): 1195-8.  Back to cited text no. 159
    
160.
Wong AJ, Bigner SH, Bigner DD, Kinzler KW, Hamilton SR, Vogelstein B. Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci USA 1987; 84(19): 6899-  Back to cited text no. 160
    
161.
Liu Z, Jiang Z, Huang J, Huang S, Li Y, Yu S, Yu S, Liu X. miR-7 inhibits glioblastoma growth by simultaneously interfering with the PI3K/ATK and Raf/MEK/ERK pathways. Int J Oncol 2014; 44(5): 1571-80.   Back to cited text no. 161
    
162.
Wu DG, Wang YY, Fan LG, Luo H, Han B, Sun LH, Wang XF, Zhang JX, Cao L, Wang XR, You YP, Liu N. MicroRNA-7 regulates glioblastoma cell invasion via targeting focal adhesion kinase expression, Chin Med J (Engl) 2011; 124(17): 2616-21.   Back to cited text no. 162
    
163.
Wang B, Sun F, Dong N, Sun Z, Diao Y, Zheng C, Sun J, Yang Y, Jiang D. MicroRNA-7 directly targets insulin-like growth factor 1 receptor to inhibit cellular growth and glucose metabolism in gliomas. Diagn Pathol 2014; 9(1): 211.  Back to cited text no. 163
    
164.
Liu Z, Liu Y, Li L, Xu Z, Bi B, Wang Y, Li JY. MiR-7-5p is frequently downregulated in glioblastoma microvasculature and inhibits vascular endothelial cell proliferation by targeting RAF1. Tumour Biol 2014; 35(10): 10177-84.   Back to cited text no. 164
    
165.
Babae N, Bourajjaj M, Liu Y, Van Beijnum JR, Cerisoli F, Scaria PV, Verheul M, Van Berkel MP, Pieters EH, Van Haastert RJ, Yousefi A, Mastrobattista E, Storm G, Berezikov E, Cuppen E, Woodle M, Schaapveld RQ, Prevost GP, Griffioen AW, Van Noort PI, Schiffelers RM. Systemic miRNA-7 delivery inhibits tumor angiogenesis and growth in murine xenograft glioblastoma. Oncotarget 2014; 5(16): 6687-700.  Back to cited text no. 165
    
166.
Song L, Huang Q, Chen K, Liu L, Lin C, Dai T, Yu C, Wu Z, Li J. miR-218 inhibits the invasive ability of glioma cells by direct downregulation of IKK-â. Biochem Biophys Res Commun 2010; 402(1): 135-40.   Back to cited text no. 166
    
167.
Xia H, Yan Y, Hu M, Wang Y, Wang Y, Dai Y, Chen J, Di G, Chen X, Jiang X. MiR-218 sensitizes glioma cells to apoptosis and inhibits tumorigenicity by regulating ECOP-mediated suppression of NF-kâ activity. Neuro Oncol 2013; 15(4): 413-22.   Back to cited text no. 167
    
168.
Park S, James CD. ECop (EGFR-coamplified and overexpressed protein), a novel protein, regulates NF-kB transcriptional activity and associated apoptotic response in an Ikk-dependent manner. Oncogene 2005; 24(15): 2495-502.  Back to cited text no. 168
    
169.
Liu Y, Yan W, Zhang W, Chen L, You G, Bao Z, Wang Y, Wang H, Kang C, Jiang T. MiR-218 reverses high invasiveness of glioblastoma cells by targeting the oncogenic transcription factor LEF1. Oncol Rep 2012; 28(3): 1013-21.   Back to cited text no. 169
    
170.
Tu Y, Gao X, Li G, Fu H, Cui D, Liu H, Jin W, Zhang Y. MicroRNA-218 Inhibits Glioma Invasion, Migration, Proliferation, and Cancer Stem-like Cell Self-Renewal by Targeting the Polycomb Group GeneBmi1. Cancer Res 2013; 73(19): 6046-55.   Back to cited text no. 170
    
171.
Mathew LK, Skuli N, Mucaj V, Lee SS, Zinn PO, Sathyan P, Imtiyaz HZ, Zhang Z, Davuluri RV, Rao S, Venneti S, Lal P, Lathia JD, Rich JN, Keith B, Minn AJ, Simon MC. miR-218 opposes a critical RTK-HIF pathway in mesenchymal glioblastoma. Proc Natl Acad Sci USA 2014; 111(1): 291-6.  Back to cited text no. 171
    
