Therapeutic Prospect For Microrna Genes In Brain Tumors Biology Essay

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MicroRNAs (miRNAs) that are endogeneous, single stranded, non-protein-coding RNA molecules, negatively regulate gene expression in a sequence-specific manner in the biological processes including cellular proliferation/differentiation, apoptosis and the cell cycle. In past few years, miRNAs has widely emerged as key regulators of not only molecular events involved in brain development but also many of the key pathways implicated in tumor pathogenesis, in the nervous system with a specific signature in each normal and cancer cell type. Aberrant miRNA expression results in a variety of cancers. Several deregulated miRNAs which contribute to the tumor initiation and prognosis, have also been uncovered in malignant CNS tumors, medulloblastoma and astrocytoma, as diagnostic and prognostic biomarkers. In addition to their potential use in diagnosis, miRNAs have also erupted as therapeutic tools into brain tumor therapies, leading novel therapeutic approaches with their tumor suppressive and oncogenic functions. In this article, the authors summarize the miRNA expression profiles that represents novel oncogenic molecules involved in brain tumor formation and the molecular pathways that drive miRNA gain-or loss-of-function in such diseases to determine potential therapeutic targets for the treatment of brain tumors. This rewiev also highlights therapeutic prospects of miRNAs in brain tumors with a focus on the potential of miRNAs for therapeutic intervention and the methods used in the delivery of miRNAs into brain tumors, indicating their limitations, safety and toxicity in miRNA-based therapy.

Introduction

Malignant central nervous system (CNS) tumors are leading cause of cancer-related death in children with a short median survival and an almost 100% tumor-related mortality. The most malignant of these, medulloblastoma and astrocytomas (frequently WHO grade-4 astrocytoma; glioblastoma multiforme) have been reported as genetically and epigenetically heterogeneous tumors, although the cellular and molecular mechanisms regulating tumor growth has been poorly characterized in such tumors.1,2 At present, current treatment approaches have limited efficacy and severe side effects to cure these diseases.3 Indeed, novel therapeutic strategies are required a better understanding of the mechanisms responsible for the development of such brain tumors.

MicroRNAs (miRNAs) are giant groups of gene regulators consisting of ~22 nucleotides non-coding single stranded RNA. These single stranded RNAs are endowed with the ability to bind to their target mRNA and repress their translation or facilitate their degradation. Since their discovery in C. elegans in 19934,5, miRNAs have captured the attention of the research community. It has been reported that there are over 700 miRNAs within a human cell6 and each miRNA is endowed with the potential to inhibit protein translation of over 200 genes7 implying a lot of work has to be done to dissect and unravel the activities of these non-protein coding RNAs.

In recent years, due to their regulatory roles in gene expression, miRNAs have been emerged as regulators of both the biological processes in normal tissues and the pathogenesis of human cancers. There is a strong evidence suggesting that miRNAs are closely linked to the molecular pathways and the gene alterations driving the development of brain tumors and regulate oncogenes involved in brain tumor formation. Several de-regulated miRNAs has been identified in medulloblastoma and astrocytomas, suggesting a role for miRNAs in diagnosis and prognosis of these diseases.8-10 miRNAs have also been associated with metastatic behavior of pediatric cancers with an influence on proliferative, anti-apoptotic and pro-angiogenic or pro-metastatic features of tumor cells.9-11 Since the discovery of tumor-suppressive functions of miRNAs involved in cancer3, miRNAs have also erupted as potential drug targets and candidates to increase the effectiveness of chemotherapeutic agents in cancer treatment.12-14 Novel miRNA-based therapeutics reguire experimental models including spesific expression patterns of miRNAs implicated in cancer versus healthy tissue and functional analysis of de-regulated miRNAs as well as successful delivery methods to introduce miRNAs into brain for silencing single target genes. In this approach, we summarize tumor-specific miRNA signatures of medulloblastoma and astrocytomas with a focus on their relationship with cancer pathways to influence cellular behavior. This review also highlights the clinical applicability of miRNAs as novel therapeutics in the treatment of human cancers including pediatric tumors, indicating the delivery methods of miRNAs, and future prospects of miRNA-based therapies.

