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Cancers 2013, 5(4), 1306-1331; doi:10.3390/cancers5041306
Abstract: Glioma represents a serious health problem worldwide. Despite advances in surgery, radiotherapy, chemotherapy, and targeting therapy, the disease remains one of the most lethal malignancies in humans, and new approaches to improvement of the efficacy of anti-glioma treatments are urgently needed. Thus, new therapeutic targets and tools should be developed based on a better understanding of the molecular pathogenesis of glioma. In this context, microRNAs (miRNAs), a class of small, non-coding RNAs, play a pivotal role in the development of the malignant phenotype of glioma cells, including cell survival, proliferation, differentiation, tumor angiogenesis, and stem cell generation. This review will discuss the biological functions of miRNAs in human glioma and their implications in improving clinical diagnosis, prediction of prognosis, and anti-glioma therapy.
Annually, 3.5 in 100,000 people are diagnosed with central nervous system (CNS) cancer, accounting for 1.9% of all new cancer cases and 2.3% of cancer deaths worldwide . Glioma, the most common neuroepithelial cancer, represents the majority of malignant brain tumors in humans . Gliomas are clinicopathologically categorized into grades I–IV according to the World Health Organization (WHO) grading criteria . Among all glioma cases diagnosed, a majority belongs to grade IV, also known as high-grade astrocytoma or glioblastoma (GBM) [2,4]; despite aggressive therapies, over 50% of patients die within one year of diagnosis [5,6]. Current standard therapies for newly diagnosed glioma includes surgical resection followed by adjuvant radiotherapy and/or chemotherapy. Nevertheless, surgical resection is often limited by a lack of clear primary tumor margin and by their locations at vital anatomical structures. Moreover, radiotherapy and chemotherapy effectiveness is suboptimal in many cases, largely due to readily developed resistance to radiation and chemotherapeutic drugs . A thorough understanding of the molecular mechanisms underlying glioma development and progression and its radioresistance and chemoresistance is crucial for improving conventional therapeutic strategies and developing novel therapies against the disease.
Numerous signaling pathways and molecules are involved in glioma pathogenesis. Genetic alterations and/or deregulated expression of genes and their protein products have been identified in gliomas. Amplification and/or mutation of the epidermal growth factor receptor (EGFR) gene were found in up to 60% of primary GBM cases  and are believed to be associated with the development of the malignant phenotype of glioma cells, e.g., proliferation and invasiveness. Furthermore, in nearly half of anaplastic astrocytoma and almost all glioblastoma cases, the p16-cyclin-dependent kinase (CDK)4/CDK6-cyclin D1 (CCND1)/retinoblastoma (RB) pathways  that negatively regulate cell cycle progression are aberrant, leading to uncontrolled tumor cell proliferation. Another important growth factor, platelet-derived growth factor (PDGF), and its receptor are upregulated in human glioma and are involved in the development of the malignant phenotype, including tumor angiogenesis . Other molecular changes in the pathological process of glioma include deregulated expression or dysfunction of tumor protein 53 (TP53) and phosphatase and tensin homolog (PTEN) [11,12,13]. Despite the accumulated findings on the molecular changes, unidentified mechanisms underlying the pathogenesis of glioma remain to be understood. To understand the molecular network involved in initiating or promoting glioma development and progression, the gaps between known signaling events within a mechanistic cascade must be filled and the molecules that mediate crosstalk among different signaling pathways identified. Furthermore, it remains puzzling how certain self-regulated feedback loops, which would otherwise be under tightly regulated control, are disrupted and thereby become oncogenic. Clarification of these issues is urgent and key to complete understanding of glioma and to the development of effective intervention strategies.
Research in the past decade has brought microRNAs (miRNAs) to the forefront of cancer molecular biology. Experimental and clinical scenarios have widely shown that miRNAs play pivotal roles in human cancer development and progression. MiRNAs, a class of non-coding 20–22-nucleotide RNAs, are encoded in introns, exons, or the intergenic regions, and miRNA-coding genes usually locate at fragile sites of chromosomes [14,15]. MiRNAs regulate gene expression via imperfect and sometimes perfect base pairing with specific sequences, leading to altered transcription and/or translation. In most cases identified thus far, miRNAs silence gene expression by suppressing mRNA translation through sequence-specific hybrids between the miRNA 5' proximal “seed” region (position 2–8) and the 3' untranslated region of mRNAs, leading to mRNA destabilization or degradation [16,17,18,19,20]. Based on such molecular interactions, the modulatory effect of a particular miRNA usually exhibits a multi-target property, providing a new dimension of regulation for gene expression and usually consequently altering the quality and/or quantity of molecular signaling in a biological context with high efficiency. Indeed, such gene expression modifications by miRNA-mediated changes are significant not only in normal physiological processes, but also in pathological conditions, including various types of cancer, for example, glioma.
2. miRNA Biological Functions in Glioma
Glioma is the cancer type with which the functional significance of miRNAs in human cancer was discovered. Since the early studies that identified in human glioma the importance of miRNAs, including miR-21 [21,22], a significant number of miRNAs have been found to be deregulated in glioma and contribute to disease development and progression. Similar to those found in other cancers, abnormalities in miRNA expression or function in glioma are usually associated with the development of representative biological hallmarks that distinguish malignant cells from normal ones, including increased cell proliferation, abrogated apoptosis, enhanced invasiveness and cell motility, and promotion of angiogenesis. With these phenotypic changes, the identified miRNAs target common oncogenic or tumor-suppressive pathway components and are therefore believed to be mechanistically linked to the role of miRNAs in glioma. Table 1 summarizes the miRNAs found in experimental or clinical human gliomas, and some of their postulated functions are discussed below.
2.1. miRNAs Modulate Glioma Cell Proliferation
Accelerated proliferation is a cancer cell characteristic that contributes to the uncontrolled growth of a malignant tumor at almost all stages of disease progression. This biological feature is believed to be particularly important in glioma, as the fast growth of this brain tumor is key to its high lethality . In this context, while some genetic alterations in cell cycle regulators, e.g., loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) or RB function and CDK4 amplification, are associated with promoting glioma cell proliferation , changes in miRNA species modulate key nodes to similarly alter proliferative signaling pathways. For example, miR-137 is downregulated in grade III and IV human gliomas. As miR-137 targets and suppresses CDK6 expression, a positive mediator of cell cycle progression, its downregulation enhances glioma cell proliferation, and lower miR-137 levels indicate a poorer prognosis [23,24]. MiR-34a, the expression of which is diminished in glioma cells, targets the mRNAs of multiple growth-promoting genes, including E2F transcription factor 1 (E2F1), hepatocyte growth factor receptor (c-met), and CCND1. Expression of miR-34a reverses the ability of these oncoproteins to sustain the growth of glioma cells in vitro and glioma xenografts in vivo [25,26,27].
|MiRNA||Target genes||Biological effects a||Postulated upstream regulators b||References|
|Mir-7||EGFR, IRS-2, FAK||Invasion (−), Radioresistance (−), Migration (−)||[28,29,30,31]|
|MiR-10b||HOXD10, Bim, TFAP2C, p16, p21, CSMD1||Invasion (+), Proliferation (+), Cell cycle (+), Apoptosis (−), Autophagy (−)||[32,33,34,35]|
|Mir-15b||CCNE1, NRP2||Cell cycle (−), Invasion (−), Angiogenesis (−)||[36,37]|
|Mir-16-1||Zyxin||Migration (−), Invasion (−), Proliferation (−)|||
|Mir-17–92 cluster||CDKN1A, E2F1, Pold2, PTEN, CTGF||Proliferation (+), Apoptosis (−), Differentiation (−)||c-Myc (+)||[39,40,41,42]|
|Mir-21||RECK, pdcd4, CDC25A, HNRPK, TIMP-3, TAp63, LRRFIP1||Invasion (+), Migration (+), Proliferation (+), Apoptosis (−), Autophagy (−), Resistance to TMZ, taxol and VM-26 (+), Radioresistance (+)||β-catenin/STAT3 pathway (+)||[43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58]|
|Mir-23b||VHL,Pyk2, HMGA2||Proliferation (±), Invasion (±), Apoptosis(−), Migration(−), Cell cycle(−)||[59,60,61]|
|Mir-34a||E2F1, Notch1, Notch2,C-met||Proliferation(−), Apoptosis(+),||P53||[25,65,66]|
|Mir-101||EZH2||Proliferation(−), Migration(−), Angiogenesis(−),|||
|Mir-125b||BMF, E2F2||Angiogenesis(−), Proliferation(±), Apoptosis (−)||VEGF (−)||[69,70,71,72]|
|Mir-128||Bmi-1, E2F3a, p70s6k1, RTKs||Proliferation(−), Self-renew(−), Apoptosis(+), Angiogenesis(−), Differentiation(+)||Ginsenoside Rh2 (+)||[74,75,76,77,78]|
|Mir-137||Cox-2, CDK6||Iinvasion(−), Migration(−), Proliferation(−), Stmeness(−), Cell cycle(−)||[23,24]|
|Mir-145||CTGF, ADAM17, NEDD9||Invasion(−), Migration (−), Proliferation(−), Stmeness(−)||[79,80,81,82]|
|Mir-153||IRS-2, Mcl-1, Bcl-2||Apoptosis(+), Proliferation(−)||Chromatin-modifying drugs (+)||[84,85]|
|Mir-181||Bcl-2||Apoptosis(+), Invasion(−), Proliferation(−), Radiorasistance(+)||[86,87]|
|Mir-182||CYLD||Proliferation(+), Angiogenesis(+)||TGF-β (+)|||
|Mir-184||Npm1, Akt2||Proliferation(−), Invasion(−)|||
|Mir-195||E2F3, CCND3, Cyclin D1, Cyclin E1||Proliferation(−), Invasion(−), TMZ resistance(+)||[90,91,92]|
|Mir-204||SOX4, EphB2||Self-renewal(−), Stemness(−), Migration(−), Invasion(−)||Methylation (+)|||
|Mir-221/222||TIMP3, PUMA, p57, PTEN, p27, ICAM-1, CX43, PTPμ||Invasion(+), Proliferation(+), Apoptosis(−), Radioresistance(+), TMZ resistance (+), Cytolysis to CTL (−)||NF-κB (+), C-Jun (+)||[94,95,96,9798,99,100,101,102,103]|
|Mir-296||HGS||Angiogenesis(+)||VEGF (+), EGF (+)|||
|Mir-326||PKM2, NOTCH1, NOTCH2||Proliferation(−), Apoptosis(+), Invasion(−)||Notch (−)||[105,106,107]|
|Mir-410||MET||Proliferation(−), Invasion(−)||Methylation (−)|||
|Mir-451||CAB39||Response to metabolic stress||Glucose (+)|||
|Mir-486||CYLD, ITCH, TNIP-1, TNIP-2, TNIP-3||Aggressiveness(+), Angiogenesis(+), Proliferation(+), Invasion(+)|||
a (+) = promoted, (−) = inhibited; b (+) = upregulated, (−) = downregulated.