172.
Shi L, Cheng Z, Zhang J, Li R, Zhao P, Fu Z, You Y. has-mir-181a and hsa-mir-181b function as tumor suppressors in human glioma cells. Brain Res 2008; 1236: 185-93.   Back to cited text no. 172
    
173.
Chen G, Zhu W, Shi D, Lv L, Zhang C, Liu P, Hu W. MicroRNA-181a sensitizes human malignant glioma U87MG cells to radiation by targeting Bcl-2. Oncol Rep 2010; 23(4): 997-1003.  Back to cited text no. 173
    
174.
She X, Yu Z, Cui Y, Lei Q, Wang Z, Xu G, Luo Z, Li G, Wu M. miR-181 subunits enhance the chemosensitivity of temozolomide by Rap1B-mediated cytoskeleton remodeling in glioblastoma cells. Med Oncol 2014; 31(4): 892.  Back to cited text no. 174
    
175.
Gong A, Ge N, Yao W, Lu L, Liang H. Aplysin enhances temozolomide sensitivity in glioma cells by increasing miR-181 level. Cancer Chemother Pharmacol 2014; 74(3): 531-8.   Back to cited text no. 175
    
176.
Wang F, Sun JY, Zhu YH, Liu NT, Wu YF, Yu F. MicroRNA-181 inhibits glioma cell proliferation by targeting cyclin B1. Mol Med Rep 2014; 10(4): 2160-4.   Back to cited text no. 176
    
177.
Du W, Liu X, Chen L, Dou Z, Lei X, Chang L, Cai J, Cui Y, Yang D, Sun Y, Li Y, Jiang C. Targeting the SMO oncogene by miR-326 inhibits glioma biological behaviors and stemness. Neuro Oncol 2015; 17(2): 243-53.  Back to cited text no. 177
    
178.
Wang S, Lu S, Geng S, Ma S, Liang Z, Jiao B. Expression and clinical significance of microRNA-326 in human glioma miR-326 expression in glioma. Med Oncol 2013; 30(1):   Back to cited text no. 178
    
179.
Wang S, Jiao B, Geng S, Ma S, Liang Z, Lu S. Combined aberrant expression of microRNA-214 and UBC9 is an independent unfavorable prognostic factor for patients with gliomas. Med Oncol 2014; 31(1): 767.  Back to cited text no. 179
    
180.
Zhang R, Luo H, Wang S, Chen Z, Hua L, Wang HW, Chen W, Yuan Y, Zhou X, Li D, Shen S, Jiang T, You Y, Liu N, Wang H. miR-622 suppresses proliferation, invasion and migration by directly targeting activating transcription factor 2 in glioma cells. J Neurooncol 2014; 121(1): 63-72.  Back to cited text no. 180
    
181.
He J, Deng Y, Yang G, Xie W. MicroRNA-203 Down-Regulation Is Associated With Unfavorable Prognosis in Human Glioma. J Surg Oncol 2013; 108(2): 121-5.   Back to cited text no. 181
    
182.
Kefas B, Floyd DH, Comeau L, Frisbee A, Dominguez C, Dipierro CG, Guessous F, Abounader R, Purow B. A miR-297/hypoxia/DGK-aaxis regulating glioblastoma survival. Neuro Oncol 2013; 15(12): 1652-63.   Back to cited text no. 182
    
183.
Silber J, Jacobsen A, Ozawa T, Harinath G, Pedraza A, Sander C, Holland EC, Huse JT. miR-34a repression in proneural malignant gliomas upregulates expression of its target PDGFRA and Promotes tumorigenesis. PLoS One 2012; 7(3): e33844.  Back to cited text no. 183
    
184.
Luan S, Sun L, Huang F. MicroRNA-34a: a novel tumor suppressor in p53-mutant glioma cell line UArch Med Res 2012; 41(2): 67-74.  Back to cited text no. 184
    
185.
Guessous F, Zhang Y, Kofman A, Catania A, Li Y, Schiff D, Purow B, Abounader R. microRNA-34a is tumor suppressive in brain tumors and glioma stem cells. Cell Cycle 2010; 9(6): 1031-6.  Back to cited text no. 185
    
186.
Li D, Chen P, Li XY, Zhang LY, Xiong W, Zhou M, Xiao L, Zeng F, Li XL, Wu MH, Li GY. Grade-specific expression profiles of miRNAs/mRNAs and docking study in human grade I-III astrocytomas. OMICS 2011; 15(10): 673-82.  Back to cited text no. 186
    
187.
Ng WL, Yan D, Zhang X, Mo YY, Wang Y. Overexpression of miR-100 is responsible for the low-expression of ATM in the human glioma cell line: M059J. DNA Repair (Amst) 2010; 9(11): 1170-5.  Back to cited text no. 187
    