Pathology of Brain tumors

The two most common classes of central nervous system (CNS) tumors are primitive neuroectodermal tumors (PNETs) and gliomas. The most common and aggressive PNET, medulloblastoma occurs to originate from cerebellar neural precursors (CGNPs) in the cerebellum as an invasive embryonal tumor, most frequently in children and to a lesser extent in young adults.9,10 Medulloblastoma (MB) arises from remnants of the primitive neuroectoderm in the roof of the fourth ventricle and grows in cerebellar vermis, filling this ventricle and often invading through the ependyma to enter the brainstem.2 The current World Health Organization (WHO) guidelines distinguish four histologic variants of MB: classic, desmoplastic, with extensive nodularity and large cell.15 It has been also classified in two groups according to risk-adapted treatments: high-risk (HR) and average risk (AR) groups.2

Several molecular alterations including karyotypic abnormality8 and deregulation of several molecular events (e.g. Shh pathway, RAS, Rb1, c-myc, TK defective TrkC, REST/NSRF) that are targeted by diverse dysregulated miRNAs, appear to be responsible for the development and progression of these genetically and epigenetically heterogeneous tumors.3,16 The presence of an isochromosome 17q or loss of heterozygosity on chromosome 9q (frequently in desmoplastic subtype) presents in about 50% of MB tumors.8 It is obvious that the mutations and alterations in sonic hedgehog signaling (SHH) pathway and its receptor Patched (Ptc), frequently in combination with Wnt pathway deregulation, promote MB formation. For instance, mutations in SUFU gene which encodes a negative regulator of Hh and Wnt pathway operate simultaneously to induce MB, suggesting the activation of Shh pathway in these tumors.17 However, growth factor receptors, ERBB-2, PDGF and IGFR1, lead poor prognosis while PDGFa correlates with metastatic behavior. The altered expression of downstream effectors of these receptors (e.g. Ras/mitogen-activated protein kinase and the transcription factor c-myc), and the mutations in cell cycle regulators including Rb and p53 pathway are also implicated in MB prognosis.2

Astrocytomas are known as the most common type of gliomas. According to WHO guidelines, glioblastoma multiforme (WHO grade-4; GBM) is associated with a uniformly poor outcome, whereas survival varies among patients with low-grade astrocytoma (WHO grade-2) and anaplastic astrocytoma (WHO grade-3). Multiple genetic alterations, frequently in target pathways governing cellular processes, have been identified in astrocytomas, correlated with the malignant progression. Gliomagenesis involves the increased levels of growth factor stimulation and the loss of tumors supressors.18 For example, the mutation of PTEN tumor suppressor gene that occur most frequently in GBM, less commonly in anaplastic astrocytoma, and only rarely in low-grade astrocytoma, has been implicated in the malignant progression of astrocytomas, with significantly worse survival. p53 mutation and EGFR gene amplification, alone or together, have also seen in astrocytomas as a prognostic utility.19 Furthermore, there is a synergistic link between activation of STAT3, MAPK, and AKT and EGFR status, correlated with tumor grade and survival. Overexpression of Notch signaling which regulates the transcription of EGFR through p53, has also observed in astrocytoma.20

Over the past decade, microRNAs (miRNAs) has emerged with their potential diagnostic and prognostic values in gliomagenesis. Aberrant miRNA expression can be altered by molecular mechanisms underlying the tumorigenesis. Based on their critical functions in downstream of classic oncogenic and tumor suppressor signaling pathways, miRNAs appear to be suitable tools for use in tumor classification, prognosis, and response to therapy. miRNA profiling may distinguish brain tumors from normal tissues and classify histotypes or molecular subtypes with altered genetic pathways, providing novel insights into the pathogenesis of MBs and astrocytomas.