In contrast, some miRNAs can induce excessive proliferative signaling. The upregulation of an oncogenic miRNA (oncomir) promotes glioma cell proliferation. MiR-182 can suppress cylindromatosis (CYLD), a deubiquitinase that mediates ubiquitin deconjugation and acts as an inhibitor of nuclear factor κB (NF-κB) activation, leading to overactivation of NF-κB signaling. MiR-182 is transcriptionally upregulated by transforming growth factor β (TGF-β) in glioma tissues and predicts poor prognosis in glioma .
2.2. miRNAs Modulate Glioma Cell Apoptosis
Almost all cancer types feature suppression of apoptosis. In glioma, it has been extensively shown that the anti-apoptotic capability of tumor cells is associated with disease progression and resistance to therapies. In a normal cell population, the balance between apoptosis and survival is well maintained and controlled by a network of pro-apoptotic and anti-apoptotic regulators; this elegantly formed modulatory network is disrupted in almost all cancers, usually characterized by pro-apoptotic factor suppression and/or anti-apoptotic (or survival) factor overactivation . Recent studies have established that alterations in miRNA expression or function are often involved in the dysregulation of cell death during human glioma development and progression. For example, miR-181 and miR-153 promote apoptosis by directly targeting B-cell chronic lymphocytic leukemia/lymphoma 2 (Bcl-2) mRNA and repressing its translation, thereby inhibiting gliomagenesis . Both miR-181 and miR-153 expression is decreased in glioma cell lines and a subset of clinical glioma specimens, suggesting roles of the two miRNAs in glioma progression. Moreover, miR-181 downregulation is more prominent in grade III and IV glioma than that in lower grades [84,87].
Conversely, upregulation of certain miRNA also inhibits apoptosis in glioma cells and supports cell survival. For example, miR-26a that is upregulated in glioma tissues suppresses PTEN, RB1 and MAP3K2/MEKK2 expression and inhibits c-JUNN-terminal kinase-dependent apoptosis [62,113]. Other anti-apoptotic miRNAs found in glioma cells are miR-221/222 and miR-21, which are both upregulated and indicated as oncogenic in glioma [43,94].
2.3. miRNAs Modulate Glioma Cell Invasion and Migration
The high lethality of glioma, particularly GBM, is closely associated with its ability to infiltrate the surrounding tissue, resulting in both the destruction of normal brain regions and a lack of clear border around the malignant lesion, which leads to rapid post-surgery recurrence due to incomplete resection. It is recognized that this biological feature can be acquired early in tumorigenesis . Molecular mechanisms underlying glioma cell invasion and migration usually involve factors that promote degradation of the extracellular matrix (ECM) or cell motility. Recent studies have identified miRNAs contributing to the above processes, and are thereby indicative of disease aggressiveness.
MiR-30e*, which represents the product of complementary DNA strand coding for miR-30e, is involved in promoting glioma cell invasiveness. By activating NF-κB inhibitor (IκBα)/NF-κB signaling, miR-30e* triggers the overexpression of invasion-promoting factors, mainly including matrix metalloproteinase-9 (MMP-9), an important enzyme that degrades ECM . Moreover, miR-21 can downregulate tissue inhibitor of MMPs-3 (TIMP3) and reversion-inducing cysteine-rich protein with Kazal motifs (RECK), which are both MMP-9 inhibitors, resulting in elevated MMP-9 activation and enhanced tumor cell invasion . In vitro invasion assays and orthotopic xenograft models, both miR-30e* and miR-21 are upregulated in glioma cells and promote their invasiveness by mediating ECM degradation. In the clinic, the two miRNAs correlate with malignant progression and poor survival [21,45,63].
MiRNAs that antagonize glioma cell invasion have also been identified. MiR-218 can directly target lymphoid enhancer-binding factor 1 (LEF1) and downregulate the expression of its downstream proteins, e.g., MMPs, reducing ECM degradation, whereas inhibition of miR-218 expression enhances glioma cell invasiveness, suggesting a tumor-suppressive role of the miRNA. MiR-218 is expressed at low levels in glioma tissues, particularly in GBM, which might contribute to the acquisition of invasive potential .
2.4. miRNAs Modulate Glioma Angiogenesis
GBM is one of the most highly vascularized human cancers. It is well recognized that the progression of human glioma is angiogenesis-dependent. Indeed, glioma is one of the first cancers in which angiogenesis was found to be a key phenotypic feature to disease progression . Accumulated evidence has shown that high vascular density, glomeruloid vessels in particular, and pro-angiogenic factor upregulation are indicative of poor prognosis for patients with gliomas . Aberrant activation of pro-angiogenic signaling pathways that are common in human cancers, e.g., the EGFR/phosphatidylinositol-3-kinase (PI3K)/Akt, vascular endothelial growth factor (VEGF), PDGF, and NF-κB pathways, is important in the development of neovessels in human gliomas [9,115,116,117,118]. Recently, miRNAs whose upregulation promotes angiogenesis, or whose downregulation suppresses tumor vasculature, were found to play a role in modulating the angiogenic properties of human glioma.
In addition to miR-30e* and miR-182, which activate NF-κB signaling and subsequent expression of downstream pro-angiogenic factors such as VEGF-C and MMPs [63,88], other miRNAs have been identified as stimulators of angiogenic endothelial proliferation, invasion, adhesion, or migration. MiR-296 levels are elevated in primary human brain microvascular endothelial cells, likely by glioma cell-derived vascular growth factors, and act as a promoter of angiogenesis by targeting hepatocyte growth factor-regulated tyrosine kinase substrate, a protein mediating the degradation of the growth factor receptors VEGFR2 and PDGFRβ .
In contrast, miR-15b attenuates the expression of a VEGF receptor, neuropilin-2 (NRP-2), abrogating VEGF-induced angiogenesis. miR-15b downregulation in glioma cells is associated with progression of glioma angiogenesis . Similarly, miR-128 inhibits P70s6 kinase 1 (P70s6k1) translation and suppresses the expression of its downstream effectors, hypoxia-inducible factor 1 (HIF-1) and VEGF, which are both key mediators of tumor angiogenesis, reducing vascularization. MiR-128 levels are lower in glioma than in normal brain tissue and are associated with glioma aggressiveness [74,75,76].
2.5. miRNAs Are Involved in Glioma Stem Cell Development and Maintenance
Cancer stem cells (CSCs), defined as a tumor cell sub-population capable of self-renewal and heterogeneous cancer cell propagation,  are believed to be a pool of cells to which uncontrolled proliferation, metastasis, and resistance to anti-cancer therapies are largely attributed. Glioma was one of the first solid tumor types from which CSCs were identified . Cascades triggered or mediated by signaling pathways such as the Wnt/β-catenin, TGF-β, EGFR, and Notch pathways have been found to play important roles in glioma stem cell (GSC) development and/or maintenance of stemness [121,122,123,124]. Along with these proteins, miRNAs are also reported to play a role in stemness.
Interestingly, miR-204 is markedly downregulated in both GSC and neural stem cells. Sex-determining region Y-box 4 (SOX4), a stemness-governing transcriptional factor, is a miR-204 target. Restoring miR-204 expression in glioma cells restrains the development of the stem cell-like phenotype of glioma cells , suggesting that miR-204 plays a role in the development or maintenance of GSC stemness. Moreover, there is increased miR-17–92 locus expression in a subset of GBM cells. By targeting differentiation-promoting genes and cell cycle promoter genes, miR-17–92 inhibits apoptosis and induces cell proliferation in GBM spheroids, in which glioma-initiating cells and GSCs are enriched. Consistently, suppression of miR-17–92 expression by nucleic acid inhibitors or differentiation-inducing agents, e.g., all-trans retinoic acid, reverses the miR-17–92 effects on GBM spheroids, suggesting a key role of miR-17–92 in sustaining GSC stemness and the potential usefulness of miRNAs as targets of GSC-targeting strategies .
2.6. miRNAs Contribute to Glioma Resistance to Therapies
Radiotherapy and chemotherapy represent the two main conventional anti-glioma treatment strategies. Their effectiveness and efficacy remain limited largely due to the development of radioresistance and chemoresistance in glioma cells and their microenvironment . Relapse following failure of conventional therapies is the most common cause of death for most glioma patients [126,127,128]. Thus, increasing sensitivity to radiation and chemotherapeutic agents and reducing resistance are of great clinical importance. Biologically, there is evidence that resistance to anti-cancer therapies is closely associated with sustained overactivation of anti-apoptotic signaling pathways involved in enhancing and sustaining cell survival . Shi et al. reported that miR-21 overexpression mediates resistance to temozolomide, a commonly used alkylating therapeutic agent, by decreasing the Bcl-2-associated X protein (Bax)/Bcl-2 ratio and caspase-3 activity in glioma cells . Moreover, miRNA suppression of leucine-rich repeat (in Flightless I)-interacting protein-1 (LRRFIP1), an NF-κB pathway inhibitor and direct target gene of miR-21, increases the proportion of teniposide-resistant cells . MiR-181a also downregulates Bcl-2 and significantly sensitizes malignant glioma cells to radiation treatment . These findings suggest that miRNAs might be possible targets for overcoming resistance.
GSCs have proven to be highly resistant to radiation and chemotherapy [7,129]. Hence, a better understanding of the molecular mechanisms responsible for sustaining GSC stemness is important for developing new therapeutic strategies to improve the effectiveness of conventional treatments . Therefore, identification of the miRNAs, and their alterations, that contribute to supporting glioma cell survival and stemness is essential for overcoming glioma resistance to treatments.Moreover, other possible mechanisms through which miRNAs can confer resistance to various therapeutic modalities, e.g., modulation of drug pumps, may also exist. Indeed, such miRNAs have been targeted to improve sensitivity to experimental anti-glioma chemotherapy. For example, in the presence of the cytotoxic agent VM-26, miR-21 sustains constitutive NF-κB activation by targeting LRRFIP1, reducing the killing effect of VM-26. In U373MG glioma cells, miR-21 suppression by specific antisense oligonucleotides enhanced VM-26 cytotoxicity . Moreover, miR-195, miR-455-3p, and miR-10a* were shown to mediate glioma cell resistance to temozolomide, although the specific underlying mechanism remains unclear .
Studies on the modulatory effects of aberrantly expressed miRNAs on glioma cell biological functions have opened up a new avenue in the understanding of glioma pathogenesis and the development of novel strategies against glioma. Depending on the specific modes of action of these miRNAs in glioma cells and through the upregulation or downregulation of these miRNAs, these molecules act either as oncogenes (oncomirs) or tumor suppressors. It is notable that miRNA post-transcriptional regulation can occur rapidly, with a short response delay, producing a rapid mode of phenotypic changes . Furthermore, due to the sequence-specific but imperfect matching property of a miRNA when interacting with its mRNA target, the modulatory functions of miRNAs exhibit a remarkable multi-target trait, enabling efficient regulation of the gene expression profiles of a cell. These features render the category of molecular regulators an interesting and attractive class of therapeutic targets for complex diseases such as human glioma.