188.
Vo DT, Qiao M, Smith AD, Burns SC, Brenner AJ, Penalva LO. The oncogenic RNA-binding protein Musashi1 is regulated by tumor suppressor miRNAs. RNA Biol 2011; 8(5): 817-28.  Back to cited text no. 188
    
189.
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. miR-101 is down-regulated in glioblastoma resulting in EZH2-induced proliferation, migration, and angiogenesis. Oncotarget 2010; 1(8): 710-20.  Back to cited text no. 189
    
190.
Yang TQ, Lu XJ, Wu TF, Ding DD, Zhao ZH, Chen GL, Xie XS, Li B, Wei YX, Guo LC, Zhang Y, Huang YL, Zhou YX, Du ZW. MicroRNA-16 inhibits glioma cell growth and invasion through suppression of BCL2 and the nuclear factor-jB1⁄MMP9 signaling pathway. Cancer Sci 2014; 105(3): 265-71.  Back to cited text no. 190
    
191.
Chen W, Yang Y, Chen B, Lu P, Zhan L, Yu Q, Cao K, Li Q. MiR-136 targets E2F1 to reverse cisplatin chemosensitivity in glioma cells. J Neurooncol 2014; 120(1): 43-53.  Back to cited text no. 191
    
192.
Wu H, Liu Q, Cai T, Chen YD, Liao F, Wang ZF. MiR-136 modulates glioma cell sensitivity to temozolomide by targeting astrocyte elevated gene-1. Diagn Pathol 2014; 9: 173.  Back to cited text no. 192
    
193.
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 CY, Zhang J, Yang Y. The use of hsa-miR-21, hsa-miR-181b and hsa-miR-106a as prognostic indicators of astrocytoma. Eur J Cancer 2010; 46(9): 1640-9.  Back to cited text no. 193
    
194.
Zhang C, Han L, Zhang A, Yang W, Zhou X, Pu P, Du Y, Zeng H, Kang C. Global changes of mRNA expression reveals an increased activity of the interferon-induced signaltransducer and activator of transcription (STAT) pathway by repression of miR-221/222 inglioblastoma U251 cells. Int J Onco 2010; 36(6): 1503-12.  Back to cited text no. 194
    
195.
Ma J, Yao Y, Wang P, Liu Y, Zhao L, Li Z, Li Z, Xue Y. MiR-152 functions as a tumor suppressor in glioblastoma stem cells by targeting Krüppel-like factor 4. Cancer Lett 2014; 355(1): 85-95.  Back to cited text no. 195
    
196.
Wang S, Jiao B, Geng S, Song J, Liang Z, Lu S. Concomitant microRNA-31 downregulation and radixin upregulation predicts advanced tumor progression and unfavorable prognosis in patients with gliomas. J Neurol Sci 2014; 338(1-2): 71-6.  Back to cited text no. 196
    
197.
Xu S, Wei J, Wang F, Kong LY, Ling XY, Nduom E, Gabrusiewicz K, Doucette T, Yang Y, Yaghi NK, Fajt V, Levine JM, Qiao W, Li XG, Lang FF, Rao G, Fuller GN, Calin GA, Heimberger AB. Effect of mir-142-3p on the M2 Macrophage and therapeutic efficacy Against Murine Glioblastoma. J Natl Cancer Inst 2014; 106(8): pii: dju162.  Back to cited text no. 197
    
198.
Hou SX, Ding BJ, Li HZ, Wang L, Xia F, Du F, Liu LJ, Liu YH, Liu XD, Jia JF, Li L, Wu ZL, Zhao G, Zhang ZG, Deng YC. Identification of microRNA-205 as a potential prognostic indicator for human glioma. J Clin Neurosci 2013; 20(7): 933-7.  Back to cited text no. 198
    
199.
Emdad L, Janjic A, Alzubi MA, Hu B, Santhekadur PK, Menezes ME, Shen XN, Das SK, Sarkar D, Fisher PB. Suppression of miR-184 in malignant gliomas upregulates SND1 and promotes tumor aggressiveness. Neuro Oncol 2014; 17(3): 412-29.  Back to cited text no. 199
    
200.
Yuan Q, Gao W, Liu B, Ye W. Upregulation of miR-184 Enhances the Malignant Biological Behavior of Human Glioma Cell Line A172 by Targeting FIH-1. Cell Physiol Biochem 2014; 34(4): 1125-36.   Back to cited text no. 200
    
