miR-21通过靶定LRRFIP1调节胶质母细胞瘤对VM-26的敏感性
摘要
microRNA是一类18-26 nt长度,通过与靶基因3'非编码区的序列特异性结合的方式对基因进行转录后水平负性调控的小分子非编码RNA。据估计,人类至少有30%的基因受到miRNA分子的调控。miRNA参与多种生理和病理过程,包括生长发育、细胞增殖、细胞死亡、应激反应、凋亡、脂肪代谢、细胞分化、大脑发展等。多项研究证明,miRNA和恶性肿瘤之间的关系密切。miRNA在多种不同的恶性肿瘤中扮演着癌基因或抑癌基因。miR-21在包括胶质瘤在内的多种肿瘤中高表达,这提示miR-21可能在肿瘤发生中扮演癌基因的角色。作为癌基因簇miR-17-92的成员之一,miR-21参与细胞增殖、凋亡、细胞迁移以及对化疗药物的耐受性增等。研究表明,利用互补寡核苷酸抑制恶性胶质瘤细胞的内源性miR-21的功能将导致caspase的活性增加,并导致细胞活性减低。此外,抑制miR-21的功能可以协同增强恶性神经胶质瘤细胞对细胞毒素NPC-S-TRAIL的敏感性。目前,关于miR-21是否与胶质瘤对化疗药物耐药有关尚不明确。
基于此,我们进一步研究miR-21能否在胶质瘤细胞中介导对化疗药物VM-26的化疗药物耐药,并通过基因芯片技术寻找并确定miR-21特异性的靶基因。为了达到这个目的,首先,我们利用反义寡核苷酸来封闭人脑胶质瘤细胞系U373MG细胞中内源性miR-21的功能,而后利用MTT实验检测细胞生长活性的变化。MTT实验检测表明,封闭miR-21的功能后,U373MG细胞表现出生长减缓和活性减低,表明miR-21在U373MG细胞中具有促进恶性表型的作用。
随后,为了研究miR-21是否参与介导胶质瘤对化疗药物耐药,我们把miR-21ASO和control ASO转染U373MG细胞后,用不同剂量的VM-26作用U373MG细胞。MTT实验表明,当封闭U373MG细胞中miR-21的功能后,VM-26对其生长的抑制作用明显增强,且呈现剂量依赖性关系。也就是说,miR-21在胶质瘤中可能起到减低其对化疗药物VM-26敏感性的作用。
miR-21对细胞表型的作用,通常是通过负性调控其特定的靶基因,影响基因功能来实现的。因此,要阐明miR-21在胶质瘤化疗药物耐药中的作用机制,就需要寻找miR-21发挥作用的靶基因。一方面,利用几种基于miRNA与靶基因作用方式算法的生物信息学数据库,比如:MIRANDA,TARGESCAN和PICTAR,对miR-21的靶基因进行了预测;另一方面,利用7267个基因的基因芯片技术,分析抑制miR-21功能后U373MG细胞的mRNA表达情况。我们综合生物信息数据库预测结果和基因芯片数据,缩小靶基因的搜寻范围,确定LRRFIP 1(leucine rich repeatinteracting protein 1)基因为miR-21候选的功能性靶基因。
为了对靶基因的正确性进行验证,我们先利用RT-PCR和Westernblot技术检测miR-21功能被抑制后LRRFIP1的mRNA水平和蛋白水平的变化。实验表明,封闭miR-21的功能后,LRRFIP1基因在mRNA水平和蛋白水平上都明显上调,
为了进一步验证miR-21与LRRFIP1的作用关系,我们采用了绿色荧光蛋白(EGFP)报告载体实验,我们将预测到的LRRFIP1基因3'非编码区与miR-21互补结合的一段序列克隆插入报告基因EGFP的下游,构建荧光报告载体,转染U373MG细胞,同时封闭miR-21的功能,检测发现miR-21的功能被封闭后,EGFP的荧光强度明显升高。而我们将报告载体中miR-21的结合位点进行定点突变后,这种miR-21变化导致的荧光强度变化不复存在。以上实验证明,LRRFIP1是miR-21的直接作用靶基因,受到miR-21的特异性调控。
LRRFIP1(也称TRAF作用蛋白,TRIP)是肿瘤坏死因子受体超家族的成员之一,包含一个RING手指序列和一个扩展的coiled-coil区域。TRIP与肿瘤坏死因子受体相关因子组成的信号复合体相互作用,抑制TRAF2介导的NF-κB活化途径,减低其对细胞凋亡的抑制作用。NF-κB的活化是肿瘤拮抗化疗药物的主要机制之一。此外,抑制NF-κB的活化后可增强肿瘤坏死因子α(TNFα)或某些化疗药物对细胞凋亡的诱导效应。本实验中,我们发现抑制miR-21的功能可增加靶基因LRRFIP1的上调,从而抑制NF-κB的活化,导致胶质瘤细胞对化疗药物VM-26敏感性增强。
本实验首次分析了miR-21与恶性胶质瘤化疗药物耐药之间的关系,机制可能是miR-21通过抑制LRRFIP1基因,从而激活NF-κB通路来降低化疗药物的毒性作用。我们希望通过对miR-21的功能的研究为恶性胶质瘤的治疗提供了新的思路和线索。但由于细胞和分子水平的调控作用是复杂的,miRNA的作用方式和作用范围也是广泛多样的,因此我们期待miRNA在肿瘤耐药中的作用方式和作用机制在以后的研究中得到进一步的阐述。
MicroRNA are a class of 18-26nt noncoding RNAs that negatively regulate the expression of target genes by interacting with complementary sites in the 3' untranslated region(3'UTR).This relatively small number of regulatory RNA molecules is predicted to regulate the expression of at least 30%of human transcripts,including those involved in cancer.Several research groups have provided evidences that miRNAs control a wide array of biological processes including early development,cell proliferation and cell death,stress reaction,apoptosis and fat metabolis,cell differentiation,and brain development.The close relationship between miRNAs and cancer was also been demonstrated.Many miRNAs have been classified to oncomiRs and suppressor genes in specific cancers.Mounting evidence indicates that MicroRNA-21(miR-21) is overexpressed in many cancers including glioblastoma and might play a fundamental role as oncogene in tumorigenesis.As a members of the miR-17-92 cluster,miR-21 was shown to be associated with cell proliferation,apotosis,migration and