3. Biological Importance of miRNAs in Glioma
3.1. miRNAs Act as “Gap Filler” in Cellular Signaling Networks
The discovery of miRNAs, and studies on their biological functions and roles in human glioma, provides important new insights in our current understanding of the molecular mechanisms underlying glioma development and progression. The molecules and pathways that contribute to the malignancy of glioma have been identified. However, gaps remain along and between the signaling cascades composed of the identified functional molecular events, and numerous miRNAs have recently been indicated as good fits as “fillers” of such gaps. For example, cyclic adenosine monophosphate response element-binding protein (CREB) is a transcription factor that promotes tumorigenesis by enhancing cell cycle progression, cell survival, and cellular metabolism . CREB is upregulated in glioma and promotes gliomagenesis. However, understanding of the specific mechanism by which CREB is linked to oncogenic signaling pathways is incomplete. MiR-23a, whose expression was recently found to be transactivated by CREB through its binding to miR-23a regulatory sequences, targets and suppresses PTEN expression, leading to hyperactivation of PI3K-Akt signaling .
Studies that identified miRNAs as “gap fillers” in cellular signaling networks suggest that this important class of regulatory molecules, newly identified “fillers” in the “gaps”, not only advance our understanding of the pathological mechanisms of glioma, but also suggest a possible unique significance of miRNAs in the biological basis of the disease. The current knowledge on the biological importance of miRNAs in human glioma is discussed below.
3.2. miRNAs Act as “Amplifiers” of Glioma-Associated Cellular Signals
Like other cancer types, glioma development and progression is essentially associated with constitutive overactivation of the oncogenic pathways, which leads to the malignant properties of a tumor cell . In normal cells, regulatory mechanisms typically control the activities of these pathways stringently so that a homeostatic state of the host cell, and the entire cell population in the microenvironment, can be achieved and sustained. The accomplishment of such homeostasis, as shown by many studies, is largely attributed to negative feedback mechanisms that balance the effects of positive stimulators and negative inhibitors of oncogenic molecules on their signaling functions, consequently preventing overactivation of the signaling molecules [133,134,135]. In cancer cells, however, such feedback loops are usually disrupted, amplifying the intensities of oncogenic signals and allowing them to predominate [136,137,138]. In human glioma, miRNAs have been identified as such “amplifier” factors that disrupt the negative feedback loops and cause constitutive activation of the oncogenic signaling molecules.
For example, as a member of the IκB family, IκBα is an intrinsic NF-κB inhibitor yet subject to transactivation by NF-κB, thus forming a negative feedback loop that places NF-κB signaling under strict control and restraining its oncogenic effect [139,140,141]. We recently reported that miR-30e* is highly upregulated in human glioma, can directly target IκBα mRNA and suppress its expression, thereby negating the inhibitory effect of IκBα on NF-κB signaling, leading to the constitutive overactivation of NF-κB. Consequently, the invasiveness and angiogenesis induced is significantly enhanced. Hence, the overexpressed miR-30e* markedly amplifies the stimulation that triggers NF-κB activation . MiR-486 is another NF-κB signaling “amplifier”. MiR-486 simultaneously suppresses the expression of multiple inhibitors of the A20, CYLD and Cezanne proteins. High level of miR-486 expression causes NF-κB overactivation and is associated with the aggressiveness of human gliomas . Identification of these “amplifier” miRNAs provides a new basis for the development of novel anti-glioma strategies.
3.3. miRNAs Act as “Fine-Tuners” of Signal Regulation
Under physiological and pathological conditions, signal transduction in a cell is subject to fine-tuning by molecules that buffer noise resulting from different signaling pathways. Such a noise-buffering mechanism is usually associated with the maintenance or dysregulation of cellular functions and phenotype [142,143]. For cells to manage signaling fluctuation, transcriptional regulation of key signaling transducers by proteins has been found to act as a fine-tuning mechanism that buffers noise by reducing the fluctuation. Recent studies show that post-transcriptional regulation by miRNAs might represent a rapid mode of action to fine-tune the signaling network within a cell . For example, the biological functions of the miR-17–92 cluster involve two regulatory loops. In one loop, miR-17–92 represses E2F1 and c-myc, two pro-proliferative transcription factors that are able to reversely activate the transcription of mi-17–92. MiR-17–92 suppresses cell cycle progression and proliferation through this signaling loop. In loop 2, however, miR-17–92 targets CDKN1A, leading to activation of the CCND1/CDK4 complex and cell proliferation. Thus, due to its multi-target property, miR-17–92 provides an intracellular fine-tuning mechanism for the proliferative signal and acts as a noise-buffering mediator in normal cells [40,41,144,145,146,147,148]. However, the miR-17–92 cluster is aberrantly overexpressed during gliomagenesis, promoting the proliferative effects of loop 2, and due to c-myc upregulation, the anti-proliferative function of miR-17–92 in loop 1 is inhibited. Hence, the compromised fine-tuning effect of miR-17–92 enhances the progression of the glioma . The fine-tuning modulation of miRNA in cell signaling is therefore an important subject in the understanding of the pathological attributes of human glioma, and restoring the functions of miRNA fine-tuners holds great potential in glioma treatment.
3.4. miRNAs Act as Crosstalk Mediators of Different Signaling Pathways
Cellular signaling pathways are not isolated from one another; instead, crosstalk between and across distinct pathways is common and essential for the functional integrity of the typically complex network . Not only proteins, but also miRNAs, play pivotal roles in signaling crosstalk. A miRNA usually has more than one target, and these targets usually function in different signaling pathways . MiR-21, upregulated in glioma, may contribute to crosstalk among the TGF-β, p53, and EGFR-PI3K-Akt axes. In this context, miR-21 targets Tap63 and several p53 activators, e.g., heterogeneous nuclear ribonucleoprotein K (HNRPK), p53-binding protein 2 (TP53BP2), topoisomerase I-binding (TOPORS), and junction-mediating and regulatory protein (JMY). Moreover, miR-21 can suppress TGF-β receptor II/III, death-associated protein 6 (DAXX, the apoptotic mediator), and TGF-β itself. The suppression of both the TGF-β and p53 pathways leads to the inhibition of apoptosis [43,151]. As mentioned earlier, miR-21 also downregulates the MMP inhibitors RECK and TIMP3 . Thus, miR-21-mediated crosstalk cooperatively links various signaling pathways to the pathogenesis of glioma.
Other examples of the crosstalk-mediating function of miRNA include the miR-221/222 cluster. The cluster directly targets p27, p57, PTEN, TIMP3, p53-upregulated modulator of apoptosis (PUMA), and connexin 43 (CX43), facilitating crosstalk and interaction among multiple signaling pathways associated with cell cycle progression, cell survival/apoptosis, and other essential cellular functions [94,95,152,153]. Hence, by mediating crosstalk among different signal transduction pathways, cooperative regulation of different pathways reinforces the oncogenic or tumor-suppressor roles of miRNAs. Based on these findings, miRNA blocking or overexpression might abrogate more than one signaling cascade and would therefore be therapeutically significant.
4. Potential Application of miRNAs in Clinical Management of Glioma: Perspective
Despite recent advances in the understanding of glioma biology and pathogenesis and in the development of new anti-glioma strategies, clinical management of this highly lethal disease still faces serious challenges. First, current glioma diagnosis mostly depends on imageological detection, which usually takes place after the presence of symptoms indicative of late disease become obvious. Early identification of WHO grade I or II gliomas is difficult due to a lack of reliable biomarker(s) and sensitive and specific detection methods. Second, current capacity in the clinic to predict disease prognosis and patient survival is very limited largely due to the clinical and biological heterogeneity of glioma, even those categorized in the same histological type or WHO grade . Better prognostic judgment would require additional parameters. Third, in a similar context, while there has been significant progress in molecular classification of human gliomas for better-guided treatment, e.g., the recently proposed molecular profiling-based subtypes  the development of new biomarkers that can distinguish differential glioma patients clinically and support personalized therapy is urgently required. Fourth, the identification of new therapeutic molecular targets to improve glioma treatments with currently limited efficacies, particularly those that can help overcome resistance to conventional chemotherapy and radiotherapy, is needed. Finally, the molecular traits of GSCs, a key basis for developing GSC-targeted therapies, must be understood and validated in clinical glioma. Recent understanding of the roles of miRNAs in glioma development and progression has provided new insights and a practical basis for developing early detection biomarkers, more accurate prognosis prediction tools, and more effective interventional targets.
Numerous miRNAs are associated with the clinical features and outcomes of human glioma (Table 2). For instance, miR-30e*, miR-21, and miR-486 levels in glioma tissues correlate closely with clinical staging and inversely with disease prognosis and patient survival, respectively [45,48,63,110]. The demonstrated stability of miRNA in the peripheral blood, possibly mechanistically due to protection by protein complexes associated with the miRNA molecules, would be noteworthy in the development of practically applicable diagnostic or prognostic biomarkers . By and large, presence of tumor-associated miRNAs in body fluids such as blood and cerebrospinal fluid (CSF), can be detected earlier than in tumor lesions, as pathologic biopsy is mostly performed after typical clinical symptoms appear. Biopsy is particularly hard to carry out for brain tumors due to the difficulty of accessing the primary tumor, making miRNAs an attractive candidate class of biomarkers for early diagnosis of glioma. Furthermore, in addition to the potential value of miRNAs for diagnosis and prognosis, some miRNAs are also complementarily indicative of glioma subtype classification. For example, oligodendrogliomas are sometimes difficult to distinguish from GBM. Genetic alterations, e.g., loss of heterozygosity on chromosomes 1p and 19q, are required quite often to assist pathological diagnosis. A group of miRNAs, including miR-218, miR-21, miR-132, miR-134, miR-155, and miR-409-5p, were reported to be overexpressed by three times as much in GBM compared with oligodendrogliomas, while miR-128 expression in oligodendrogliomas is four times higher than that in GBM. Thus, a specific miRNA signature might aid in the discrimination of oligodendrogliomas from GBM . As the need to establish better detection methodologies for clinical diagnosis, outcome prediction, and molecular classification of gliomas is urgent, the possibility of employing miRNAs as noninvasive diagnostic and prognostic biomarkers warrants further laboratory investigation and clinical evaluation.
|MiRNA||Test||Expression alteration a||Fold change||Relevance to grading b||Relevance to prognosis c||References|
|MiR-10b||qRT-PCR||T(+), C(+)||90.4 (tissues), 94.8 (U87), 18.4 (U251)||(+)||(−)||[32,33,34]|
|Mir-15b||MicroRNAarray, qRT-PCR||T(−), C(−)||0.11 (tissues)||[36,37]|
|Mir-17||qRT-PCR||T(+), C(+)||2.7–5.6 (tissues)||(+)||(−)|||
|Mir-17–92 cluster||qRT-PCR||T(+)||1.5–5 (tissues)||(+)|||
|Mir-21||qRT-PCR, In situ hybridization||T(+), C(+)||(+)||[21,45]|
|Mir-23b||qRT-PCR||T(+), C(+)||7.48–16.04 (cell lines)|||
|Mir-26a||MicroRNA array||T(+)||6 (GBM tissues)|||
|Mir-30e*||MicroRNA array, qRT-PCR||T(+), C(+)||(+)||(−)|||
|Mir-124||qRT-PCR||T(−), C(−)||57 (GBM tissues)||[23,68]|
|Mir-125b||Northern blotting, In situ localization, MicroRNA array, qRT-PCR||Glioblastoma-associated endothelial cells(−), ATRA-treated human glioma cell lines(−), CD133+ cells(−)||[69,70,71,72]|
|MiR-125b-2||qRT-PCR||GBM tissues(+), cells treated with TMZ(+), CD133+(+)|||
|Mir-128||MicroRNA array, qRT-PCR||T(−), C(−)||(−)||[74,75,76]|
|Mir-137||MicroRNA array, qRT-PCR||T(−), C(−)||(−)|||
|Mir-145||TCGA analysis, qRT-PCR, MicroRNA array||T(−), C(−)||<0.1 (cell lines)||(−)||(+)||[79,80,81,82]|
|Mir-152||qRT-PCR||T(−), C(−)||0.14 (tissues)|||
|Mir-184||Stem-loop real-time RT-PCR||T(−)||0.02–0.56 (tissues)|||
|Mir-195||qRT-PCR||T(−), C(−)||<0.6 (cell lines), <0.4 (tissues)||[91,92]|
|Mir-221/222||qRT-PCR, MicroRNA array||T(+), C(+)||2.74 (cell lines), 6.23 (tissues)||(+)||(−)||[101,102]|
|Mir-410||TCGA analysis, qRT-PCR||T(−),|||
|Mir-451||qRT-PCR, Fluorescent in situ hybridization||T(−), C(−)||(−)||[161,162]|
|Mir-455||MicroRNA array||Cells resistant to TMZ(+)|||
|Mir-486||MicroRNA array, qRT-PCR||T(+), C(+)||(+)||(−)|||
a T = Tumor tissues, C = glioma cell lines, (+) = overexpression, (−) = downregulation; b (+) = Higher WHO grade with higher expression, (−) = higher WHO grade with lower expression; c (+) = Shorter survival with higher expression, (−) = longer survival with higher expression.