201.
Cui QK, Liu WD, Zhu JX, Wang YH, Wang ZG. MicroRNA-184 promotes proliferation ability of glioma cells by regulating FOXO3. Asian Pac J Trop Med 2014; 7(10): 776-9.  Back to cited text no. 201
    
202.
Foley NH, Bray IM, Tivnan A, Bryan K, Murphy DM, Buckley PG, Ryan J, O'Meara A, O'Sullivan M, Stallings RL. MicroRNA-184 inhibits neuroblastoma cell survival through targeting the serine/threonine kinase AKT2. Mol Cancer 2010; 9:83.  Back to cited text no. 202
    
203.
Tivnan A, Foley NH, Tracey L, Davidoff AM, Stallings RL. MicroRNA-184-Mediated Inhibition of Tumour Growth in an Orthotopic Murine Model of Neuroblastoma. Anticancer Res 2010; 30(11): 4391-5.  Back to cited text no. 203
    
204.
Gao B, Gao K, Li L, Huang Z, Lin L. miR-184 functions as an oncogenic regulator in hepatocellular carcinoma (HCC). Biomed Pharmacother 2014; 68(2): 143-8.   Back to cited text no. 204
    
205.
Wu GG, Li WH, He WG, Jiang N, Zhang GX, Chen W, Yang HF, Liu QL, Huang YN, Zhang L, Zhang T, Zeng XC. Mir-184 Post-Transcriptionally Regulates SOX7 Expression and Promotes Cell Proliferation in Human Hepatocellular Carcinoma. PLoS One 2014; 9(2): e88  Back to cited text no. 205
    
206.
Wong TS, Liu XB, Wong BY, Ng RW, Yuen AP, Wei WI. Mature miR-184 as Potential Oncogenic microRNA of Squamous Cell Carcinoma of Tongu. Clin Cancer Res 2008; 14(9): 2588-92.   Back to cited text no. 206
    
207.
Rani SB, Rathod SS, Karthik S, Kaur N, Muzumdar D, Shiras AS. MiR-145 functions as a tumor-suppressive RNA by targeting Sox9 and adducin 3 in human glioma cells. Neuro Oncol 2013; 15(10): 1302-16.   Back to cited text no. 207
    
208.
Yang YP, Chien Y, Chiou GY, Cherng JY, Wang ML, Lo WL, Chang YL, Huang PI, Chen YW, Shih YH, Chen MT, Chiou SH. Inhibition of cancer stem cell-like properties and reduced chemoradioresistance of glioblastoma using microRNA145 with cationic polyurethane-short branch PEI. Biomaterials 2012; 33(5): 1462-76.   Back to cited text no. 208
    
209.
Koo S, Martin GS, Schulz KJ, Ronck M, Toussaint LG. Serial selection for invasiveness increases expression of miR-143/miR-145 in glioblastoma cell lines. BMC Cancer 2012; 12: 143.  Back to cited text no. 209
    
210.
Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR. MicroRNA expression profiles classify human cancers. Nature 2005; 435(7043): 834-8.  Back to cited text no. 210
    
211.
Roldo C, Missiaglia E, Hagan JP, Falconi M, Capelli P, Bersani S, Calin GA, Volinia S, Liu CG, Scarpa A, Croce CM. MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior. J Clin Oncol 2006; 24(29): 4677-84.  Back to cited text no. 211
    
212.
Bloomston M, Frankel WL, Petrocca F, Volinia S, Alder H, Hagan JP, Liu CG, Bhatt D, Taccioli C, Croce CM. MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA 2007; 297(17): 1901-8.   Back to cited text no. 212
    
213.
Satzger I, Mattern A, Kuettler U, Weinspach D, Voelker B, Kapp A, Gutzmer R. MicroRNA-15b represents an independent prognostic parameter and is correlated with tumor cell proliferation and apoptosis in malignant melanoma. Int J Cancer 2010; 126(11): 2553-62.   Back to cited text no. 213
    
214.
Ji J, Shi J, Budhu A, Yu Z, Forgues M, Roessler S, Ambs S, Chen Y, Meltzer PS, Croce CM, Qin LX, Man K, Lo CM, Lee J, Ng IO, Fan J, Tang ZY, Sun HC, Wang XW. MicroRNA expression, survival, and response to interferon in liver cancer. N Engl J Med 2009; 361(15): 1437-47.  Back to cited text no. 214
    
215.
Nelson KM, Weiss GJ. MicroRNAs and cancer: past, present, and potential future. Mol Cancer Ther 2008; 7(12): 3655-60.  Back to cited text no. 215
    