drug resistant and contributes to tumor resistance to chemotherapy.Such as,The introduction of complementary oligonucleotides into glioma cells with high miR-21 levels leads to reduction of glioma cell viability associated with an increase in activity of caspases.The synergistic cytotoxicity of miR-21 knockdown and S-TRAIL in glioblastoma therapy has been found.These facts lead us to ask Whether miR-21 is also involved in the resistance to chemotherapeutic agents in treatment of glioblastoma.
We investigated whether miR-21 mediated chemoresistance to the chemotherapeutic agent VM-26 in glioblastoma cells and sought to identify the candidate target genes for miR-21 by gene expression profiling.In order to examine the effect of miR-21 on glioblastoma cell proliferation.U373MG cells were transfected with miR-21ASO or control ASO and cell viability was detected by MTT assay.In U373MG cells,miR-21 ASO showed a significant antiproliferation effect compared with the control group,suggesting that miR-21 could accelerate glioblastoma cell proliferation.
To explore the role of miR-21 in chemoresisitance of glioblastoma,U373MG cells were transfected with either miR-21 ASO or control ASO,and were subsequently incubated with different doses of VM-26.Then the cells were examined for viability levels by MTT assay.The result indicated that knockdown of miR-21 enhanced VM26-induced cell viability reduction in U373MG cells,and the sensitization effect of miR-21 inhibition showed a drug dose-dependent manner,suggesting that miR-21 could suppress chemo-sensitivity of glioblastoma。
miR-21 usually affect cell phenotype through negatively regulating the expression of specific target genes.To explore the mechanism involving in miR-21-mediated drug resistance in glioblastoma,We selected combined strategies to identify new target gene which may participate in miR-21-mediated drug resistance.Frist step was searched candidate target genes of miR-21 through several bioinformatic database.Such as MIRANDA,TARGESCAN and PICTAR.Second,the 7267-gene microarray was applied to investigate the gene expression profile of miR-21 ASO treated U373MG cells comparing with control cells.Combining target prediction bioinformatics with expression profiling.LRRFIPl,which was up-regulated in miR-21 ASO treated cells,was predicted as a candidate target gene of miR-21.
To determine the effect of miR-21 on LRRFIP1 mRNA and protein expression level, U373MG cells were transfected with miR-21 ASO or control ASO,and the mRNA level and protein level of LRRFIP1 was detected.The result indicated that suppression of miR-21 significantly increased expression of LRRFIP1 in both mRNA level and protein level.To confirm the specificity of this regulation,U373MG cells were transfected with EGFP report vector along with either miR-21 ASO or control ASO,the expression level of EGFP is obviously increased when endogenous miR-21 was blocked.However,when the reporter vector containing a mutational miR-21 binding site was used in the fluorescent reporter assay,the miR-21 ASO mediated fluorescent increase could no longer be detected. It is revealed that LRRFIP1 was directly regulated by miR-21.