Biology of miRNA

Location, Biogenesis and Processing

MiRNAs are located in diverse regions within the human genome with a vast majority found within introns of protein coding and non-coding genes.21,22 Biogenesis and the function of miRNAs are founded on the components of the RNA interference (RNAi) machinery. Transcription of miRNA occurs within the nucleus and is mediated by RNA pol II21 or RNA pol III23 resulting in the generation of a stem-loop structure referred to as primary miRNA (pri-miRNA). pri-miRNA is cropped by the microprocessor complex which consists of a nuclear enzyme Drosha and its double stranded co-factor DGCR8/Pasha into a 70 nucleotide long precursor miRNA (pre-miRNA) having a 3'overhang and a messenger RNA (mRNA) stemming from the same transcription unit.24-26 To ensure a continuous source of cytoplasmic miRNA necessary for gene regulation and prevents nuclear accumulation of miRNA, the 3'overhang on the pre-miRNA is recognized by Exportin 5 which mediate the transport of pre-miRNA through nuclear pore channels in the presence of RanGTP.27 Hydrolysis of Ran-GTP results in the liberation of the 70nt stem-loop pre-miRNA into the cytoplasm for further RNase modification by Dicer, a member of the RNA-induced silencing complex (RISC) which is a polypeptide comprising of Argonate2 (Ago2), TEBP Protein and an RNase-3 enzyme.28,29 The RISC complex Dicer. Upon interaction with the pre-miRNA, Dicer generates an approximately 22 nucleotide non-stem-loop RNA which maintains its 3'overhang generated by the enzymatic action of Drosha and a Dicer cleavage site at the other end.30,31 The 22 nucleotides double stranded RNA (dsRNA) consist of a guide strand (mature miRNA) and a passenger miRNA strand, both of which can be recognized and distinguished by RISC Following the completion of Dicer activity, the dsRNA is subjected to the catalytic activity of Ago2 which degrades the passenger strand and incorporates the guide strand (mature miRNA) into specific gene regulatory activity without the aid of ATP.32 Upon release from RISC, mature miRNA begins their "quarterback" or regulatory role by binding to the 3'UTR33 of targeted mRNA and repress their subsequent translation (Figure-1). Translational repression by miRNA is a valuable tool used by the cell to control the activities of hundred of genes (e.g oncogenes, apoptotic and anti-apoptotic factors) and hence prevent or initiate diseases like cancer.

MicroRNA and Cancer

miRNAs are known to regulate various cellular processes including proliferation, differentiation and the stres response as well as oncogenes, tumour suppressors and variety of cancer-related genes controlling cell cycle, apoptosis, cell migration and angiogenesis.3,7 Thus, the alterations in the expression of miRNAs may be the hallmark of human cancers. Although the mechanisms which cause abnormal miRNA expression, remain unclear, it may altered by several mechanisms. For example, miRNA genes are located in cancer-associated genomic regions22, thus genomic alterations such as chromosomal abnormalities, chromosomal deletions, point mutations and aberrant promoter methylation, can result in the activation of oncogenic functions of miRNAs as well as the inactivation of their tumor suppressive functions and these changes can be tumorigenic.34 Also, the events which affect their processing such as the mutations or polimorphisms which occur in miRNA genomic regions35 or the loss of the RNase III Drosha36 can cause altered miRNA expression, resulting in the development of cancers. Hypoxia which leads genetic and cellular changes as a cause of cancers, also induces alterations in the expression levels of miRNAs, although one of miRNAs, miR-21 displays an adaptation to the effects of hypoxia, mediating cancer cell survival.37 Indeed, numerous studies have identified increased and decreased miRNA expressions in human (colon, kidney, prostate, urinary bladder, lung, breast38 and brain3,10,11) cancers, suggesting their role for tumorigenesis and maintenance of cancer cells. There is evidence that miRNA signatures not only distinquish cancer tissues from normal tissues but also can be powerful tools to determine the stages in multistep tumorigenesis because of their ability to lead tumor cell invasion and metastasis.39 Aberrant miRNA expressions may also play a critical role in the proliferation, self-renewal and differentiation of both normal stem cells (SCs) and cancer stem cells (CSC)40 which have been regarded as the root of cancer origin and recurrence. miRNAs may regulate the division and self-renewal of SCs by targeting cell cycle regulators.41 Recent data suggest that miRNAs play a role in driving both cell differentiation in normal tissues42 and the transformation of SCs to CSCs.43 Molecular and functional studies demonstrated diagnostic potential of miRNAs as well as their importance in the treatment of human cancers. These studies have commonly used cloning, northern blot and micro-array based methods for miRNA identification and quantification. It is clear that additional studies are needed to optimize miRNA analysis and designate miRNA signatures of human cancers and identify the genes and pathways that they target for better consistency understanding of oncogenic processes involved in carcinogenesis.