Altered miRNA expression contributes to glioma development and progression, and some of these miRNAs, e.g., miR-21, miR-30e*, and miR-486, might serve as or provide essential regulation to critical nodes in the signaling pathways that are key to glioma pathogenesis. As critical cell signaling nodes are essential mediators that play important roles in a physiological or pathological condition , the aforementioned glioma-associated miRNAs might represent a class of potentially effective therapeutic targets. MiRNAs typically modulate protein expression in a timely and efficient fashion via simultaneous suppression of multiple target genes. Moreover, a probable lack of oligonucleotide immunogenicity might provide an additional advantage for the clinical use of miRNAs or their specific antagonists.
MiRNA-based therapy might also be useful for increasing the efficacy of conventional chemotherapy and radiotherapy. As discussed above, some miRNAs, e.g., miR-21 and miR-181a, are associated with acquisition of resistance or sensitization of glioma cells to anti-glioma treatments. Based on these findings, combining miRNA-based therapy and chemotherapy or radiotherapy might lead to higher treatment efficacy. Furthermore, targeting miRNAs that sustain GSC stemness, or employing those suppressing GSC, could be effective in increasing the overall sensitivity of a glioma tumor to chemotherapy and radiotherapy.
Nevertheless, the application of miRNA-based approaches in clinical diagnosis and treatment faces serious challenges. Larger-scale and prospective trials are needed to validate the effectiveness of miRNAs that were identified in studies using relatively limited patient samples in disease diagnosis, staging, and molecular subtyping, or to predict disease progression, patient survival, and efficacy of therapy. Moreover, the methods currently used to quantify miRNAs in surgical specimens and to correlate them qualitatively or semi-qualitatively to the clinical features of a glioma case should be improved for practical application. Defining cut-off values that can effectively distinguish “high” and “low” expression of a particular miRNA and avoid interference from nonspecific detection of other miRNAs with high sequence similarities is always a challenge. Furthermore, miRNA detection should be explored in clinically accessible samples, e.g., blood or CSF, which also offers opportunities to detect glioma-associated miRNAs at an early disease stage or before symptoms occur. In addition, miRNA-based functional imaging of clinical glioma could be an interesting direction to investigate [164,165].
Development of miRNA-based anti-glioma treatments presents even more challenges than those against other cancer types. Issues remaining to be addressed include specific and effective systemic delivery of miRNA and miRNA-targeted agents into the CNS protected by the blood-brain barrier, and prevention of off-target effects of a miRNA or anti-miRNA construct. There have been efforts to facilitate the delivery of miRNAs or their inhibitors in vivo. The efficacy of cholesterol-conjugated antisense oligonucleotides against oncomirs and poly(amido-amine)-carried tumor-suppressive miRNA oligonucleotides has been tested against xenografted glioma in animal models with fairly positive results. With encouraging results from recent human studies using synthetic RNAi as anti-tumor therapeutic agents [166,167], future studies investigating the efficiency, efficacy, and safety of miRNA-based therapeutic strategies are warranted.
microRNAs have been suggested by a large number of studies to play a pivotal role in the development of malignant phenotype of glioma, characterized by enhanced cell survival, proliferation, tumor angiogenesis, dedifferentiation as well as generation of cell stemness. Discoveries of the biological significance of miRNAs dysregulation in glioma cells not only fill some disconnected gaps between previously identified, but disconnected, mechanistic components underlying the pathogenesis of the disease, but also provide a model system through which the role of miRNA in tumorigenesis and cancer progression can be better understood. Moreover, it has been increasingly revealed that changes in the expression level of particular miRNAs might represent a new class of benchmarks indicative of the presence and/or progression of glioma tumors, and therefore might be of diagnostic or prognostic value. Furthermore, it is important to also acknowledge that as key molecules involved in mediating cellular behaviors essential for establishment of primary tumors as well as invasive growth of glioma, miRNAs are potentially promising targets of future anti-glioma intervention, despite the apparently pressing challenges lying ahead along the path towards the eventual clinical application of miRNA-based therapies. Thus, further and more in-depth mechanistic studies on the biological basis upon which miRNAs contribute to gliomagenesis and lethality of the disease, as well as translational research to overcome the technical barriers impeding the applicability of miRNA as diagnostic, prognostic, therapeutic or preventive tool, are equally urgent.
Supports for this work include grants from the Ministry of Science and Technology of China grant (No. 973-2011CB11305), the Natural Science Foundation of China (No.81272339, 81272417), the Guangdong Recruitment Program of Creative Research Groups grant (No. 2009010058), China, the National Science and Technology Major Project grant (No. 311030, 201305017), China, and the Key Science and Technology Research Project of Guangzhou Province, China (No. 12B292060029).
Conflicts of Interest
The authors declare no conflict of interest.
- International Agency for Research on Cancer (IARC). GLOBOCAN 2008. Estimated Incidence, Mortality and 5-Year Prevalence: Both Sexes. Available online: http://globocan.iarc.fr (accessed on 16 October 2013).
- Dolecek, T.A.; Propp, J.M.; Stroup, N.E.; Kruchko, C. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro-Oncology 2012, 14, v1–v49. [Google Scholar] [CrossRef]
- Louis, D.N.; Ohgaki, H.; Wiestler, O.D.; Cavenee, W.K.; Burger, P.C.; Jouvet, A.; Scheithauer, B.W.; Kleihues, P. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007, 114, 97–109. [Google Scholar] [CrossRef]
- Wen, P.Y.; Kesari, S. Malignant gliomas in adults. N. Engl. J. Med. 2008, 359, 492–507. [Google Scholar] [CrossRef]
- Stupp, R.; Mason, W.P.; van den Bent, M.J.; Weller, M.; Fisher, B.; Taphoorn, M.J.; Belanger, K.; Brandes, A.A.; Marosi, C.; Bogdahn, U.; et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 2005, 352, 987–996. [Google Scholar] [CrossRef]
- Grossman, S.A.; Ye, X.; Piantadosi, S.; Desideri, S.; Nabors, L.B.; Rosenfeld, M.; Fisher, J. Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States. Clin. Cancer Res. 2010, 16, 2443–2449. [Google Scholar] [CrossRef]
- Bao, S.; Wu, Q.; McLendon, R.E.; Hao, Y.; Shi, Q.; Hjelmeland, A.B.; Dewhirst, M.W.; Bigner, D.D.; Rich, J.N. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006, 444, 756–760. [Google Scholar] [CrossRef]
- Gladson, C.L.; Prayson, R.A.; Liu, W.M. The pathobiology of glioma tumors. Annu. Rev. Pathol. 2010, 5, 33–50. [Google Scholar] [CrossRef]
- Louis, D.N. Molecular pathology of malignant gliomas. Annu. Rev. Pathol. 2006, 1, 97–117. [Google Scholar] [CrossRef]
- Lokker, N.A.; Sullivan, C.M.; Hollenbach, S.J.; Israel, M.A.; Giese, N.A. Platelet-derived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells: Evidence that the novel PDGF-C and PDGF-D ligands may play a role in the development of brain tumors. Cancer Res. 2002, 62, 3729–3735. [Google Scholar]
- Watanabe, K.; Tachibana, O.; Sata, K.; Yonekawa, Y.; Kleihues, P.; Ohgaki, H. Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol. 1996, 6, 217–223. [Google Scholar] [CrossRef]
- Smith, J.S.; Tachibana, I.; Passe, S.M.; Huntley, B.K.; Borell, T.J.; Iturria, N.; O’Fallon, J.R.; Schaefer, P.L.; Scheithauer, B.W.; James, C.D.; et al. PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J. Natl. Cancer Inst. 2001, 93, 1246–1256. [Google Scholar] [CrossRef]
- Wang, S.I.; Puc, J.; Li, J.; Bruce, J.N.; Cairns, P.; Sidransky, D.; Parsons, R. Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res. 1997, 57, 4183–4186. [Google Scholar]
- Lee, Y.S.; Dutta, A. MicroRNAs in cancer. Annu. Rev. Pathol. 2009, 4, 199–227. [Google Scholar] [CrossRef]
- Ambros, V. The functions of animal microRNAs. Nature 2004, 431, 350–355. [Google Scholar] [CrossRef]
- Bushati, N.; Cohen, S.M. microRNA functions. Annu. Rev. Cell Dev. Biol. 2007, 23, 175–205. [Google Scholar] [CrossRef]