LRRFIP,also known as TRAF-interacting protein(TRIP),is a signaling component of the TNFR(tumor necrosis factor receptor) superfamily and contains a RING finger motif and an extended coiled-coil domain.TRIP interacts with the receptor/TRAF(TNF receptor-associated factor) signaling complex,and inhibits the TRAF2-mediated NF-κB activation.Activation of NF-κB is required for cell activation and also for protection against apoptosis and is a principal mechanism of tumor chemoresistance,which is primarily mediated by its antiapoptotic activity.Constitutive NF-κB activation has been described in various tumors,where it has been implicated in conferring chemoresistance. Additionally,inhibition of NF-κB signaling has been reported to sensitize tumor cells to apoptosis induced by TNF-αor anticancer agents.Here we find that suppression of miR-21 could up-regulate the expression of its target gene LRRFIP1,which inhibits NF-κB activation and leads to enhancement of VM26-mediated cell death in glioblastoma cells.
This research is the first to show the chemosensitivity associated miR-21 in glioblastoma.MiR-21 contributes to VM-26 drug resistance through excessive depression of LRRFIP1 gene,leading to reduction of the cytotoxicity of chemotherapy drugs through activation of the NF-κB pathway.Our findings suggest that miR-21 represents a promising target for therapeutic manipulation to increase the efficacy of chemotherapeutic agents in treating glioblastoma.Since the partern of the interaction between cells and moleculars is complex and The express and fuction models of miRNA is diverse.more detail works are needed to evaluate the mechanisms miRNA-mediated drug resistance.
基于此,我们进一步研究miR-21能否在胶质瘤细胞中介导对化疗药物VM-26的化疗药物耐药,并通过基因芯片技术寻找并确定miR-21特异性的靶基因。为了达到这个目的,首先,我们利用反义寡核苷酸来封闭人脑胶质瘤细胞系U373MG细胞中内源性miR-21的功能,而后利用MTT实验检测细胞生长活性的变化。MTT实验检测表明,封闭miR-21的功能后,U373MG细胞表现出生长减缓和活性减低,表明miR-21在U373MG细胞中具有促进恶性表型的作用。
随后,为了研究miR-21是否参与介导胶质瘤对化疗药物耐药,我们把miR-21ASO和control ASO转染U373MG细胞后,用不同剂量的VM-26作用U373MG细胞。MTT实验表明,当封闭U373MG细胞中miR-21的功能后,VM-26对其生长的抑制作用明显增强,且呈现剂量依赖性关系。也就是说,miR-21在胶质瘤中可能起到减低其对化疗药物VM-26敏感性的作用。
miR-21对细胞表型的作用,通常是通过负性调控其特定的靶基因,影响基因功能来实现的。因此,要阐明miR-21在胶质瘤化疗药物耐药中的作用机制,就需要寻找miR-21发挥作用的靶基因。一方面,利用几种基于miRNA与靶基因作用方式算法的生物信息学数据库,比如:MIRANDA,TARGESCAN和PICTAR,对miR-21的靶基因进行了预测;另一方面,利用7267个基因的基因芯片技术,分析抑制miR-21功能后U373MG细胞的mRNA表达情况。我们综合生物信息数据库预测结果和基因芯片数据,缩小靶基因的搜寻范围,确定LRRFIP 1(leucine rich repeatinteracting protein 1)基因为miR-21候选的功能性靶基因。
为了对靶基因的正确性进行验证,我们先利用RT-PCR和Westernblot技术检测miR-21功能被抑制后LRRFIP1的mRNA水平和蛋白水平的变化。实验表明,封闭miR-21的功能后,LRRFIP1基因在mRNA水平和蛋白水平上都明显上调,
为了进一步验证miR-21与LRRFIP1的作用关系,我们采用了绿色荧光蛋白(EGFP)报告载体实验,我们将预测到的LRRFIP1基因3'非编码区与miR-21互补结合的一段序列克隆插入报告基因EGFP的下游,构建荧光报告载体,转染U373MG细胞,同时封闭miR-21的功能,检测发现miR-21的功能被封闭后,EGFP的荧光强度明显升高。而我们将报告载体中miR-21的结合位点进行定点突变后,这种miR-21变化导致的荧光强度变化不复存在。以上实验证明,LRRFIP1是miR-21的直接作用靶基因,受到miR-21的特异性调控。
LRRFIP1(也称TRAF作用蛋白,TRIP)是肿瘤坏死因子受体超家族的成员之一,包含一个RING手指序列和一个扩展的coiled-coil区域。TRIP与肿瘤坏死因子受体相关因子组成的信号复合体相互作用,抑制TRAF2介导的NF-κB活化途径,减低其对细胞凋亡的抑制作用。NF-κB的活化是肿瘤拮抗化疗药物的主要机制之一。此外,抑制NF-κB的活化后可增强肿瘤坏死因子α(TNFα)或某些化疗药物对细胞凋亡的诱导效应。本实验中,我们发现抑制miR-21的功能可增加靶基因LRRFIP1的上调,从而抑制NF-κB的活化,导致胶质瘤细胞对化疗药物VM-26敏感性增强。
本实验首次分析了miR-21与恶性胶质瘤化疗药物耐药之间的关系,机制可能是miR-21通过抑制LRRFIP1基因,从而激活NF-κB通路来降低化疗药物的毒性作用。我们希望通过对miR-21的功能的研究为恶性胶质瘤的治疗提供了新的思路和线索。但由于细胞和分子水平的调控作用是复杂的,miRNA的作用方式和作用范围也是广泛多样的,因此我们期待miRNA在肿瘤耐药中的作用方式和作用机制在以后的研究中得到进一步的阐述。
