MicroRNAs and cell cycle of malignant glioma.

Just Accepted by International Journal of Neuroscience

MicroRNAs and cell cycle of malignant glioma Ouyang Qing, Xu Lunshan, Cui Hongjuan, Xu Minhui, Yi Liang doi:10.3109/00207454.2015.1017881

Int J Neurosci Downloaded from informahealthcare.com by Nyu Medical Center on 05/23/15 For personal use only.

Abstract The control of malignant glioma cell cycle by microRNAs (miRNAs) is well established. The deregulation of miRNAs in glioma may contribute to tumor proliferation by directly targeting the critical cell cycle regulators. Tumor suppressive miRNAs inhibit cell cycle through repressing the expression of positive cell cycle regulators. However, oncogenic miRNAs promote the cell cycle progression by targeting cell cycle negative regulators. Recent studies have identified that transcription factors had involved in the expression of miRNAs. Transcription factors and miRNAs are implicated in regulatory network of glioma cell cycle, the deregulation of these transcription factors might be a cause of the deregulation of miRNAs. Abnormal versions of miRNAs have been implicated in the cell cycle of glioma. Based on those, miRNAs are excellent biomarker candidates and potential targets for therapeutic intervention in glioma.

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Running title: microRNAs control cell cycle of malignant glioma

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MicroRNAs and cell cycle of malignant glioma

Ouyang Qing1; Xu Lunshan1; Cui Hongjuan2; Xu Minhui1*; Yi Liang1*

Department of Neurosurgery, Daping Hospital & Research Institute of Surgery,

Third Military Medical University, Chongqing, China

State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and

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Systems Biology, Southwest University, Chongqing, China

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* Corresponding Author: Yi Liang, M.D, Ph.D. Department of Neurosurgery, Daping Hospital & Research Institute of Surgery, Third Military Medical University 10# Changjiangzhilu, Daping, Yuzhong District, Chongqing 400042, China Tel:

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+86-23-6875-7975 E-mail: [email protected], Xu Minhui, M.D, Ph.D. Department of Neurosurgery, Daping Hospital & Research Institute of Surgery, Third Military Medical University 10# Changjiangzhilu, Daping, Yuzhong District,

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1

Chongqing 400042, China Tel: +86-23-6875-7975 E-mail: [email protected]

Abstract The control of malignant glioma cell cycle by microRNAs (miRNAs) is well established. The deregulation of miRNAs in glioma may contribute to tumor proliferation by directly targeting the critical cell cycle regulators. Tumor suppressive miRNAs inhibit cell cycle through repressing the expression of positive cell cycle regulators. However, oncogenic miRNAs promote the cell cycle progression by targeting cell cycle negative regulators. Recent studies have identified that

transcription factors had involved in the expression of miRNAs. Transcription factors and miRNAs are implicated in regulatory network of glioma cell cycle, the deregulation of these transcription factors might be a cause of the deregulation of miRNAs. Abnormal versions of miRNAs have been implicated in the cell cycle of glioma. Based on those, miRNAs are excellent biomarker candidates and potential targets for therapeutic intervention in glioma.

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Keywords: Glioma; microRNAs; Cell cycle; Transcription factor; Biomarkers