MicroRNAs and brain tumor therapy using experimental models

MicroRNAs and medulloblastomas

Recent studies have uncovered several deregulated miRNAs which contribute to tumor initiation in MBs. It is now clear that some miRNAs (e.g. miR-17-92 cluster family) act as oncogenes, increasing proliferation and angiogenesis when up-regulated, whereas others (e.g. let-7) act as tumor suppressors when downregulated to lead progression in MB.44,45

miR-17-92 cluster, Oncomir-1 which is located on chromosome-13 is the most significantly up-regulated miRNA family in MBs. miR-17/92 family (miR-19a, miR-20 and miR-92) targets Shh pathway by mediating c-myc oncogene activity and modulating E2F1 to lead MB tumorigenesis while enforced expression of its paralogues (miR-106a and miR-10b clusters) fail to induce MB. Its amplification and overexpression may be a hallmark of Shh-associated MBs, driven by an aberrant Shh/Ptch pathway.3,46 Amplification and overexpression of miR-30b and miR-30d at chromosome 8, have also been independent on myc amplification.10 Interestingly, the tumor suppressor genes, FASTK and TOPORS, have been potential targets of both miR-17 and miR-106b.47 miR-125b, miR-326 and miR-324-5p also associate with Shh pathway by targeting its effector Gli1 through repressing Shh activator Smo. Downregulation of miR-324-5p is caused by deletion of its gene as a consequence of the loss of chromosome 17p, the most frequent mutation in MB. Other Shh-associated miRNA, miR-214 has been up-regulated in Gli1high tumors, thus increased expression of miR-214 in human MB may be responsible for the loss of one Hh antagonist.8

miRNAs regulates diverse neoplastic events through target molecules whose amplication lead tumor progression in MB (Figure-2). Indeed, miR-10b, miR-135a/b, miR-125b, miR-153 and miR-199 are up-regulated by overexpression of EGFR encoded protein, ErbB2, whereas up-regulation of miR-128a, miR-128b and miR-181b correlate with c-myc expression.3 Overexpression of miR-9 and miR-125a which have been described as a part of the growth-inhibitory pathway, promote tumor growth arrest. miR-9 targets the repressor element-1 silencing transcription factor complex, REST/NRSF which initiates tumor formation, whereas miR-125a targets the neurotropin receptor t-Trk-C which has been correlated with MB. Moreover, miR-124 which is regulated by REST during neural differentiation, plays an important role in MB pathogenesis by modulating cell-cycle regulation via CDK6 whose overexpression has been an adverse prognostic marker in MB.48 Additionally, miR-100 targets carcinogenesis-mediated tumor suppressor genes SUFU, PTCH1, and RB1 in MB whereas downregulation of miR-218 promotes development and invasion of tumor cells by targeting pro-oncogenes such as ROS1, EGFR, Bcl-2, β-catenin and MAPK9.47