MicroRNA are a class of 18-26nt noncoding RNAs that negatively regulate the expression of target genes by interacting with complementary sites in the 3' untranslated region(3'UTR).This relatively small number of regulatory RNA molecules is predicted to regulate the expression of at least 30%of human transcripts,including those involved in cancer.Several research groups have provided evidences that miRNAs control a wide array of biological processes including early development,cell proliferation and cell death,stress reaction,apoptosis and fat metabolis,cell differentiation,and brain development.The close relationship between miRNAs and cancer was also been demonstrated.Many miRNAs have been classified to oncomiRs and suppressor genes in specific cancers.Mounting evidence indicates that MicroRNA-21(miR-21) is overexpressed in many cancers including glioblastoma and might play a fundamental role as oncogene in tumorigenesis.As a members of the miR-17-92 cluster,miR-21 was shown to be associated with cell proliferation,apotosis,migration and drug resistant and contributes to tumor resistance to chemotherapy.Such as,The introduction of complementary oligonucleotides into glioma cells with high miR-21 levels leads to reduction of glioma cell viability associated with an increase in activity of caspases.The synergistic cytotoxicity of miR-21 knockdown and S-TRAIL in glioblastoma therapy has been found.These facts lead us to ask Whether miR-21 is also involved in the resistance to chemotherapeutic agents in treatment of glioblastoma.
We investigated whether miR-21 mediated chemoresistance to the chemotherapeutic agent VM-26 in glioblastoma cells and sought to identify the candidate target genes for miR-21 by gene expression profiling.In order to examine the effect of miR-21 on glioblastoma cell proliferation.U373MG cells were transfected with miR-21ASO or control ASO and cell viability was detected by MTT assay.In U373MG cells,miR-21 ASO showed a significant antiproliferation effect compared with the control group,suggesting that miR-21 could accelerate glioblastoma cell proliferation.
To explore the role of miR-21 in chemoresisitance of glioblastoma,U373MG cells were transfected with either miR-21 ASO or control ASO,and were subsequently incubated with different doses of VM-26.Then the cells were examined for viability levels by MTT assay.The result indicated that knockdown of miR-21 enhanced VM26-induced cell viability reduction in U373MG cells,and the sensitization effect of miR-21 inhibition showed a drug dose-dependent manner,suggesting that miR-21 could suppress chemo-sensitivity of glioblastoma。
miR-21 usually affect cell phenotype through negatively regulating the expression of specific target genes.To explore the mechanism involving in miR-21-mediated drug resistance in glioblastoma,We selected combined strategies to identify new target gene which may participate in miR-21-mediated drug resistance.Frist step was searched candidate target genes of miR-21 through several bioinformatic database.Such as MIRANDA,TARGESCAN and PICTAR.Second,the 7267-gene microarray was applied to investigate the gene expression profile of miR-21 ASO treated U373MG cells comparing with control cells.Combining target prediction bioinformatics with expression profiling.LRRFIPl,which was up-regulated in miR-21 ASO treated cells,was predicted as a candidate target gene of miR-21.
To determine the effect of miR-21 on LRRFIP1 mRNA and protein expression level, U373MG cells were transfected with miR-21 ASO or control ASO,and the mRNA level and protein level of LRRFIP1 was detected.The result indicated that suppression of miR-21 significantly increased expression of LRRFIP1 in both mRNA level and protein level.To confirm the specificity of this regulation,U373MG cells were transfected with EGFP report vector along with either miR-21 ASO or control ASO,the expression level of EGFP is obviously increased when endogenous miR-21 was blocked.However,when the reporter vector containing a mutational miR-21 binding site was used in the fluorescent reporter assay,the miR-21 ASO mediated fluorescent increase could no longer be detected. It is revealed that LRRFIP1 was directly regulated by miR-21.