- Fabian, M.R.; Sonenberg, N.; Filipowicz, W. Regulation of mRNA translation and stability by microRNAs. Annu. Rev. Biochem. 2010, 79, 351–379. [Google Scholar] [CrossRef]
- Ghildiyal, M.; Zamore, P.D. Small silencing RNAs: An expanding universe. Nat. Rev. Genet. 2009, 10, 94–108. [Google Scholar] [CrossRef]
- Filipowicz, W.; Bhattacharyya, S.N.; Sonenberg, N. Mechanisms of post-transcriptional regulation by microRNAs: Are the answers in sight? Nat. Rev. Genet. 2008, 9, 102–114. [Google Scholar]
- Bartel, D.P. MicroRNAs: Target recognition and regulatory functions. Cell 2009, 136, 215–233. [Google Scholar] [CrossRef]
- Chan, J.A.; Krichevsky, A.M.; Kosik, K.S. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 2005, 65, 6029–6033. [Google Scholar] [CrossRef]
- Ciafre, S.A.; Galardi, S.; Mangiola, A.; Ferracin, M.; Liu, C.G.; Sabatino, G.; Negrini, M.; Maira, G.; Croce, C.M.; Farace, M.G. Extensive modulation of a set of microRNAs in primary glioblastoma. Biochem. Biophys. Res. Commun. 2005, 334, 1351–1358. [Google Scholar] [CrossRef]
- Silber, J.; Lim, D.A.; Petritsch, C.; Persson, A.I.; Maunakea, A.K.; Yu, M.; Vandenberg, S.R.; Ginzinger, D.G.; James, C.D.; Costello, J.F.; et al. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med. 2008, 6, e14. [Google Scholar] [CrossRef]
- Chen, L.; Wang, X.; Wang, H.; Li, Y.; Yan, W.; Han, L.; Zhang, K.; Zhang, J.; Wang, Y.; Feng, Y.; et al. miR-137 is frequently down-regulated in glioblastoma and is a negative regulator of Cox-2. Eur. J. Cancer 2012, 48, 3104–3111. [Google Scholar] [CrossRef]
- Li, Y.; Guessous, F.; Zhang, Y.; Dipierro, C.; Kefas, B.; Johnson, E.; Marcinkiewicz, L.; Jiang, J.; Yang, Y.; Schmittgen, T.D.; et al. MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Res. 2009, 69, 7569–7576. [Google Scholar] [CrossRef]
- Li, N.; Fu, H.; Tie, Y.; Hu, Z.; Kong, W.; Wu, Y.; Zheng, X. miR-34a inhibits migration and invasion by down-regulation of c-Met expression in human hepatocellular carcinoma cells. Cancer Lett. 2009, 275, 44–53. [Google Scholar] [CrossRef]
- Sun, F.; Fu, H.; Liu, Q.; Tie, Y.; Zhu, J.; Xing, R.; Sun, Z.; Zheng, X. Downregulation of CCND1 and CDK6 by miR-34a induces cell cycle arrest. FEBS Lett. 2008, 582, 1564–1568. [Google Scholar] [CrossRef]
- Kefas, B.; Godlewski, J.; Comeau, L.; Li, Y.; Abounader, R.; Hawkinson, M.; Lee, J.; Fine, H.; Chiocca, E.A.; Lawler, S.; et al. microRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma. Cancer Res. 2008, 68, 3566–3572. [Google Scholar] [CrossRef]
- Lee, K.M.; Choi, E.J.; Kim, I.A. microRNA-7 increases radiosensitivity of human cancer cells with activated EGFR-associated signaling. Radiother. Oncol. 2011, 101, 171–176. [Google Scholar] [CrossRef]
- Wu, D.G.; Wang, Y.Y.; Fan, L.G.; Luo, H.; Han, B.; Sun, L.H.; Wang, X.F.; Zhang, J.X.; Cao, L.; Wang, X.R.; et al. MicroRNA-7 regulates glioblastoma cell invasion via targeting focal adhesion kinase expression. Chin. Med. J. 2011, 124, 2616–2621. [Google Scholar]
- Lu, Z.J.; Liu, S.Y.; Yao, Y.Q.; Zhou, Y.J.; Zhang, S.; Dai, L.; Tian, H.W.; Zhou, Y.; Deng, H.X.; Yang, J.L.; et al. The effect of miR-7 on behavior and global protein expression in glioma cell lines. Electrophoresis 2011, 32, 3612–3620. [Google Scholar] [CrossRef]
- Lang, M.F.; Yang, S.; Zhao, C.; Sun, G.; Murai, K.; Wu, X.; Wang, J.; Gao, H.; Brown, C.E.; Liu, X.; et al. Genome-wide profiling identified a set of miRNAs that are differentially expressed in glioblastoma stem cells and normal neural stem cells. PLoS One 2012, 7, e36248. [Google Scholar] [CrossRef]
- Gabriely, G.; Yi, M.; Narayan, R.S.; Niers, J.M.; Wurdinger, T.; Imitola, J.; Ligon, K.L.; Kesari, S.; Esau, C.; Stephens, R.M.; et al. Human glioma growth is controlled by microRNA-10b. Cancer Res. 2011, 71, 3563–3572. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef]
- 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, 1407–1413. [Google Scholar] [CrossRef]
- Zheng, X.; Chopp, M.; Lu, Y.; Buller, B.; Jiang, F. MiR-15b and miR-152 reduce glioma cell invasion and angiogenesis via NRP-2 and MMP-3. Cancer Lett. 2013, 329, 146–154. [Google Scholar] [CrossRef]
- Xia, H.; Qi, Y.; Ng, S.S.; Chen, X.; Chen, S.; Fang, M.; Li, D.; Zhao, Y.; Ge, R.; Li, G.; et al. MicroRNA-15b regulates cell cycle progression by targeting cyclins in glioma cells. Biochem. Biophys. Res. Commun. 2009, 380, 205–210. [Google Scholar] [CrossRef]
- Li, X.; Ling, N.; Bai, Y.; Dong, W.; Hui, G.Z.; Liu, D.; Zhao, J.; Hu, J. MiR-16–1 plays a role in reducing migration and invasion of glioma cells. Anat. Rec. 2013, 296, 427–432. [Google Scholar]
- Ernst, A.; Campos, B.; Meier, J.; Devens, F.; Liesenberg, F.; Wolter, M.; Reifenberger, G.; Herold-Mende, C.; Lichter, P.; Radlwimmer, B. De-repression of CTGF via the miR-17-92 cluster upon differentiation of human glioblastoma spheroid cultures. Oncogene 2010, 29, 3411–3422. [Google Scholar] [CrossRef]
- Knoll, S.; Emmrich, S.; Putzer, B.M. The E2F1-miRNA Cancer Progression Network. Adv. Exp. Med. Biol. 2013, 774, 135–147. [Google Scholar] [CrossRef]
- Pickering, M.T.; Stadler, B.M.; Kowalik, T.F. miR-17 and miR-20a temper an E2F1-induced G1 checkpoint to regulate cell cycle progression. Oncogene 2009, 28, 140–145. [Google Scholar] [CrossRef]
- 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, e970761. [Google Scholar]
- Papagiannakopoulos, T.; Shapiro, A.; Kosik, K.S. MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Res. 2008, 68, 8164–8172. [Google Scholar] [CrossRef]
- Gabriely, G.; Wurdinger, T.; Kesari, S.; Esau, C.C.; Burchard, J.; Linsley, P.S.; Krichevsky, A.M. MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators. Mol. Cell. Biol. 2008, 28, 5369–5380. [Google Scholar] [CrossRef]
- Han, L.; Yue, X.; Zhou, X.; Lan, F.M.; You, G.; Zhang, W.; Zhang, K.L.; Zhang, C.Z.; Cheng, J.Q.; Yu, S.Z.; et al. MicroRNA-21 expression is regulated by beta-catenin/STAT3 pathway and promotes glioma cell invasion by direct targeting RECK. CNS Neurosci. Ther. 2012, 18, 573–583. [Google Scholar] [CrossRef]
- Shi, L.; Chen, J.; Yang, J.; Pan, T.; Zhang, S.; Wang, Z. MiR-21 protected human glioblastoma U87MG cells from chemotherapeutic drug temozolomide induced apoptosis by decreasing Bax/Bcl-2 ratio and caspase-3 activity. Brain Res. 2010, 1352, 255–264. [Google Scholar] [CrossRef]
- Li, Y.; Li, W.; Yang, Y.; Lu, Y.; He, C.; Hu, G.; Liu, H.; Chen, J.; He, J.; Yu, H. MicroRNA-21 targets LRRFIP1 and contributes to VM-26 resistance in glioblastoma multiforme. Brain Res. 2009, 1286, 13–18. [Google Scholar] [CrossRef]
- Wang, Y.Y.; Sun, G.; Luo, H.; Wang, X.F.; Lan, F.M.; Yue, X.; Fu, L.S.; Pu, P.Y.; Kang, C.S.; Liu, N.; et al. MiR-21 modulates hTERT through a STAT3-dependent manner on glioblastoma cell growth. CNS Neurosci. Ther. 2012, 18, 722–728. [Google Scholar] [CrossRef]
- Zhou, X.; Ren, Y.; Moore, L.; Mei, M.; You, Y.; Xu, P.; Wang, B.; Wang, G.; Jia, Z.; Pu, P.; et al. Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status. Lab. Invest. 2010, 90, 144–155. [Google Scholar] [CrossRef]
- Costa, P.M.; Cardoso, A.L.; Pereira, D.A.L.; Bruce, J.N.; Canoll, P.; Pedroso, D.L.M. PDGF-B-mediated downregulation of miR-21: New insights into PDGF signaling in glioblastoma. Hum. Mol. Genet. 2012, 21, 5118–5130. [Google Scholar] [CrossRef]
- Gaur, A.B.; Holbeck, S.L.; Colburn, N.H.; Israel, M.A. Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo. Neuro-Oncolology 2011, 13, 580–590. [Google Scholar] [CrossRef]
- Li, Y.; Zhao, S.; Zhen, Y.; Li, Q.; Teng, L.; Asai, A.; Kawamoto, K. A miR-21 inhibitor enhances apoptosis and reduces G(2)-M accumulation induced by ionizing radiation in human glioblastoma U251 cells. Brain Tumor Pathol. 2011, 28, 209–214. [Google Scholar] [CrossRef]
- Chen, Y.; Liu, W.; Chao, T.; Zhang, Y.; Yan, X.; Gong, Y.; Qiang, B.; Yuan, J.; Sun, M.; Peng, X. MicroRNA-21 down-regulates the expression of tumor suppressor PDCD4 in human glioblastoma cell T98G. Cancer Lett. 2008, 272, 197–205. [Google Scholar] [CrossRef]
- Ren, Y.; Zhou, X.; Mei, M.; Yuan, X.B.; Han, L.; Wang, G.X.; Jia, Z.F.; Xu, P.; Pu, P.Y.; Kang, C.S. MicroRNA-21 inhibitor sensitizes human glioblastoma cells U251 (PTEN-mutant) and LN229 (PTEN-wild type) to taxol. BMC Cancer 2010, 10, e27. [Google Scholar] [CrossRef]
- Zhang, S.; Wan, Y.; Pan, T.; Gu, X.; Qian, C.; Sun, G.; Sun, L.; Xiang, Y.; Wang, Z.; Shi, L. MicroRNA-21 inhibitor sensitizes human glioblastoma U251 stem cells to chemotherapeutic drug temozolomide. J. Mol. Neurosci. 2012, 47, 346–356. [Google Scholar] [CrossRef]
- Gwak, H.S.; Kim, T.H.; Jo, G.H.; Kim, Y.J.; Kwak, H.J.; Kim, J.H.; Yin, J.; Yoo, H.; Lee, S.H.; Park, J.B. 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, e47449. [Google Scholar] [CrossRef]