The expression profiles of miRNA classify MB histotype as prognostic and diagnostic tools. The lower expression of miR-31 and miR-153 in HR versus AR groups whereas overexpression of up-regulated miRNAs (miR-191, miR-19a, miR-106b and let-7) and also miR-17/92 host gene, MIRHG1, have been correlated with aggressive behavior and poor prognosis in MB patients, as the indicators of aggressive MB anaplastic histotype.3,16 Among these, let-7 which inhibits RAS oncogene expression and is down-regulated by RAS/MAPK pathway activation, has been associated with aggressive metastatic behavior, although no mutations of RAS has been described in MB. let-7g and miR-106b have been differentially expressed in desmoplastic MBs, while miR-19a is upregulated in anaplastic histotype compared with classic MBs.3 Some miRNAs can play a critical role in the maintenance of a differentiation state both in normal cells and cancer cells. Recently, Nass and colleagues11 reported that miR-9 and miR-92 differentiate accurately between primary and metastatic brain tumors, representing a potential biomarker for the identification of primary MBs. Furthermore, Notch signaling pathway and its downstream effector HES1 have been associated with worse clinical outcome in MB patients.49 miR-199-5p targets HES1, as a new molecular marker for a poor-risk class and loss of function in metastatic MB. Therefore, miR-199-5p may impair the proliferation and engrafting potential of MB cells via the regulation of the Notch pathway and its down-regulation in metastatic MBs indicates a mechanism of silencing through epigenetic and genetic alterations.9 In addition, Notch target-ErbB2 expression displays poor prognostic impact in patients with MB, thus the reduced expression of miR-10b, miR-135a/b, miR-125b, miR-153 and miR-199 may have similar effects.3

Current treatment have severe side effects and limited efficiency because of the resistance of brain tumor stem cells (BTSCs) to apoptosis and chemotherapy in patients with MB as well as other brain tumors.3 miRNA therapy may afford patients a survival advantage, leading novel therapeutic approaches. miRNAs influence on proliferative, anti-apoptotic and pro-angiogenic or pro-metastatic features of tumor cells and their effects can be applied for synthetic miRNAs.50 Moreover, different miRNAs have been found to predict sensitivity to anticancer treatment or influence sensitivity to chemo- or radiotherapy.51 Smo antagonists such as KAAD-cyclopamine and SANT1-4 are promising new class of antitumor agents for the treatment.52 In this context, miRNAs which targets Shh pathway and its receptors including miR-17/92 cluster, miR-125b, miR-326 and miR-324-5p acquire importance. Also, miR-100 which targets SUFU whose downregulation result in maximal activation of Gli in the presence of Hh, might be a potential drug target. Nonetheless, the effectiveness of many chemotherapeutic drugs has been correlated with their ability to induce apoptosis.53 The inhibition of Notch pathway leads to depletion of BTSCs via induction of apoptosis, thus miR-199-5p may sensitize BTSCs by depleting the side population cells in MB.9 Moreover, the induction of upregulation in miR-9 and miR-125a and blockade of miR-21 may be new candidates to sensitize chemotherapy resistance by promoting apoptosis. Also, STAT3 activation, alone or in concurrence with EGFR expression, has been correlated with tumor grade and sensitize these tumors to chemotherapeutic agents, such as DNA-damaging alkylating agents.13 In this approach, let-7 which targets STAT3 and miR-218 which targets EGFR might be good candidates for future applications of miRNA theurapeutics via VEGF and EGFR pathways. miR-218 also targets Bcl-2 whose expression has been important for the resistance to -chemo and -radio therapy in brain tumors.47 Taken together, microRNAs which lead tumor initiation and prognosis by targeting stem cell compartment and molecular pathways related to prognosis and tumor formation, might be drug targets for therapeutic approaches in MBs.

miRNAs and Astrocytomas

Astrocytomas display a characteristic miRNA expression pattern, similar to MBs (Figure-3c). miRNA profiling studies, have involved the identification of differently expressed miRNAs in astrocytomas compared with normal brain tissues. In these studies, reduced levels of miR-181b expression has been in grade II-IV astrocytomas whereas expression levels of miR-181a are similar to that of normal brain. miR-181b acts as a tumor suppressor by inducing cell growth and decreasing anchorage dependent growth and invasion ability.54 The expression of miR-124 and miR-137 also reduce in anaplastic astrocytomas and GBM.43 Nevertheless, the down-regulation of miR-128 and the upregulation of E2F3 are both significiant in grade III and IV than those in grade II, indicating the role of miR-128 and E2F3 in the classification of astrocytomas.31 miR-128 targets a positive regulator of stem cell renewal, Bmi1, that has been up-regulated in several cancer types. Thus, miR-128 may also be a candidate for the therapeutic targeting of BTSCs.55 In contrast, miR-21 homogeneously in low and high-grade astrocytomas whereas miR-221 has been more evident in anaplastic astrocytomas.54 There is evidence of the association between miR-21 and the tumor supressor, PDCD4 downregulation and also PGDF whose alterations can drive gliomagenesis.56 Oncogenic miRNA, miR-21 functions as a antiapoptotic factor in GBM while miR-221/222 represses the expression of the cell cycle regulatory protein p27Kip1 that acts as a tumor suppressor.57,58