LRRFIP,also known as TRAF-interacting protein(TRIP),is a signaling component of the TNFR(tumor necrosis factor receptor) superfamily and contains a RING finger motif and an extended coiled-coil domain.TRIP interacts with the receptor/TRAF(TNF receptor-associated factor) signaling complex,and inhibits the TRAF2-mediated NF-κB activation.Activation of NF-κB is required for cell activation and also for protection against apoptosis and is a principal mechanism of tumor chemoresistance,which is primarily mediated by its antiapoptotic activity.Constitutive NF-κB activation has been described in various tumors,where it has been implicated in conferring chemoresistance. Additionally,inhibition of NF-κB signaling has been reported to sensitize tumor cells to apoptosis induced by TNF-αor anticancer agents.Here we find that suppression of miR-21 could up-regulate the expression of its target gene LRRFIP1,which inhibits NF-κB activation and leads to enhancement of VM26-mediated cell death in glioblastoma cells.
This research is the first to show the chemosensitivity associated miR-21 in glioblastoma.MiR-21 contributes to VM-26 drug resistance through excessive depression of LRRFIP1 gene,leading to reduction of the cytotoxicity of chemotherapy drugs through activation of the NF-κB pathway.Our findings suggest that miR-21 represents a promising target for therapeutic manipulation to increase the efficacy of chemotherapeutic agents in treating glioblastoma.Since the partern of the interaction between cells and moleculars is complex and The express and fuction models of miRNA is diverse.more detail works are needed to evaluate the mechanisms miRNA-mediated drug resistance.
引文
[1]Ohgaki H.Epidemiology of brain tumors.Methods Mol Biol.2009;472:323-42.
[2]Louis DN,Gusella JE A tiger behind many doors:multiple genetic pathways to malignant glioma.Trends Genet.1995;11:412-5.
[3]Hochberg FH,Pruitt A.Assumptions in the radiotherapy of glioblastoma.Neurology.1980;30:907-11.
[4]Stupp R,Mason WP,van den Bent MJ et al.Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.N EnglJMed.2005;352:987-96.
[5]Shu HK,Kim MM,Chen P,Furman F,Julin CM,Israel MA.The intrinsic radioresistance of glioblastoma-derived cell lines is associated with a failure of p53 to induce p21(BAX) expression.Proc NatlAcad Sci USA.1998;95:14453-8.
[6]Bandres E,Andion E,Escalada Aet al.Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression.JNeurooncol.2005;73:189-98.
[7]Gupta M,Brewer G.MicroRNAs:new players in an old game.Proc Natl Acad Sci U S A.2006;103:3951-2.
[8]Poy MN,Eliasson L,Krutzfeldt Jet al.A pancreatic islet-specific microRNA regulates insulin secretion.Nature.2004;432:226-30.
[9]Lee Y,Kim M,Han Jet al.MicroRNA genes are transcribed by RNA polymerase II.EMBO J.2004;23:4051-60.
[10]Cai X,Hagedorn CH,Cullen BR.Human microRNAs are processed from capped,polyadenylated transcripts that can also function as mRNAs.RNA.2004;10:1957-66.
[11]Lee Y,Jeon K,Lee JT,Kim S,Kim VN.MicroRNA maturation:stepwise processing and subcellular localization.EMBO J.2002;21:4663-70.
[12]Lee Y,Ahn C,Han Jet al.The nuclear RNase III Drosha initiates microRNA processing.Nature.2003;425:415-9.
[13]Denli AM,Tops BB,Plasterk RH,Ketting RF,Hannon GJ.Processing of primary microRNAs by the Microprocessor complex.Nature.2004;432:231-5.
[14]Gregory RI,Yan KP,Amuthan G et al.The Microprocessor complex mediates the genesis of microRNAs.Nature.2004;432:235-40.
[15]Han J,Lee Y,Yeom KH,Kim YK,Jin H,Kim VN.The Drosha-DGCR8 complex in primary microRNA processing.Genes Dev.2004;18:3016-27.
[16]Landthaler M,Yalcin A,Tuschl T.The human DiGeorge syndrome critical region gene 8 and Its D.melanogaster homolog are required for miRNA biogenesis.Curr Biol.2004;14:2162-7.
[17]Lund E,Guttinger S,Calado A,Dahlberg JE,Kutay U.Nuclear export of microRNA precursors.Science.2004;303:95-8.
[18]Yi R,Qin Y,Macara IG,Cullen BR.Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs.Genes Dev.2003;17:3011-6.
[19]Bohnsack MT,Czaplinski K,Gorlich D.Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs.RNA.2004;10:185-91.
[20]Hutvagner G,McLachlan J,Pasquinelli AE,Balint E,Tuschl T,Zamore PD.A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA.Science.2001;293:834-8.
[21]Grishok A,Pasquinelli AE,Conte D et al.Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C.elegans developmental timing.Cell.2001;106:23-34.