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Cell cycle is tightly regulated through multiple molecular pathways and checkpoints in most adult mammalian cells. However, the deregulation of cell cycle appears to be the main mechanism of the indefinite proliferation of malignant glioma cells. Unlike normal adult mammalian cells, most malignant glioma cells are not quiescent (at G0 phase) [1]. Amplification and over-expression of CCND1 (Cyclin D1) is frequent in malignant glioma cells, which results in the persistently activation of Cyclin dependent kinases such as CDK4, CDK6 and CDK2 [2]. These kinases, as well as CCND1, are amplified and over-expressed in malignant glioma [3]. The activated CDK4/6-cyclin D/E complexes could phosphorylate and inactivate the pRb, which is able to inhibit E2F transcription factor and recruit chromatin remodeling complexes that lead to the repression of targeted genes. The pRb-E2F pathway acts as critical role in G1/S phase transition. The mutation and/ or deletion of the Rb gene in glioma cells leads to transcription factor E2F in continuous active stage and promotes the E2F-dependent transcription of cell cycle genes [4,5]. Deregulation of G1/S checkpoint is a frequent event in the development of malignant glioma, which leads to the glioma cells lose the ability to arrest or delay the cell cycle in response to DNA damage. Moreover, several cell cycle inhibitors, such as the members of the INK4 family (P16, P15, P18, P19) and Cip/ Kip families (P21, P27, P57), are also dysregulated in malignant glioma [6,7]. Once the DNA replication machinery is expressed in G1 phase, the genome of glioma cells will be replicated in S phase. DNA replication is monitored by a variety of checkpoints, which are able to arrest or delay the cell cycle in the presence of defective replication or DNA damage. The deregulation of these checkpoints causes the deficiency of DNA repair capacity, gene instability and the malignant progression of malignant glioma [8]. Once the DNA replication is completed in S phase, glioma cells are committed to G2 phase and genome will be segregated into two daughter cells in M phase. Most regulators required for the G2/M transition and mitotic exit mostly are precisely regulated in normal adult cells. In contrast, the deregulations of these regulators are involved in malignant glioma development. For instance, CDK1-Cyclin A/B complex, required for mitotic entry, is exceptional increased and activated in malignant glioma [9,10]. Other kinases required for the duplication and maturation of centrosomes, such as Polo-like kinases (PLK) and Aurora kinases also have been observed to be unusually over-expressed in malignant glioma [11-14]. As above, the deregulation and aberrant activation of cell cycle regulators result in promoting the cell cycle progression of malignant glioma. Suggesting the deregulation of these regulators is a central issue in the understanding of the control of glioma cell cycle. Recently evidences suggest that the levels of cell cycle regulators are controlled by post-transcriptional (such as MicroRNAs) mechanisms [15]. The relevance of miRNAs to glioma is suggested by changes in their expression. Deregulation of miRNAs controls the levels of multiple cell cycle regulators and incorporates into a large regulatory network. In malignant glioma cells, the abnormality of cell cycle relative miRNAs are frequently observed, which abnormally

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Introduction

control cell cycle progression by altering the protein levels of critical oncogenes or/and tumor suppressive genes [16,17]. Interestingly and importantly, the expression of these miRNAs is regulated by typical cell cycle pathways, suggesting the miRNAs should be considered as important players of the malignant glioma cell cycle.

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miRNAs are a class of endogenously expressed and non-coding RNAs, which control the stability or translational efficiency of targeted messenger RNA(mRNA) [18]. Mature miRNAs need incorporated into a ribonucleoprotein complex known as RNA-induced silencing complex (RISC), the miRNAs-RISC complex leads to base-pairing interactions between miRNAs and the 3’-untraslated region (UTR) of their target mRNA [19]. Each human miRNA may binds to multiple gene targets, therefore, bioinformatics estimates suggest that about 30~60% of the human genome may be regulated by miRNAs [20]. The cell cycle relative miRNAs change in their expression patterns, such as the recurrent amplification and/or deletion of miRNA gene in malignant glioma. In general, miRNAs have been classified as oncogenic or tumor-suppressive according to their function in malignant glioma. Many of the oncogenic miRNAs are frequently amplified and target negative cell cycle regulators, however, tumor-suppressive miRNAs are usually deleted or down-regulated and target positive cell cycle regulators in glioma cells. No wonder, the control of these critical targets by miRNAs are implicated in the cell cycle progression of malignant glioma [21].