The mutation or deletion of PTEN is the other most common alteration in GBM and frequently occurs with loss of its locus on chromosome 10q. miR-26a which targets PTEN has been observed in GBM with high expression levels and strongly associated with monoallelic PTEN loss. miR-26a repress PTEN, resulting in Akt activation to enhance de-novo tumor formation in GBMs. Nonetheless, coexpression of miR-26a with the PDGF impacts tumor grade through a synergistic link with CDK4. miR-26a has also other targets such as Rb1 in oncogenic process of GBM.59 Another downregulated miRNA, miRNA-146b inhibits cell migration and invasion, directly targeting matrix metalloproteinase family60 whereas miR-10b contribute to invasion and migration by targeting RhoC and uPA.61

miRNAs are also potential drug targets and candidates to increase the effectiveness of chemotherapeutic agents in the treatment of astrocytomas. miR-21 represses p53-mediated apoptosis by targeting the genes related to p53 tumor-suppressive activity, in response to chemotherapeutic-induced DNA damage, contributing to drug resistance in GBM cells.41 In addition, the combined effect of miR-21 antagonism and NPC-mediated S-TRAIL delivery decreases glioma cell viability by increasing caspase activity, suggesting that mi-21 suppression might sensitize astrocytomas for cytotoxic tumor therapy.12 Nevertheless, high EGFR expression associated with resistance to concomitant chemoradiotherapy in GBM62 and also hyaluronan interactions in glioma cells influence on their therapy resistant via EGFR, AKT and c-met related to ABC family of drug efflux transporters.63 These datas suggest the potential utility of miR-7 which inhibits Akt and EGFR activity64 and miR-34 family which is mediated by c-met and transactivated by p53.65 miR-34a displays the effects on cell cycle via forced expression of c-met whereas forced Notch1 and Notch2 protein expression rescues its effects on cell death in glioma cells.65 miR-15b may be another drug target to prevent cell cycle progression.66 Furthermore, miRNAs can be applied in a combination with drugs, providing a novel approach for modulating GBM tumorigenicity. In this context, Gal and colleagues14, showed the synergistic effect of the combined therapy of miR-451 and Imatinib-mesylate to inhibit tumor growth in GBM by inhibiting neurosphere formation.

Over last decade, antiangiogenic therapeutic approaches have also emerged for the treatment of astrocytomas. Angiogenesis is known to mediate glioma formation and can be induced by BTSCs via endothelial cells and increased VEGF secretion. Several VEGF agents (e.g. bevacizumab/avastin) have been developed to block the proangiogenic effects of BTSCs.67 Recently, the role of miR-296 as well as Let-7 family, miR-27 and miR-126 in promoting angiogenesis via VEGF, has been demonstrated in gliomas.68 Therefore, the combination of these miRNAs and antiangiogenic agents might lead novel therapeutic approaches. Furthermore, dicer-regulated miR-222 and miR-339 which repress intercellular cell adhesion molecule, ICAM-1 that correlates with poor diagnosis in GBM, provide a therapeutic utility for astrocytoma immunotherapy.69 Although these findings imply the great potential clinical applicability of miRNAs in astrocytomas, further verification is required to reveal the role of miRNAs in combined therapies and the association between miRNAs and both MGMT promoter that is important for chemotherapy resistant and BTSC sensitivity for chemotherapeutic agents.