[22]Ketting RF,Fischer SE,Bernstein E,Sijen T,Hannon GJ,Plasterk RH.Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C.elegans.Genes Dev.2001;15:2654-9.
[23]Khvorova A,Reynolds A,Jayasena SD.Functional siRNAs and miRNAs exhibit strand bias.Cell.2003;115:209-16.
[24]Hampton JK.Long-term effects of hemodialysis in diabetic patients with end stage renal disease.ANNA J.1992;19:455-6.
[25]Hutvagner G Small RNA asymmetry in RNAi:function in RISC assembly and gene regulation.FEBS Lett.2005;579:5850-7.
[26]Hutvagner G,Zamore PD.A microRNA in a multiple-turnover RNAi enzyme complex.Science.2002;297:2056-60.
[27]Meister G,Landthaler M,Dorsett Y,Tuschl T.Sequence-specific inhibition of microRNA-and siRNA-induced RNA silencing.RNA.2004;10:544-50.
[28]Reinhart BJ,Slack FJ,Basson M et al.The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans.Nature.2000;403:901-6.
[29]Lewis BP,Burge CB,Bartel DP.Conserved seed pairing,often flanked by adenosines,indicates that thousands of human genes are microRNA targets.Cell.2005;120:15-20.
[30]Ma L,Teruya-Feldstein J,Weinberg RA.Tumour invasion and metastasis initiated by microRNA-10b in breast cancer.Nature.2007;449:682-8.
[31]Scherr M,Venrurini L,Battmer K et al.Lentivirus-mediated antagomir expression for specific inhibition of miRNA function.Nucleic Acids Res.2007;35:e149.
[32]Lee YS,Kim HK,Chung S,Kim KS,Dutta A.Depletion of human micro-RNA miR-125b reveals that it is critical for the proliferation of differentiated cells but not for the down-regulation of putative targets during differentiation.J Biol Chem.2005;280:16635-41.
[33]Lee RC,Feinbaum RL,Ambros V.The C.elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14.Cell.1993;75:843-54.
[34]Johnston RJ,Hobert O.A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans.Nature.2003;426:845-9.
[35]Lai EC.microRNAs:runts of the genome assert themselves.Curr Biol.2003;13:R925-36.
[36]Ambros V,Lee RC,Lavanway A,Williams PT,Jewell D.MicroRNAs and other tiny endogenous RNAs in C.elegans.CurrBiol.2003;13:807-18.
[37]Lagos-Quintana M,Rauhut R,Meyer J,Borkhardt A,Tuschl T.New microRNAs from mouse and human.RNA.2003;9:175-9.
[38]Lagos-Quintana M,Rauhut R,Yalcin A,Meyer J,Lendeckel W,Tuschl T.Identification of tissue-specific microRNAs from mouse.Curr Biol.2002;12:735-9.
[39]Kim J,Krichevsky A,Grad Y et al.Identification of many microRNAs that copurify with polyribosomes in mammalian neurons.Proc Natl Acad Sci USA.2004;101:360-5.
[40]Mourelatos Z,Dostie J,Paushkin S et al.miRNPs:a novel class of ribonucleoproteins containing numerous microRNAs.Genes Dev.2002;16:720-8.
[41]Miska EA,Alvarez-Saavedra E,Townsend M et al.Microarray analysis of microRNA expression in the developing mammalian brain.Genome Biol.2004;5:R68.
[42]Houbaviy HB,Murray MF,Sharp PA.Embryonic stem cell-specific MicroRNAs.Dev Cell.2003;5:351-8.
[43]Suh MR,Lee Y,Kim JY et al.Human embryonic stem cells express a unique set of microRNAs.Dev Biol.2004;270:488-98.
[44]Watanabe T,Takeda A,Mise K et al.Stage-specific expression of microRNAs during Xenopus development.FEBS Lett.2005;579:318-24.
[45]Pfeffer S,Sewer A,Lagos-Quintana M et al.Identification of microRNAs of the herpesvirus family.Nat Methods.2005;2:269-76.
[46]Lim LP,Glasner ME,Yekta S,Burge CB,Bartel DP.Vertebrate microRNA genes.Science.2003;299:1540.
[47]Lim LP,Lau NC,Weinstein EG et al.The microRNAs of Caenorhabditis elegans.Genes Dev.2003;17:991-1008.
[48]Ohler U,Yekta S,Lim LP,Bartel DP,Burge CB.Patterns of flanking sequence conservation and a characteristic upstream motif for microRNA gene identification.RNA.2004;10:1309-22.
[49]Grad Y,Aach J,Hayes GD et al.Computational and experimental identification of C.elegans microRNAs.Mol Cell.2003;11:1253-63.