MiRNAs control the G1/S phase transition in glioma cells

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The first link between miRNAs and glioma cell cycle regulation was established in the analysis of the pro-proliferative potential of the miR-221/222 cluster. This cluster contains two mature miRNAs, miR-221 and miR-222, which are over-expressed in malignant glioma [22]. It has been identified that the P27 (Kip1), a negative regulator of cell cycle (CDKI), is a direct target of miR-221/222 in malignant glioma [16,23]. When Compared with normal brain tissue, the level of the P27 is lower in malignant glioma tissue, suggesting that miR-221/222 may participates in the glioma associated repression of P27 by over-expressing miR-221/222 cluster [24]. In addition to P27, Medina et al identified that miR-221 and miR-222 also prevent cells quiescence and induce precocious S-phase entry through targeting P57 (Kip2) [25]. Therefore, the over-expression of miR-221/222 cluster is functionally implicated in cell cycle progression of malignant glioma cells. It has been reported that miR-15b could induce cell cycle arrest at the G0/G1 phase by directly targeting critical positive cell cycle regulators, such as Cyclin E1, Cyclin D1 in malignant glioma [26]. D-type Cyclins are major integrators of mitogenic signaling as their synthesis is one of the main endpoints of the MAPK pathway. In addition to miR-15b, recent studies also have shown that miR-149, miR-195, miR-708 and let-7b could induce G1 arrest by directly targeting Cyclin D and Cyclin E of glioma cells in vitro [27-30]. Without Cyclins, CDKs have little kinase activity, only the Cyclin-CDK complex is an active kinase. In malignant

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MiRNAs play an essential role in cell cycle of glioma

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glioma, CDKs are overexpressed and hyperactivated [31-33]. CDKs, as well as Cyclins, are targeted by miRNAs in malignant glioma. Recent evidences have identified that CDK4/6 are directly targets of miR-124, miR-124a, miR-125b, miR-495, miR-491, miR-34a, miR-29c, miR-107, miR-137 and miR-138 [34-41], suggesting that the decreased expression of these miRNAs probable result in CDKs over-expression in malignant glioma cells [34,35,42-45](Figure 1). In addition to the CDKs associated miRNAs, deregulation of miRNAs also targets CDC25A in malignant glioma. CDC25A is a positive regulator of CDKs activity through eliminating inactivating phosphates in CDKs. The up-regulation of CDC25A is observed in human glioma specimens and human glioma cell lines. What’s more, the depletion of CDC25A could suppress glioma cell proliferation in vitro [46]. It has been shown that the low levels of miR-125b inversely correlated with CDC25A levels in glioma [43]. Recent studies have identified that CDC25A is negatively regulated by miR-21 and miR-125b in malignant glioma [37,47]. Unlike miR-125b, the high level of miR-21 is significantly associated with high pathological grades of glioma. Some studies also show that multiple important components of the P53 are direct targets of miR-21. Down-regulation of miR-21 leads to repression of growth and cell cycle arrest in malignant glioma [48,49]. These evidences suggest that oncogenic miR-21 may target both positive and negative regulators of the cell cycle. Tumor suppressive miRNAs display anti-proliferative properties, most of these miRNAs are inactivated or dysregulated in malignant glioma by different mechanisms. As above, lose of tumor suppressive miRNAs may result in the over-expression of Cyclin-CDK complex, which is likely to increase the phosphorylation of pRb, thus liberating active E2F factors to drive G1 progression and S phase entry. Zhang et al firstly shows that transcription factor E2F is targeted by miRNAs[50], this study reveals the fact that brain-enriched miR-128 is significantly down-regulated in malignant glioma when compared to control. MiR-128 seemed like a candidate for the over-expression of E2F-3a since it was down-regulatedin malignant glioma. Luciferase assay has demonstrated that E2F-3a is a direct target of miR-128 in glioma cells. In addition to miR-128, other miRNAs also play roles in cell cycle progression by targeting E2F. For instance, E2F1 has been identified as a direct target of miR-136, miR-329 and miR-106a. Low levels of these miRNAs inversely correlated with E2F1 level has been observed in human glioma samples. Moreover, E2F2/3 have been confirmed as direct targets of the down-regulation of miR-125b, miR-138, miR-195 and miR-302b in glioma [41,43,51-56]. Cell cycle relative miRNAs are also able to facilitate G1 phase progress by targeting negative cell cycle regulators. Retinoblastoma-like protein (RBL) is a member of Rb family, which is similar to the Rb in sequence and function. Rb and RBL act as tumor suppressors by inhibiting the transcription of cell cycle genes and G1/S phase transition. It has been identified that RBL itself is targeted by miR-106-5p, the aberrant high-level of miR-106-5p results in the down-regulation of RBL in glioma [57]. Rb is also controlled by miRNAs, such as miR-26a. Up-regulation of miR-26a has been observed in glioma, leading to glioma cell proliferation in vitro and vivo by repressing Rb [58,59].