- Quintavalle, C.; Donnarumma, E.; Iaboni, M.; Roscigno, G.; Garofalo, M.; Romano, G.; Fiore, D.; de Marinis, P.; Croce, C.M.; Condorelli, G. Effect of miR-21 and miR-30b/c on TRAIL-induced apoptosis in glioma cells. Oncogene 2012. [Google Scholar] [CrossRef]
- Kwak, H.J.; Kim, Y.J.; Chun, K.R.; Woo, Y.M.; Park, S.J.; Jeong, J.A.; Jo, S.H.; Kim, T.H.; Min, H.S.; Chae, J.S.; et al. Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas. Oncogene 2011, 30, 2433–2442. [Google Scholar] [CrossRef]
- Geng, J.; Luo, H.; Pu, Y.; Zhou, Z.; Wu, X.; Xu, W.; Yang, Z. Methylation mediated silencing of miR-23b expression and its role in glioma stem cells. Neurosci. Lett. 2012, 528, 185–189. [Google Scholar] [CrossRef]
- Loftus, J.C.; Ross, J.T.; Paquette, K.M.; Paulino, V.M.; Nasser, S.; Yang, Z.; Kloss, J.; Kim, S.; Berens, M.E.; Tran, N.L. miRNA expression profiling in migrating glioblastoma cells: Regulation of cell migration and invasion by miR-23b via targeting of Pyk2. PLoS One 2012, 7, e39818. [Google Scholar] [CrossRef]
- Chen, L.; Han, L.; Zhang, K.; Shi, Z.; Zhang, J.; Zhang, A.; Wang, Y.; Song, Y.; Li, Y.; Jiang, T.; et al. VHL regulates the effects of miR-23b on glioma survival and invasion via suppression of HIF-1alpha/VEGF and beta-catenin/Tcf-4 signaling. Neuro-Oncology 2012, 14, 1026–1036. [Google Scholar] [CrossRef]
- Huse, J.T.; Brennan, C.; Hambardzumyan, D.; Wee, B.; Pena, J.; Rouhanifard, S.H.; Sohn-Lee, C.; le Sage, C.; Agami, R.; Tuschl, T.; et al. The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo. Genes Dev. 2009, 23, 1327–1337. [Google Scholar] [CrossRef]
- Jiang, L.; Lin, C.; Song, L.; Wu, J.; Chen, B.; Ying, Z.; Fang, L.; Yan, X.; He, M.; Li, J.; et al. MicroRNA-30e* promotes human glioma cell invasiveness in an orthotopic xenotransplantation model by disrupting the NF-kappaB/IkappaBalpha negative feedback loop. J. Clin. Invest. 2012, 122, 33–47. [Google Scholar] [CrossRef]
- Hua, D.; Ding, D.; Han, X.; Zhang, W.; Zhao, N.; Foltz, G.; Lan, Q.; Huang, Q.; Lin, B. Human miR-31 targets radixin and inhibits migration and invasion of glioma cells. Oncol. Rep. 2012, 27, 700–706. [Google Scholar]
- Chang, T.C.; Wentzel, E.A.; Kent, O.A.; Ramachandran, K.; Mullendore, M.; Lee, K.H.; Feldmann, G.; Yamakuchi, M.; Ferlito, M.; Lowenstein, C.J.; et al. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol. Cell 2007, 26, 745–752. [Google Scholar] [CrossRef]
- Sun, L.; Wu, Z.; Shao, Y.; Pu, Y.; Miu, W.; Yao, J.; Wu, Y.; Yang, Z. MicroRNA-34a suppresses cell proliferation and induces apoptosis in U87 glioma stem cells. Technol. Cancer Res. Treat. 2012, 11, 483–490. [Google Scholar]
- Smits, M.; Nilsson, J.; Mir, S.E.; van der Stoop, P.M.; Hulleman, E.; Niers, J.M.; de Witt, H.P.; Marquez, V.E.; Cloos, J.; Krichevsky, A.M.; et al. miR-101 is down-regulated in glioblastoma resulting in EZH2-induced proliferation, migration, and angiogenesis. Oncotarget 2010, 1, 710–720. [Google Scholar]
- Xia, H.; Cheung, W.K.; Ng, S.S.; Jiang, X.; Jiang, S.; Sze, J.; Leung, G.K.; Lu, G.; Chan, D.T.; Bian, X.W.; et al. Loss of brain-enriched miR-124 microRNA enhances stem-like traits and invasiveness of glioma cells. J. Biol. Chem. 2012, 287, 9962–9971. [Google Scholar] [CrossRef]
- Shi, L.; Zhang, J.; Pan, T.; Zhou, J.; Gong, W.; Liu, N.; Fu, Z.; You, Y. MiR-125b is critical for the suppression of human U251 glioma stem cell proliferation. Brain Res. 2010, 1312, 120–126. [Google Scholar] [CrossRef]
- Xia, H.F.; He, T.Z.; Liu, C.M.; Cui, Y.; Song, P.P.; Jin, X.H.; Ma, X. MiR-125b expression affects the proliferation and apoptosis of human glioma cells by targeting Bmf. Cell. Physiol. Biochem. 2009, 23, 347–358. [Google Scholar] [CrossRef]
- Smits, M.; Wurdinger, T.; van Het, H.B.; Drexhage, J.A.; Geerts, D.; Wesseling, P.; Noske, D.P.; Vandertop, W.P.; de Vries, H.E.; Reijerkerk, A. Myc-associated zinc finger protein (MAZ) is regulated by miR-125b and mediates VEGF-induced angiogenesis in glioblastoma. FASEB J. 2012, 26, 2639–2647. [Google Scholar] [CrossRef]
- Wu, N.; Xiao, L.; Zhao, X.; Zhao, J.; Wang, J.; Wang, F.; Cao, S.; Lin, X. miR-125b regulates the proliferation of glioblastoma stem cells by targeting E2F2. FEBS Lett. 2012, 586, 3831–3839. [Google Scholar] [CrossRef]
- Shi, L.; Zhang, S.; Feng, K.; Wu, F.; Wan, Y.; Wang, Z.; Zhang, J.; Wang, Y.; Yan, W.; Fu, Z.; et al. MicroRNA-125b-2 confers human glioblastoma stem cells resistance to temozolomide through the mitochondrial pathway of apoptosis. Int. J. Oncol. 2012, 40, 119–129. [Google Scholar]
- Godlewski, J.; Nowicki, M.O.; Bronisz, A.; Williams, S.; Otsuki, A.; Nuovo, G.; Raychaudhury, A.; Newton, H.B.; Chiocca, E.A.; 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, 9125–9130. [Google Scholar] [CrossRef]
- Zhang, Y.; Chao, T.; Li, R.; Liu, W.; Chen, Y.; Yan, X.; Gong, Y.; Yin, B.; Liu, W.; Qiang, B.; et al. MicroRNA-128 inhibits glioma cells proliferation by targeting transcription factor E2F3a. J. Mol. Med. 2009, 87, 43–51. [Google Scholar] [CrossRef]
- Shi, Z.M.; Wang, J.; Yan, Z.; You, Y.P.; Li, C.Y.; Qian, X.; Yin, Y.; Zhao, P.; Wang, Y.Y.; Wang, X.F.; et al. MiR-128 inhibits tumor growth and angiogenesis by targeting p70S6K1. PLoS One 2012, 7, e32709. [Google Scholar] [CrossRef]
- Wu, N.; Wu, G.C.; Hu, R.; Li, M.; Feng, H. Ginsenoside Rh2 inhibits glioma cell proliferation by targeting microRNA-128. Acta Pharmacol. Sin. 2011, 32, 345–353. [Google Scholar] [CrossRef]
- Papagiannakopoulos, T.; Friedmann-Morvinski, D.; Neveu, P.; Dugas, J.C.; Gill, R.M.; Huillard, E.; Liu, C.; Zong, H.; Rowitch, D.H.; Barres, B.A.; et al. Pro-neural miR-128 is a glioma tumor suppressor that targets mitogenic kinases. Oncogene 2012, 31, 1884–1895. [Google Scholar] [CrossRef]
- Lee, H.K.; Bier, A.; Cazacu, S.; Finniss, S.; Xiang, C.; Twito, H.; Poisson, L.M.; Mikkelsen, T.; Slavin, S.; Jacoby, E.; et al. MicroRNA-145 is downregulated in glial tumors and regulates glioma cell migration by targeting connective tissue growth factor. PLoS One 2013, 8, e54652. [Google Scholar] [CrossRef]
- Lu, Y.; Chopp, M.; Zheng, X.; Katakowski, M.; Buller, B.; Jiang, F. MiR-145 reduces ADAM17 expression and inhibits in vitro migration and invasion of glioma cells. Oncol. Rep. 2013, 29, 67–72. [Google Scholar]
- Speranza, M.C.; Frattini, V.; Pisati, F.; Kapetis, D.; Porrati, P.; Eoli, M.; Pellegatta, S.; Finocchiaro, G. NEDD9, a novel target of miR-145, increases the invasiveness of glioblastoma. Oncotarget 2012, 3, 723–734. [Google Scholar]
- Lee, S.J.; Kim, S.J.; Seo, H.H.; Shin, S.P.; Kim, D.; Park, C.S.; Kim, K.T.; Kim, Y.H.; Jeong, J.S.; Kim, I.H. Over-expression of miR-145 enhances the effectiveness of HSVtk gene therapy for malignant glioma. Cancer Lett. 2012, 320, 72–80. [Google Scholar] [CrossRef]
- Katakowski, M.; Zheng, X.; Jiang, F.; Rogers, T.; Szalad, A.; Chopp, M. MiR-146b-5p suppresses EGFR expression and reduces in vitro migration and invasion of glioma. Cancer Invest. 2010, 28, 1024–1030. [Google Scholar] [CrossRef]
- Xu, J.; Liao, X.; Wong, C. Downregulations of B-cell lymphoma 2 and myeloid cell leukemia sequence 1 by microRNA 153 induce apoptosis in a glioblastoma cell line DBTRG-05MG. Int. J. Cancer 2010, 126, 1029–1035. [Google Scholar]
- Xu, J.; Liao, X.; Lu, N.; Liu, W.; Wong, C.W. Chromatin-modifying drugs induce miRNA-153 expression to suppress Irs-2 in glioblastoma cell lines. Int. J. Cancer 2011, 129, 2527–2531. [Google Scholar] [CrossRef]
- Shi, L.; Cheng, Z.; Zhang, J.; Li, R.; Zhao, P.; Fu, Z.; You, Y. hsa-mir-181a and hsa-mir-181b function as tumor suppressors in human glioma cells. Brain Res. 2008, 1236, 185–193. [Google Scholar] [CrossRef]
- 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, 997–1003. [Google Scholar]
- Song, L.; Liu, L.; Wu, Z.; Li, Y.; Ying, Z.; Lin, C.; Wu, J.; Hu, B.; Cheng, S.Y.; Li, M.; et al. TGF-beta induces miR-182 to sustain NF-kappaB activation in glioma subsets. J. Clin. Invest. 2012, 122, 3563–3578. [Google Scholar] [CrossRef]
- Malzkorn, B.; Wolter, M.; Liesenberg, F.; Grzendowski, M.; Stuhler, K.; Meyer, H.E.; Reifenberger, G. Identification and functional characterization of microRNAs involved in the malignant progression of gliomas. Brain Pathol. 2010, 20, 539–550. [Google Scholar]
- Ujifuku, K.; Mitsutake, N.; Takakura, S.; Matsuse, M.; Saenko, V.; Suzuki, K.; Hayashi, K.; Matsuo, T.; Kamada, K.; Nagata, I.; et al. miR-195, miR-455-3p and miR-10a (*) are implicated in acquired temozolomide resistance in glioblastoma multiforme cells. Cancer Lett. 2010, 296, 241–248. [Google Scholar] [CrossRef]