[50]Okamura K,Ishizuka A,Siomi H,Siomi MC.Distinct roles for Argonaute proteins in small RNA-directed RNA cleavage pathways.Genes Dev.2004;18:1655-66.
[51]Brennecke J,Hipmer DR,Stark A,Russell RB,Cohen SM.bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila.Cell.2003;113:25-36.
[52]Zeng Y,Cullen BR.Sequence requirements for micro RNA processing and function in human cells.RNA.2003;9:112-23.
[53]Krichevsky AM,King KS,Donahue CP,Khrapko K,Kosik KS.A microRNA array reveals extensive regulation of microRNAs during brain development.RNA.2003;9:1274-81.
[54]Michael MZ,SM OC,van Hoist Pellekaan NG,Young GP,James RJ.Reduced accumulation of specific microRNAs in colorectal neoplasia.Mol Cancer Res.2003;1:882-91.
[55]Desmeules M,Mikkelsen T,Mao Y.Increasing incidence of primary malignant brain tumors:influence of diagnostic methods.J Natl Cancer Inst.1992;84:442-5.
[56]McKinley BP,Michalek AM,Fenstermaker RA,Plunkett RJ.The impact of age and sex on the incidence of glial tumors in New York state from 1976 to 1995.J Neurosurg.2000;93:932-9.
[57]Bartel DP.MicroRNAs:genomics,biogenesis,mechanism,and function.Cell.2004;116:281-97.
[58]He L,Thomson JM,Hemann MT et al.A microRNA polycistron as a potential human oncogene.Nature.2005;435:828-33.
[59]Iorio MV,Ferracin M,Liu CG et al.MicroRNA gene expression deregulation in human breast cancer.Cancer Res.2005;65:7065-70.
[60]Si ML,Zhu S,Wu H,Lu Z,Wu F,Mo YY.miR-21-mediated tumor growth.Oncogene.2007;26:2799-803.
[61]Zhu S,Si ML,Wu H,Mo YY.MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1).J Biol Chem.2007;282:14328-36.
[62]Tran N,McLean T,Zhang X et al.MicroRNA expression profiles in head and neck cancer cell lines.Biochem Biophys Res Commun.2007;358:12-7.
[63]Fulci V,Chiaretti S,Goldoni M et al.Quantitative technologies establish a novel microRNA profile of chronic lymphocytic leukemia.Blood.2007;109:4944-51.
[64]Ciafre SA,Galardi S,Mangiola A et al.Extensive modulation of a set of microRNAs in primary glioblastoma.Biochem Biophys Res Commun.2005;334:1351-8.
[65]Chan JA,Krichevsky AM,Kosik KS.MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells.Cancer Res.2005;65:6029-33.
[66]Corsten MF,Miranda R,Kasmieh R,Krichevsky AM,Weissleder R,Shah K.MicroRNA-21 knockdown disrupts glioma growth in vivo and displays synergistic cytotoxicity with neural precursor cell delivered S-TRAIL in human gliomas.Cancer Res.2007;67:8994-9000.
[67]Chen Y,Liu W,Chao T et al.MicroRNA-21 down-regulates the expression of tumor suppressor PDCD4 in human glioblastoma cell T98G.Cancer Lett.2008;272:197-205.
[68]Gabriely G,Wurdinger T,Kesari S et al.MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators.Mol Cell Biol.2008;28:5369-80.
[69]Blower PE,Verducci JS,Lin S et al.MicroRNA expression profiles for the NCI-60 cancer cell panel.Mol Cancer Ther.2007;6:1483-91.
[70]Fojo T.Multiple paths to a drug resistance phenotype:mutations,translocations,deletions and amplification of coding genes or promoter regions,epigenetic changes and microRNAs.Drug Resist Updat.2007;10:59-67.
[71]Mishra PJ,Humeniuk R,Longo-Sorbello GS,Banerjee D,Bertino JR.A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance.Proc Natl Acad Sci USA.2007;104:13513-8.
[72]Biedler JL,Spengler BA.A novel chromosome abnormality in human neuroblastoma and antifolate-resistant Chinese hamster cell lives in culture.J Natl Cancer Inst.1976;57:683-95.
[73]Schimke RT,Kaufman RJ,Alt FW,Kellems RF.Gene amplification and drug resistance in cultured murine cells.Science.1978;202:1051-5.
[74]Roninson IB,Abelson HT,Housman DE,Howell N,Varshavsky A.Amplification of specific DNA sequences correlates with multi-drug resistance in Chinese hamster cells.Nature.1984;309:626-8.
[75]Fojo AT,Whang-Peng J,Gottesman MM,Pastan I.Amplification of DNA sequences in human multidrug-resistant KB carcinoma cells.Proc Natl Acad Sci USA.1985;82:7661-5.