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Finally, INK4 or Cip/Kip families, the members of cell cycle inhibitors (CDKI), are also tightly regulated by miRNAs in malignant glioma. P16 is a CDK4/6 specific inhibitors, the loss of P16 is a frequent event in the progression of malignant glioma. Recent studies prove that P16 is controlled by miR-10b in glioma, suggesting that the loss of p16 may be through up-regulating miR-10b in malignant glioma. P21, a target of P53, is also negatively regulated by miR-10b in glioma [60]. In addition to miR-10b, ectopic up-expression of miR-221/222 cluster also increase cell proliferation by directly repressing the levels of P27 and P57 in malignant glioma [25, 61](Figure 1).

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DNA replication in S phase is monitored by S phase checkpoint, which is able to arrest or delay the cell cycle in the presence of DNA damage or defective replication. The first link between miRNAs and S phase checkpoint is established in the analysis of pro-sensitive potential of miR-100 in glioma cells. Over-expression of miR-100 is observed in M059J glioma cell line, which is responsible for the low-expression of ataxia-telangiectasia mutated (ATM) by binding to the 3'-UTR of ATM [62]. ATM, a serine/ threonine protein kinase, functions as a transducer of the DNA damage signal to the downstream effectors machinery. Variation in the level of ATM protein is observed in a panel of human malignant glioma cell lines. Except M059J glioma cell line, malignant glioma has low-level of miR-100 and resistant to radiation therapy [63]. Unlike miR-100, the up-regulation of miR-26a is frequent observed in glioma cells, which is also a direct regulator of ATM. The high level of miR-26a could enhance the radiosensitivity of malignant glioma by targeting ATM [62,64]. Although most miRNAs modulate cell cycle entry and the G1/S transition by directly targeting cell cycle regulators. So far, a few examples exist for the role of miRNAs in later phases of the glioma cell cycle. Oncegenome has been duplicated in S phase. The control of the cell cycle is mostly driven by CDK1-Cyclin A/B complex, without example of miRNAs directly regulating this complex in glioma. However, recent study shows that miR-128 is down-regulated in glioma tissue and cell line, this miRNA has been proposed to target WEE1 in glioma [50,65]. WEE1 function as a negative regulator of the CDK1-Cyclin B complex at G2/M transition. WEE1 is over-expressed in malignant glioma, suggesting the low level of miR-128 is associated with high level of WEE1 in malignant glioma[66], As described in the previous section, the control of Cip/Kip CDK inhibitor by miRNAs may also affect CDK-Cyclin complex in S phase (Figure 1). Not many examples of glioma-associated miRNAs regulating mitosis, suggesting that the functional significance of the control of these mitotic proteins by miRNAs remains mostly unexplored in malignant glioma.

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Entry and progression through S phase and mitosis

The regulation of miRNAs in glioma cell cycle

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C-Myc is a transcription factor, which controls the cell cycle progression by regulating the levels of several regulators [68]. Deregulation of c-Myc has been detected in malignant glioma [69]. Recent studies have identified that c-Myc controls the production of many non-coding RNAs, such as tRNA and miRNAs [70]. A pioneer study thatreveals the miRNAs are targeted by c-Myc in glioma cells is by Guo et al. It reports that miR-26a is a direct target of c-Myc, this miRNA is able to negatively controls the tumor suppressor PTEN and accelerate tumor development in malignant glioma [71,72]. The miR-26a is frequently amplified at the DNA level and associated with monoallelic PTEN loss in human glioma, therefore it is considered as an oncogenic miRNAs in glioma. In addition to miR-26a, recent study demonstrates that the up-regulation of miR-106b boosts glioma proliferation by targeting multiple tumor suppressive genes [57]. Interestingly, this miRNA cluster (miR-106b and miR-25), as well as miR-26a, is considered as an oncogene miRNAs and directly inducted by c-Myc. Moreover, it has been identified that miR-32 is directly induced by transcription factor c-Myc[73](Figure 2). However, neither miR-32 nor miR-25 has been identified with definite effect on glioma cell cycle progression. Despite the transcription factor c-Myc induce the expression of miR-26a, miR-32 and miR-106b/25 cluster in malignant glioma. There is a few example of this transcription factor has a major effect as a repressor of many other miRNAs in glioma cells. It has been identified that several miRNAs are repressed by c-Myc, such as miR-29c, miR-34a and miR-195.