- Hui, W.; Yuntao, L.; Lun, L.; Wensheng, L.; Chaofeng, L.; Haiyong, H.; Yueyang, B. MicroRNA-195 inhibits the proliferation of human glioma cells by directly targeting cyclin D1 and Cyclin E1. PLoS One 2013, 8, e54932. [Google Scholar]
- Zhang, Q.Q.; Xu, H.; Huang, M.B.; Ma, L.M.; Huang, Q.J.; Yao, Q.; Zhou, H.; Qu, L.H. MicroRNA-195 plays a tumor-suppressor role in human glioblastoma cells by targeting signaling pathways involved in cellular proliferation and invasion. Neuro-Oncology 2012, 14, 278–287. [Google Scholar] [CrossRef]
- Ying, Z.; Li, Y.; Wu, J.; Zhu, X.; Yang, Y.; Tian, H.; Li, W.; Hu, B.; Cheng, S.Y.; Li, M. Loss of miR-204 expression enhances glioma migration and stem cell-like phenotype. Cancer Res. 2013, 73, 990–999. [Google Scholar] [CrossRef]
- Zhang, C.Z.; Zhang, J.X.; Zhang, A.L.; Shi, Z.D.; Han, L.; Jia, Z.F.; Yang, W.D.; Wang, G.X.; Jiang, T.; You, Y.P.; et al. MiR-221 and miR-222 target PUMA to induce cell survival in glioblastoma. Mol. Cancer 2010, 9, e229. [Google Scholar] [CrossRef]
- Hao, J.; Zhang, C.; Zhang, A.; Wang, K.; Jia, Z.; Wang, G.; Han, L.; Kang, C.; Pu, P. miR-221/222 is the regulator of Cx43 expression in human glioblastoma cells. Oncol. Rep. 2012, 27, 1504–1510. [Google Scholar]
- Zhang, C.; Kang, C.; You, Y.; Pu, P.; Yang, W.; Zhao, P.; Wang, G.; Zhang, A.; Jia, Z.; Han, L.; et al. Co-suppression of miR-221/222 cluster suppresses human glioma cell growth by targeting p27kip1 in vitro and in vivo. Int. J. Oncol. 2009, 34, 1653–1660. [Google Scholar]
- Medina, R.; Zaidi, S.K.; Liu, C.G.; Stein, J.L.; van Wijnen, A.J.; Croce, C.M.; Stein, G.S. MicroRNAs 221 and 222 bypass quiescence and compromise cell survival. Cancer Res. 2008, 68, 2773–2780. [Google Scholar] [CrossRef]
- Chen, L.; Zhang, J.; Han, L.; Zhang, A.; Zhang, C.; Zheng, Y.; Jiang, T.; Pu, P.; Jiang, C.; Kang, C. Downregulation of miR-221/222 sensitizes glioma cells to temozolomide by regulating apoptosis independently of p53 status. Oncol. Rep. 2012, 27, 854–860. [Google Scholar]
- 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 signal transducer and activator of transcription (STAT) pathway by repression of miR-221/222 in glioblastoma U251 cells. Int. J. Oncol. 2010, 36, 1503–1512. [Google Scholar]
- 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, 913–920. [Google Scholar]
- Zhang, C.; Zhang, J.; Hao, J.; Shi, Z.; Wang, Y.; Han, L.; Yu, S.; You, Y.; Jiang, T.; Wang, J.; et al. High level of miR-221/222 confers increased cell invasion and poor prognosis in glioma. J. Transl. Med. 2012, 10, e119. [Google Scholar] [CrossRef]
- Quintavalle, C.; Garofalo, M.; Zanca, C.; Romano, G.; Iaboni, M.; del Basso De Caro, M.; Martinez-Montero, J.C.; Incoronato, M.; Nuovo, G.; Croce, C.M.; et al. miR-221/222 overexpession in human glioblastoma increases invasiveness by targeting the protein phosphate PTPmμ. Oncogene 2012, 31, 858–868. [Google Scholar] [CrossRef]
- Galardi, S.; Mercatelli, N.; Farace, M.G.; Ciafre, S.A. NF-kB and c-Jun induce the expression of the oncogenic miR-221 and miR-222 in prostate carcinoma and glioblastoma cells. Nucleic Acids Res. 2011, 39, 3892–3902. [Google Scholar] [CrossRef]
- Wurdinger, T.; Tannous, B.A.; Saydam, O.; Skog, J.; Grau, S.; Soutschek, J.; Weissleder, R.; Breakefield, X.O.; Krichevsky, A.M. miR-296 regulates growth factor receptor overexpression in angiogenic endothelial cells. Cancer Cell 2008, 14, 382–393. [Google Scholar] [CrossRef]
- Kefas, B.; Comeau, L.; Floyd, D.H.; Seleverstov, O.; Godlewski, J.; Schmittgen, T.; Jiang, J.; DiPierro, C.G.; Li, Y.; Chiocca, E.A.; et al. The neuronal microRNA miR-326 acts in a feedback loop with notch and has therapeutic potential against brain tumors. J. Neurosci. 2009, 29, 15161–15168. [Google Scholar] [CrossRef]
- 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-Oncology 2010, 12, 1102–1112. [Google Scholar] [CrossRef]
- 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, e373. [Google Scholar] [CrossRef]
- Chen, L.; Zhang, J.; Feng, Y.; Li, R.; Sun, X.; Du, W.; Piao, X.; Wang, H.; Yang, D.; Sun, Y.; et al. MiR-410 regulates MET to influence the proliferation and invasion of glioma. Int. J. Biochem. Cell Biol. 2012, 44, 1711–1717. [Google Scholar] [CrossRef]
- Godlewski, J.; Nowicki, M.O.; Bronisz, A.; Nuovo, G.; Palatini, J.; de Lay, M.; van Brocklyn, J.; Ostrowski, M.C.; Chiocca, E.A.; Lawler, S.E. MicroRNA-451 regulates LKB1/AMPK signaling and allows adaptation to metabolic stress in glioma cells. Mol. Cell 2010, 37, 620–632. [Google Scholar] [CrossRef]
- Song, L.; Lin, C.; Gong, H.; Wang, C.; Liu, L.; Wu, J.; Tao, S.; Hu, B.; Cheng, S.Y.; Li, M.; et al. miR-486 sustains NF-kappaB activity by disrupting multiple NF-kappaB-negative feedback loops. Cell Res. 2013, 23, 274–289. [Google Scholar] [CrossRef]
- Lee, S.T.; Chu, K.; Oh, H.J.; Im, W.S.; Lim, J.Y.; Kim, S.K.; Park, C.K.; Jung, K.H.; Lee, S.K.; Kim, M.; et al. Let-7 microRNA inhibits the proliferation of human glioblastoma cells. J. Neurooncol. 2011, 102, 19–24. [Google Scholar] [CrossRef]
- Adams, J.M.; Cory, S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 2007, 26, 1324–1337. [Google Scholar] [CrossRef]
- Kim, H.; Huang, W.; Jiang, X.; Pennicooke, B.; Park, P.J.; Johnson, M.D. Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship. Proc. Natl. Acad. Sci. USA 2010, 107, 2183–2188. [Google Scholar]
- 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, 1013–1021. [Google Scholar]
- Cheng, S.Y.; Huang, H.J.; Nagane, M.; Ji, X.D.; Wang, D.; Shih, C.C.; Arap, W.; Huang, C.M.; Cavenee, W.K. Suppression of glioblastoma angiogenicity and tumorigenicity by inhibition of endogenous expression of vascular endothelial growth factor. Proc. Natl. Acad. Sci. USA 1996, 93, 8502–8507. [Google Scholar] [CrossRef]
- Guo, P.; Hu, B.; Gu, W.; Xu, L.; Wang, D.; Huang, H.J.; Cavenee, W.K.; Cheng, S.Y. Platelet-derived growth factor-B enhances glioma angiogenesis by stimulating vascular endothelial growth factor expression in tumor endothelia and by promoting pericyte recruitment. Am. J. Pathol. 2003, 162, 1083–1093. [Google Scholar] [CrossRef]
- Guo, P.; Xu, L.; Pan, S.; Brekken, R.A.; Yang, S.T.; Whitaker, G.B.; Nagane, M.; Thorpe, P.E.; Rosenbaum, J.S.; Su, H.H.; et al. Vascular endothelial growth factor isoforms display distinct activities in promoting tumor angiogenesis at different anatomic sites. Cancer Res. 2001, 61, 8569–8577. [Google Scholar]
- Hu, B.; Guo, P.; Fang, Q.; Tao, H.Q.; Wang, D.; Nagane, M.; Huang, H.J.; Gunji, Y.; Nishikawa, R.; Alitalo, K.; et al. Angiopoietin-2 induces human glioma invasion through the activation of matrix metalloprotease-2. Proc. Natl. Acad. Sci. USA 2003, 100, 8904–8909. [Google Scholar] [CrossRef]
- Reya, T.; Morrison, S.J.; Clarke, M.F.; Weissman, I.L. Stem cells, cancer, and cancer stem cells. Nature 2001, 414, 105–111. [Google Scholar] [CrossRef]
- Singh, S.K.; Hawkins, C.; Clarke, I.D.; Squire, J.A.; Bayani, J.; Hide, T.; Henkelman, R.M.; Cusimano, M.D.; Dirks, P.B. Identification of human brain tumour initiating cells. Nature 2004, 432, 396–401. [Google Scholar] [CrossRef]
- Morrison, S.J.; Perez, S.E.; Qiao, Z.; Verdi, J.M.; Hicks, C.; Weinmaster, G.; Anderson, D.J. Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells. Cell 2000, 101, 499–510. [Google Scholar] [CrossRef]
- Lee, J.; Kotliarova, S.; Kotliarov, Y.; Li, A.; Su, Q.; Donin, N.M.; Pastorino, S.; Purow, B.W.; Christopher, N.; Zhang, W.; et al. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 2006, 9, 391–403. [Google Scholar] [CrossRef]
- Ikushima, H.; Todo, T.; Ino, Y.; Takahashi, M.; Miyazawa, K.; Miyazono, K. Autocrine TGF-beta signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. Cell Stem Cell 2009, 5, 504–514. [Google Scholar] [CrossRef]
- Shiras, A.; Chettiar, S.T.; Shepal, V.; Rajendran, G.; Prasad, G.R.; Shastry, P. Spontaneous transformation of human adult nontumorigenic stem cells to cancer stem cells is driven by genomic instability in a human model of glioblastoma. Stem Cells 2007, 25, 1478–1489. [Google Scholar] [CrossRef]
- Drappatz, J.; Norden, A.D.; Wen, P.Y. Therapeutic strategies for inhibiting invasion in glioblastoma. Expert Rev. Neurother. 2009, 9, 519–534. [Google Scholar] [CrossRef]
- Nieder, C.; Grosu, A.L.; Molls, M. A comparison of treatment results for recurrent malignant gliomas. Cancer Treat. Rev. 2000, 26, 397–409. [Google Scholar] [CrossRef]
- Brada, M.; Hoang-Xuan, K.; Rampling, R.; Dietrich, P.Y.; Dirix, L.Y.; Macdonald, D.; Heimans, J.J.; Zonnenberg, B.A.; Bravo-Marques, J.M.; Henriksson, R.; et al. Multicenter phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse. Ann. Oncol. 2001, 12, 259–266. [Google Scholar] [CrossRef]