Delivery of microRNAs into tumors

miRNA therapy shares many disadvantages of short interfering RNA (siRNA)-therapy, including delivery limitations, instability, and off target effects. miRNAs do not freely diffuse into cells, thus, efficient in vivo delivery of therapeutic oligonucleotides may be a critical factor for the development of successful miRNA-based treatment modalities (Figure-4).70 Two main therapeutic strategies are involved in miRNA-based therapy. (1) The loss function of tumor suppressor miRNAs can be restored by using miRNA-mimetics which can bind specifically to its target gene and produce posttranscriptional repression, by mimicking an endogenous miRNA. They can be modified to be more potent than their naturally occurring forms.71 (2) Gain functions of oncogenic miRNAs can be inhibited by using miRNA antagonists. Anti-miRNA antisense inhibitor oligoribonucleotide (AMO) technology has undergone many important modifications to enhance the efficiency and specificity of miRNA interference.72 The modified AMOs, called "antagomirs" which are chemically modified, cholesterol-conjugated single-stranded RNA analogues complementary to miRNAs, can effectively silence miRNAs in vivo, carrying a role for the rapid generation of mice lacking specific miRNAs.73 Scherr and colleagues74 reported that lentivirus-mediated expression of miRNAs and miRNA-specific antagomirs can induce stable gain- and loss-of-function phenotypes for individual miRNAs. Antisense oligonucleotids (ASOs) and nucleic asid enzymes (antagomirzymes) also be valuable tools for specific knock-down of miRNAs in vitro and in vivo.12,75 "miRNA-sponges" which are as effective as ASOs, are not degraded so rapidly as to be ineffective at competing miRNA from targets with a potential use to validate target predictions and assay miRNA loss-of-function phenotypes.76 The modification of anti-miRNA oligonucleotids by packaging and conjugation with high-affinity molecules for guidance to target tissues using nanotechnology may alleviate their in vivo delivery problem, enhancing their up-take and decreasing their toxicity.77 Recently, Cornsten and colleageus12 revealed that LNA-antimiR molecules may be well class of potential therapeutics for brain tumors. Locked nucleic acids (LNA) posses the highest affinity for complementary target RNA and LNA-antimiRs displays high stability, increased nuclease resistance with lack of acute and subchronic toxicities and increases the half-life of miRNAs by stabilizing the miRNA-target duplex structure and enhancing degradation resistance.78

Therapeutic strategies based on modulation of miRNA activity and therapeutic miRNA delivery may have unique technical advantages by influencing cellular behavior (Table). The risk of off-target gene silencing is likely to be lower and miRNAs targets multiple pathways compared with siRNAs which targets a single transcript. Adeno-associated virus (AAV)-based vector systems provide an attractive platform for therapeutic delivery of miRNAs to tissues or cell cultures due to their lack of pathogenicity for delivery of microRNAs to tissues or cell cultures.79 Recently, Amendola and colleageus80, developed a lentiviral platform to efficiently coexpress one or more natural/artificial-miRNA together with a gene of interest from constitutive or regulated Pol-II promoters. This approach allowed to quantitatively assess at steady state the target suppression activity and expression level of each delivered miRNA and to compare it to those of endogenous miRNA. Nonetheless, present gene delivery systems (e.g,viral vector or cationic liposomes) can not be effective due to the blood-brain barrier.81 New developing stragies including lipid encapsulation and targeted delivery of nucleic acids and direct administration may circumvent this problem.43 The PIL gene transfer technology is also promising with its non-toxic features, to deliver therapeutic genes to the brain via the transvascular route.81 Alternative studies that have been tested for siRNA delivery can be also applied to miRNA-based therapy. Indeed, additional studies are needed to optimize controlled-delivery of miRNAs and determine whether carrying any toxic effects, for the therapeutic promise of this approach.

Concluding Remarks

Recent studies have pointed to the critical roles of miRNAs in brain tumorigenesis. Because of the potential utility of miRNAs to modulate several targets involved in multiple genetic pathways implicating in cellular events both in brain development and brain tumorigenesis, direct administration of miRNA therapeutics, alone or in combined treatment with chemotherautic agents, may affrod survival for patients, normalizing the regulatory network and signaling pathways in cancer cells and/or sensitizing cancer cells to the therapy. This approach requires detailed identification and validation of target genes regulated by miRNAs for our better understanding of unique miRNA pathways involved in brain tumor formation. Therefore, additional studies are needed to improve delivery systems for administration of miRNAs into brain, to replace gain-or loss-of-function of miRNAs by silencing target genes.

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