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Transcription regulation of miRNAs by c-Myc

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miRNAs - encoding genes are transcribed by RNA polymerases to yield primary miRNAs (pri-miRNAs), which are processed by the nuclear RNase Drosha to form pre-miRNA (stem-loop). Then pre-miRNAs are transported to the cytoplasm and cleaved by RNase Dicer, the double strand RNA gives rise to the mature miRNA. The transcription of miRNAs is thought to be regulated similarly to that of protein-coding genes [67]. Recently study shows that the expression of miRNAs are induced or repressed by critical transcription factors that control the cell cycle, these miRNAs in turn affects the cell cycle.

NF-kB dependent transcription of miRNAs The transcription factors are well involved in almost all aspects of human cancer. NF-kB is good candidate as potent activator of miRNAs. The activated form of NF-kB enters the nucleus and controls transcription of a wide variety of genes. It has been demonstrated that NF-kB is up-regulated and functional correlated with malignant glioma. NF-kB also has been shown to regulate cell cycle progression in glioma [74]. Interestingly, recent studies show that the directly correlation between miRNAs and NF-kB transcription factor [75]. NF-kB could directly bind the promoter of miR-21 and induce its transcription. This miR-21 is an oncogenic miRNA and

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Another transcription factors mediated induction of miRNAs

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Activator Protein 1(AP-1) acts as transcription factor and regulates the expression of numerous genes, leading to cell cycle progression, senescence in response to chemotherapeutic drugs and epithelial mesenchymal transition (EMT) in glioma [80,81]. Among these functions, AP-1 is able to mediate the cell proliferation by transcriptional regulation of the cell cycle associated miRNAs in malignant glioma. The report of Shao in 2011 has identified that the induction of miR-146b by c-fos (subunit of AP-1 complex) in response to Platelet derived growth factor (PDGF). The transcription factor c-fos could direct bind to the promoter of the miR-146b transcript and induce its expression at the transcriptional level [82]. However, the level of miR-146b is low in malignant glioma [83]. The transfection of ectogenic miR-146b significantly reduced growth of glioma cells in vitro and vivo [84], suggesting the regulatory mechanism of miR-146b is complicated, the high level of c-fos not sufficient to increase the expression of miR-146b in glioma. The oncogenic miR-221/222 cluster in glioma cells are also induced by c-Jun (subunit of AP-1 complex), leading to up-regulation of miR-221 and miR-222 [78]. These miRNAs are capable of inducing cell cycle progression by targeting P27 and P57 in glioma [25]. It also has been reported that signal transducer and activator of transcription 3 (STAT3) directly induces the expression of miR-21 in glioma [85]. STAT3 is latent cytoplasmic transcription factors, which is involved in promoting cell cycle progression, cellular transformation and preventing apoptosis. Aberrant activation of STAT3 has been found in gliomas and may contribute to oncogenesis [86]. The expression of miR-21 is marked elevated in glioma by STAT3 dependent manner, leading to the down-regulation of tumor suppressor P53 in malignant glioma[49,87].

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over-expressed in human GBM cell lines and tumor tissue, repressing miR-21 in malignant glioma cells leads to causing repression of growth and cell cycle arrest [49,76,77]. In addition to miR-21, NF-kB also participates in the glioma-associated induction of miRNAs by directly inducing the expression of miR-221/222 cluster. The oncogenic miRNA cluster is over-expressed in glioma and promotes cell cycle progression by targeting tumor suppressor P27 and P57, which reveals a new transcription factor-miRNA-target gene axis of cell cycle in malignant glioma [78,79](Figure 2). The overall induction of miRNAs by NF-kB transcription factor has been recently analyzed using chromatin immunoprecipitation assay (ChIP). At least miR-221/222 clusters is direct targets of NF-kB in malignant glioma cells [78]. Additionally miRNAs are also induced by NF-kB factor during glioma cell cycles, however, the consequences of the regulation have not been studied in detail.