- Rich, J.N.; Reardon, D.A.; Peery, T.; Dowell, J.M.; Quinn, J.A.; Penne, K.L.; Wikstrand, C.J.; van Duyn, L.B.; Dancey, J.E.; McLendon, R.E.; et al. Phase II trial of gefitinib in recurrent glioblastoma. J. Clin. Oncol. 2004, 22, 133–142. [Google Scholar]
- Eramo, A.; Ricci-Vitiani, L.; Zeuner, A.; Pallini, R.; Lotti, F.; Sette, G.; Pilozzi, E.; Larocca, L.M.; Peschle, C.; de Maria, R. Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ. 2006, 13, 1238–1241. [Google Scholar] [CrossRef]
- Hornstein, E.; Shomron, N. Canalization of development by microRNAs. Nat. Genet. 2006, 38, S20–S24. [Google Scholar] [CrossRef]
- Zhang, X.; Odom, D.T.; Koo, S.H.; Conkright, M.D.; Canettieri, G.; Best, J.; Chen, H.; Jenner, R.; Herbolsheimer, E.; Jacobsen, E.; et al. Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues. Proc. Natl. Acad. Sci. USA 2005, 102, 4459–4464. [Google Scholar] [CrossRef]
- Tan, X.; Wang, S.; Zhu, L.; Wu, C.; Yin, B.; Zhao, J.; Yuan, J.; Qiang, B.; Peng, X. cAMP response element-binding protein promotes gliomagenesis by modulating the expression of oncogenic microRNA-23a. Proc. Natl. Acad. Sci. USA 2012, 109, 15805–15810. [Google Scholar]
- Zhang, H.; Chen, Y.; Chen, Y. Noise propagation in gene regulation networks involving interlinked positive and negative feedback loops. PLoS One 2012, 7, e51840. [Google Scholar] [CrossRef]
- Hooshangi, S.; Weiss, R. The effect of negative feedback on noise propagation in transcriptional gene networks. Chaos 2006, 16, e26108. [Google Scholar] [CrossRef]
- Milo, R.; Shen-Orr, S.; Itzkovitz, S.; Kashtan, N.; Chklovskii, D.; Alon, U. Network motifs: Simple building blocks of complex networks. Science 2002, 298, 824–827. [Google Scholar] [CrossRef]
- Engelmann, D.; Mayoli-Nussle, D.; Mayrhofer, C.; Furst, K.; Alla, V.; Stoll, A.; Spitschak, A.; Abshagen, K.; Vollmar, B.; Ran, S.; et al. E2F1 promotes angiogenesis through the VEGF-C/VEGFR-3 axis in a feedback loop for cooperative induction of PDGF-B. J. Mol. Cell Biol. 2013. [Google Scholar] [CrossRef]
- Aronchik, I.; Bjeldanes, L.F.; Firestone, G.L. Direct inhibition of elastase activity by indole-3-carbinol triggers a CD40-TRAF regulatory cascade that disrupts NF-kappaB transcriptional activity in human breast cancer cells. Cancer Res. 2010, 70, 4961–4971. [Google Scholar] [CrossRef]
- Shin, Y.J.; Hencey, B.; Lipkin, S.M.; Shen, X. Frequency domain analysis reveals external periodic fluctuations can generate sustained p53 oscillation. PLoS One 2011, 6, e22852. [Google Scholar]
- Sun, S.C.; Ganchi, P.A.; Ballard, D.W.; Greene, W.C. NF-kappa B controls expression of inhibitor I kappa B alpha: Evidence for an inducible autoregulatory pathway. Science 1993, 259, 1912–1915. [Google Scholar]
- Johnson, C.; van Antwerp, D.; Hope, T.J. An N-terminal nuclear export signal is required for the nucleocytoplasmic shuttling of IkappaBalpha. EMBO J. 1999, 18, 6682–6693. [Google Scholar] [CrossRef]
- Huang, T.T.; Kudo, N.; Yoshida, M.; Miyamoto, S. A nuclear export signal in the N-terminal regulatory domain of IkappaBalpha controls cytoplasmic localization of inactive NF-kappaB/IkappaBalpha complexes. Proc. Natl. Acad. Sci. USA 2000, 97, 1014–1019. [Google Scholar] [CrossRef]
- Kaern, M.; Elston, T.C.; Blake, W.J.; Collins, J.J. Stochasticity in gene expression: From theories to phenotypes. Nat. Rev. Genet. 2005, 6, 451–464. [Google Scholar] [CrossRef]
- Raser, J.M.; O’Shea, E.K. Noise in gene expression: Origins, consequences, and control. Science 2005, 309, 2010–2013. [Google Scholar] [CrossRef]
- Osada, H.; Takahashi, T. Let-7 and miR-17–92: Small-sized major players in lung cancer development. Cancer Sci. 2011, 102, 9–17. [Google Scholar] [CrossRef]
- Woods, K.; Thomson, J.M.; Hammond, S.M. Direct regulation of an oncogenic micro-RNA cluster by E2F transcription factors. J. Biol. Chem. 2007, 282, 2130–2134. [Google Scholar]
- Sylvestre, Y.; de Guire, V.; Querido, E.; Mukhopadhyay, U.K.; Bourdeau, V.; Major, F.; Ferbeyre, G.; Chartrand, P. An E2F/miR-20a autoregulatory feedback loop. J. Biol. Chem. 2007, 282, 2135–2143. [Google Scholar]
- Monzo, M.; Navarro, A.; Bandres, E.; Artells, R.; Moreno, I.; Gel, B.; Ibeas, R.; Moreno, J.; Martinez, F.; Diaz, T.; et al. Overlapping expression of microRNAs in human embryonic colon and colorectal cancer. Cell Res. 2008, 18, 823–833. [Google Scholar] [CrossRef]
- Esquela-Kerscher, A.; Slack, F.J. Oncomirs—microRNAs with a role in cancer. Nat. Rev. Cancer 2006, 6, 259–269. [Google Scholar] [CrossRef]
- Becskei, A.; Serrano, L. Engineering stability in gene networks by autoregulation. Nature 2000, 405, 590–593. [Google Scholar] [CrossRef]
- Tsang, J.; Zhu, J.; van Oudenaarden, A. MicroRNA-mediated feedback and feedforward loops are recurrent network motifs in mammals. Mol. Cell 2007, 26, 753–767. [Google Scholar] [CrossRef]
- Zavadil, J.; Narasimhan, M.; Blumenberg, M.; Schneider, R.J. Transforming growth factor-beta and microRNA:mRNA regulatory networks in epithelial plasticity. Cells Tissues Organs 2007, 185, 157–161. [Google Scholar] [CrossRef]
- Garofalo, M.; di Leva, G.; Romano, G.; Nuovo, G.; Suh, S.S.; Ngankeu, A.; Taccioli, C.; Pichiorri, F.; Alder, H.; Secchiero, P.; et al. miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell 2009, 16, 498–509. [Google Scholar] [CrossRef]
- Fornari, F.; Gramantieri, L.; Ferracin, M.; Veronese, A.; Sabbioni, S.; Calin, G.A.; Grazi, G.L.; Giovannini, C.; Croce, C.M.; Bolondi, L.; et al. MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Oncogene 2008, 27, 5651–5661. [Google Scholar]
- Verhaak, R.G.; Hoadley, K.A.; Purdom, E.; Wang, V.; Qi, Y.; Wilkerson, M.D.; Miller, C.R.; Ding, L.; Golub, T.; Mesirov, J.P.; et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 2010, 17, 98–110. [Google Scholar] [CrossRef]
- Arroyo, J.D.; Chevillet, J.R.; Kroh, E.M.; Ruf, I.K.; Pritchard, C.C.; Gibson, D.F.; Mitchell, P.S.; Bennett, C.F.; Pogosova-Agadjanyan, E.L.; Stirewalt, D.L.; et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc. Natl. Acad. Sci. USA 2011, 108, 5003–5008. [Google Scholar] [CrossRef]
- Lages, E.; Guttin, A.; El Atifi, M.; Ramus, C.; Ipas, H.; Dupre, I.; Rolland, D.; Salon, C.; Godfraind, C.; DeFraipont, F.; et al. MicroRNA and target protein patterns reveal physiopathological features of glioma subtypes. PLoS One 2011, 6, e20600. [Google Scholar] [CrossRef]
- Welch, C.; Chen, Y.; Stallings, R.L. MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells. Oncogene 2007, 26, 5017–5022. [Google Scholar] [CrossRef]
- Katakowski, M.; Buller, B.; Zheng, X.; Lu, Y.; Rogers, T.; Osobamiro, O.; Shu, W.; Jiang, F.; Chopp, M. Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. Cancer Lett. 2013, 335, 201–204. [Google Scholar] [CrossRef]
- Xia, H.; Qi, Y.; Ng, S.S.; Chen, X.; Li, D.; Chen, S.; Ge, R.; Jiang, S.; Li, G.; Chen, Y.; et al. microRNA-146b inhibits glioma cell migration and invasion by targeting MMPs. Brain Res. 2009, 1269, 158–165. [Google Scholar] [CrossRef]
- Jiang, L.; Mao, P.; Song, L.; Wu, J.; Huang, J.; Lin, C.; Yuan, J.; Qu, L.; Cheng, S.Y.; Li, J. miR-182 as a prognostic marker for glioma progression and patient survival. Am. J. Pathol. 2010, 177, 29–38. [Google Scholar] [CrossRef]
- Tian, Y.; Nan, Y.; Han, L.; Zhang, A.; Wang, G.; Jia, Z.; Hao, J.; Pu, P.; Zhong, Y.; Kang, C. MicroRNA miR-451 downregulates the PI3K/AKT pathway through CAB39 in human glioma. Int. J. Oncol. 2012, 40, 1105–1112. [Google Scholar]
- Nan, Y.; Han, L.; Zhang, A.; Wang, G.; Jia, Z.; Yang, Y.; Yue, X.; Pu, P.; Zhong, Y.; Kang, C. MiRNA-451 plays a role as tumor suppressor in human glioma cells. Brain Res. 2012, 1359, 14–21. [Google Scholar]
- Taniguchi, C.M.; Emanuelli, B.; Kahn, C.R. Critical nodes in signalling pathways: Insights into insulin action. Nat. Rev. Mol. Cell Biol. 2006, 7, 85–96. [Google Scholar] [CrossRef]
- Kim, J.K.; Choi, K.J.; Lee, M.; Jo, M.H.; Kim, S. Molecular imaging of a cancer-targeting theragnostics probe using a nucleolin aptamer- and microRNA-221 molecular beacon-conjugated nanoparticle. Biomaterials 2012, 33, 207–217. [Google Scholar] [CrossRef]
- Hwang, D.W.; Song, I.C.; Lee, D.S.; Kim, S. Smart magnetic fluorescent nanoparticle imaging probes to monitor microRNAs. Small 2010, 6, 81–88. [Google Scholar] [CrossRef]
- Davis, M.E.; Zuckerman, J.E.; Choi, C.H.; Seligson, D.; Tolcher, A.; Alabi, C.A.; Yen, Y.; Heidel, J.D.; Ribas, A. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 2010, 464, 1067–1070. [Google Scholar] [CrossRef]
- Davis, M.E. The first targeted delivery of siRNA in humans via a self-assembling, cyclodextrin polymer-based nanoparticle: from concept to clinic. Mol. Pharm. 2009, 6, 659–668. [Google Scholar] [CrossRef]
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