216.
O'Hara SP, Mott JL, Splinter PL, Gores GJ, LaRusso NF. MicroRNAs: key modulators of posttranscriptional gene expression. Gastroenterology 2009; 136(1): 17-25.  Back to cited text no. 216
    
217.
Wong ST, Zhang XQ, Zhuang JT, Chan HL, Li CH, Leung GK. MicroRNA-21 Inhibition Enhances In Vitro Chemosensitivity of Temozolomide-resistant Glioblastoma Cells. Anticancer Res 2012; 32(7): 2835-41.  Back to cited text no. 217
    
218.
Griveau A, Bejaud J, Anthiya S, Avril S, Autret D, Garcion E. Silencing of miR-21 by locked nucleic acid-lipid nanocapsule complexes sensitize human glioblastoma cells to radiation-induced cell death. Int J Pharm 2013; 454(2): 765-74.   Back to cited text no. 218
    
219.
Raver-Shapira N, Marciano E, Meiri E, Spector Y, Rosenfeld N, Moskovits N, Bentwich Z, Oren M.Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol Cell 2007; 26(5): 731-43.  Back to cited text no. 219
    
220.
Tarasov V, Jung P, Verdoodt B, Lodygin D, Epanchintsev A, Menssen A, Meister G, Hermeking H. Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR-34a is a p53 target that induces apoptosis and G1-arrest. Cell Cycle 2007; 6(13): 1586-93.  Back to cited text no. 220
    
221.
He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang Y, Xue W, Zender L, Magnus J, Ridzon D, Jackson AL, Linsley PS, Chen C, Lowe SW, Cleary MA, Hannon GJ. A microRNA component of the p53 tumour suppressor network. Nature 2007; 447 (7148): 1130-4.  Back to cited text no. 221
    
222.
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. MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Res 2009; 69(19): 7569-76.  Back to cited text no. 222
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2]


This article has been cited by
1 The Role of MicroRNA in Regulation of Signaling Pathways in Gliomas
O. I. Kit,D. I. Vodolazhsky,E. E. Rostorguev,D. H. Porksheyan,S. B. Panina
Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry. 2018; 12(1): 1
[Pubmed] | [DOI]
2 MicroRNAs in glioblastoma pathogenesis and therapy: A comprehensive review
Bhavesh K. Ahir,Howard Ozer,Herbert H. Engelhard,Sajani S. Lakka
Critical Reviews in Oncology/Hematology. 2017; 120: 22
[Pubmed] | [DOI]
3 Hexokinase 2 (HK2), the tumor promoter in glioma, is downregulated by miR-218/Bmi1 pathway
Hui Liu,Nan Liu,Yingduan Cheng,Weilin Jin,Pengxing Zhang,Xin Wang,Hongwei Yang,Xiaoshan Xu,Zhen Wang,Yanyang Tu,Aamir Ahmad
PLOS ONE. 2017; 12(12): e0189353
[Pubmed] | [DOI]
4 Serum microRNA-376 family as diagnostic and prognostic markers in human gliomas
Qing Huang,Changjiang Wang,Ziming Hou,Gang Wang,Jianghua Lv,Hao Wang,Jun Yang,Zhe Zhang,Hongbing Zhang
Cancer Biomarkers. 2017; : 1
[Pubmed] | [DOI]
5 Prognostic value of combined and individual expression of microRNA-1290 and its target gene nuclear factor I/X in human esophageal squamous cell carcinoma
Rui Xie,Shang-Nong Wu,Cheng-Cheng Gao,Xiao-Zhong Yang,Hong-Gang Wang,Jia-Ling Zhang,Wei Yan,Tian-Heng Ma
Cancer Biomarkers. 2017; : 1
[Pubmed] | [DOI]
6 MicroRNA-302a targets GAB2 to suppress cell proliferation, migration and invasion of glioma
Jiuhong Ma,Jia Yu,Jingmei Liu,Xing Yang,Miao Lou,Jinghui Liu,Fuqiang Feng,Peigang Ji,Liang Wang
Oncology Reports. 2017; 37(2): 1159
[Pubmed] | [DOI]
7 Reduced expression of microRNA-497 is associated with greater angiogenesis and poor prognosis in human gliomas
Fuqiang Feng,Dong Kuai,Hongqin Wang,Tao Li,Wang Miao,Yueting Liu,Yimin Fan
Human Pathology. 2016; 58: 47
[Pubmed] | [DOI]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Micrornas Deregu...
Therapeutic Pote...
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed3870    
    Printed135    
    Emailed0    
    PDF Downloaded496    
    Comments [Add]    
    Cited by others 7    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]