Networks between miRNAs and transcription factors The experimental data described in the previous sections suggest that transcriptional factors and miRNAs may cooperate in multigene transcriptional and post-transcriptional feed-forward. E2F and c-Myc display multiple connections,

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Conclusions and perspectives

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Many miRNAs are functional integrated into some crucial cell cycle control pathways. Tumor suppressive miRNAs are anti-proliferative and this function is mediated by repressing the mitogenic pathways that lead to activation of Cyclin-CDK complexes. On the contrary, a few miRNAs could induce glioma cells proliferation (oncogenic miRNAs) by targeting negative regulators, such as CDK inhibitors, P53, ATM/ATR or member of the pRb family. In general, most normal cells are quiescent and re-entry into the cell cycle requires the activation of mitogenic pathway. The disturbing expression of cell cycle related miRNAs may play an important role in proliferation and pathogenesis of malignant glioma. Interestingly and importantly, the control of miRNAs by cell cycle dependent transcription factors is complex. For instance, NF-kB, an oncogenic transcription factor, could positively regulate the progression of cell cycle by inducing oncogenic miR-221/222 cluster. On the contrary, NF-kB also negatively regulates cell cycle by inducing the miR-21, leading to the down-regulation of CDC25A in glioma cells. Unfortunately, most miRNAs-targets of transcription factors are still unknown in glioma cells, suggesting that we are missing a big portion of the connections between miRNAs and the cell cycle. Despite the knowledge of miRNAs targeting cell cycle regulator is accumulated in the last years, the regulation of miRNAs by transcription factors is limited. Oncogenic and tumor suppressor transcription factors, such as P53, AP-1, c-Myc, NF-kB, E2F and STAT, are able to regulate miRNAs expression in glioma cells. In addition to transcription factors, recent papers also show how epigenetic regulation manner is a novel approach to regulate the expression of miRNAs in glioma cells. For instance, miR-124a, a tumor suppressor miRNAs, is regulated by epigenetic silencing as well

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transcriptional factor c-Myc positively regulate the expression of E2F and promote glioma cell proliferation, and vice versa. C-Myc also activate E2F in a Rb dependent manner, low level of Rb in glioma cells relieves depressive effect of Rb on E2F activity. The expression of Rb is negatively regulated by c-Myc- induced miR-106b and miR-26a in glioma (Figure 2). The E2F transcription factor promotes the cell cycle progression by inducing the CDKs and Cyclins. In turn, Cyclin-CDK complex is able to activate E2F in a Rb dependent manner. Moreover, E2F also induces the expression of oncogenic miR-106, leading to the down-regulation of Rb. C-Myc (as well as E2F) could activate the Cyclin-CDK complex by repress the tumor suppressor miR-29c, miR-34a and miR-195. However, c-Myc and CDKI are negatively regulated by each other, CDKI is the negative regulator of cell cycle through repressing the activation of Cyclin-CDK complex. Moreover, transcription factor NF-kB induces oncogenic miR-221/222 cluster, this miRNA cluster could represses the expression of CDKI and promote cell proliferation. P53 is able to suppress Cyclin-CDK complex in a post- transcription manner, the P53 mediated miR-107 could repress the expression of CDK6. In addition to CDK6, P53 also could suppress c-Myc transcription directly or by a P21 dependent manner indirectly (Figure 2). How P53 represses c-Myc through miRNA in glioma is not clear at this moment.

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Acknowledgements

This study was supported by the National Natural Science Foundations of China

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as transcriptional factor in glioma cells [88]. Moreover, the epigenetic deregulation of miR-142-3p, miR-211 and miR-1275 by promoter DNA methylation are observed and involved in the regulation of glioma biology [89-91]. More and more evidences demonstrate that miRNAs are excellent biomarker candidates as they are commonly deregulated in glioma. When compared with normal brain tissues, glioma tissue samples show aberrant expression of numerous miRNAs . Understanding the alterations of cell cycle related miRNAs in glioma is a key to develop new miRNAs biomarkers. In fact, miRNAs are beginning to be validated as diagnostic, prognostic and predictive biomarkers in gliomas [92-94]. From a diagnostics perspective, the deregulation of miRNAs in plasma or CSF seems to sensitivity and specificity for diagnosis of glioma [95-97]. Diagnosing brain tumors without surgery would be a novel approach and would be of particular importance for patients who are not surgical candidates. The association of miRNA deregulation and cell cycle progression of malignant glioma illustrates great potentiality of utilizing miRNAs as targets for therapeutic intervention. The basic strategy of current miRNA-based treatment studies is either to antagonize the expression of oncogenic miRNAs or to restore or strengthen the function of tumor-suppressor miRNAs to inhibit the expression of target mRNA [93, 98]. There are loads of experiments that have proved miRNAs presenting potential therapeutic targets in glioblastoma [99,100]. All of these reports show the modulation of cell cycle entry or progression by miRNAs, supporting a great future for miRNAs as biomarkers and therapeutic targets in glioma. However, significant discrepancies exist across studies and future improved evaluation will require standardization of methods and normalization in glioma. Moreover, functional studies of miRNAs are important to better understand the connections between miRNAs and the cell division cycle in the future.

(NSFC, Nos. 81270039 and 30901538), Chinese Postdoctoral Science Foundation (No. 2013M530388) and the National Natural Science Foundation from Chongqing Science and Technology Committee (No.cstc2012jjA0306). The authors would like to thank Dr. Zhou J and Dr. Zhong XX for technical assistance.

Footnotes Conflicts of interest statement. No conflicts of interest are disclosed.

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An overview to cell cycle is controlled by microRNAs in glioma. Most cell cycle regulators of G1 and S phase are regulated by microRNAs. Up-regulation of microRNAs is shown in red whereas down-regulation of microRNAs is in blue. S, S

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Figure 1| Cell cycle control by microRNAs in glioma.

phase; M, Mitosis; G1 and G2 indicate transition phase of the cell cycle. Please note that most of these interactions come from luciferase reporter assays and need to be validated using additional methods.

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cell cycle.

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Only a few miRNAs are indicated and additional connections between the indicated regulators have been omitted for clarity.

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Figure 2| Networks between miRNAs and transcription regulators of the glioma

Role of MicroRNAs in Malignant Glioma.

Combination of lentivirus-mediated silencing of PPM1D and temozolomide chemotherapy eradicates malignant glioma through cell apoptosis and cell cycle arrest.

BCNU and malignant glioma.

CHD1L Regulates Cell Cycle, Apoptosis, and Migration in Glioma.

microRNAs and HDL life cycle.

Efficacy of ribavirin against malignant glioma cell lines.

Herpesvirus saimiri MicroRNAs Preferentially Target Host Cell Cycle Regulators.

Immunotherapy for malignant glioma.

Radioresponse and prognosis of malignant glioma.

Vaccine therapies in malignant glioma.

Gene therapy for malignant glioma.

Malignant glioma in laboratory workers.

Interstitial radiotherapy for malignant glioma.

Hyperbaric oxygen promotes malignant glioma cell growth and inhibits cell apoptosis.

i suppress human glioma cell invasion and migration by targeting IKBKE directly.

Germacrone inhibits the proliferation of glioma cells by promoting apoptosis and inducing cell cycle arrest.

Promoting oligodendroglial-oriented differentiation of glioma stem cell: a repurposing of quetiapine for the treatment of malignant glioma.

Response of malignant glioma cell lines to activation and inhibition of protein kinase C-mediated pathways.

Two Virus-Induced MicroRNAs Known Only from Teleost Fishes Are Orthologues of MicroRNAs Involved in Cell Cycle Control in Humans.

IKBKE regulates cell proliferation and epithelial-mesenchymal transition of human malignant glioma via the Hippo pathway.

Effects of estramustine on DNA and cell membrane in malignant glioma cells.

New advances of microRNAs in glioma stem cells, with special emphasis on aberrant methylation of microRNAs.

Fluvastatin inhibits growth and alters the malignant phenotype of the C6 glioma cell line.

Oncogenic MicroRNAs: Key Players in Malignant Transformation.