[76]Van der Bliek AM,Van der Velde-Koerts T,Ling V,Borst P.Overexpression and amplification of five genes in a multidrug-resistant Chinese hamster ovary cell line.Mol Cell Biol.1986;6:1671-8.
[77]Carlson RW,Moench SJ,Hammond ME et al.HER2 testing in breast cancer:NCCN Task Force report and recommendations.J Natl Compr Cane Netw.2006;4 Suppl 3:Sl-22;quiz S3-4.
[78]Campbell LJ,Patsouris C,Rayeroux KC,Somana K,Januszewicz EH,Szer J.BCR/ABL amplification in chronic myelocytic leukemia blast crisis following imatinib mesylate administration.Cancer Genet Cytogenet.2002;139:30-3.
[79]Lievre A,Bachet JB,Le Corre D et al.KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer.Cancer Res.2006;66:3992-5.
[80]Pegoraro L,Palumbo A,Erikson J et al.A 14;18 and an 8;14 chromosome translocation in a cell line derived from an acute B-cell leukemia.Proc Natl Acad Sci USA.1984;81:7166-70.
[81]Mashima T,Tsuruo T.Defects of the apoptotic pathway as therapeutic target against cancer.Drug Resist Updat.2005;8:339-43.
[82]Huff LM,Lee JS,Robey RW,Fojo T.Characterization of gene rearrangements leading to activation of MDR-1.J Biol Chem.2006;281:36501-9.
[83]Rozovskaia T,Ravid-Amir O,Tillib S et al.Expression profiles of acute lymphoblastic and myeloblastic leukemias with ALL-1 rearrangements.Proc Natl Acad Sci USA.2003;100:7853-8.
[84]Glasspool RM,Teodoridis JM,Brown R.Epigenetics as a mechanism driving polygenic clinical drug resistance.Br J Cancer.2006;94:1087-92.
[85]Meng F,Henson R,Lang M et al.Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines.Gastroenterology.2006;130:2113-29.
[86]Miklos GL,De Couet HG The mutations previously designated as flightless-I3,flightless-02 and standby are members of the W-2 lethal complementation group at the base of the X-chromosome of Drosophila melanogaster.JNeurogenet.1990;6:133-51.
[87]Campbell HD,Schimansky T,Claudianos C et al.The Drosophila melanogaster flightless-I gene involved in gastrulation and muscle degeneration encodes gelsolin-like and leucine-rich repeat domains and is conserved in Caenorhabditis elegans and humans.Proc Natl Acad Sci USA.1993;90:11386-90.
[88]Liu YT,Yin HL.Identification of the binding partners for flightless I,A novel protein bridging the leucine-rich repeat and the gelsolin superfamilies.J Biol Chem.1998;273:7920-7.
[89]Wilson SA,Brown EC,Kingsman AJ,Kingsman SM.TRIP:a novel double stranded RNA binding protein which interacts with the leucine rich repeat of flightless I.Nucleic Acids Res.1998;26:3460-7.
[90]Lee SY,Choi Y.TRAF-interacting protein (TRIP):a novel component of the tumor necrosis factor receptor (TNFR)-and CD30-TRAF signaling complexes that inhibits TRAF2-mediated NF-kappaB activation.J Exp Med.1997;185:1275-85.
[91]Smith CA,Farrah T,Goodwin RG The TNF receptor superfamily of cellular and viral proteins:activation,costimulation,and death.Cell.1994;76:959-62.
[92]Tartaglia LA,Ayres TM,Wong GH,Goeddel DV.A novel domain within the 55 kd TNF receptor signals cell death.Cell.1993;74:845-53.
[93]Itoh N,Nagata S.A novel protein domain required for apoptosis.Mutational analysis of human Fas antigen.J Biol Chem.1993;268:10932-7.
[94]Stanger BZ,Leder P,Lee TH,Kim E,Seed B.RIP:a novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death.Cell.1995;81:513-23.
[95]Muzio M,Chinnaiyan AM,Kischkel FC et al.FLICE,a novel FADD-homologous ICE/CED-3-like protease,is recruited to the CD95 (Fas/APO-1) death—inducing signaling complex.Cell.1996;85:817-27.
[96]Boldin MP,Goncharov TM,Goltsev YV,Wallach D.Involvement of MACH,a novel MORTl/FADD-interacting protease,in Fas/APO-1-and TNF receptor-induced cell death.Cell.1996;85:803-15.
[97]Rothe M,Wong SC,Henzel WJ,Goeddel DV.A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor.Cell.1994;78:681-92.
[98]Cheng G,Cleary AM,Ye ZS,Hong DI,Lederman S,Baltimore D.Involvement of CRAF1,a relative of TRAF,in CD40 signaling.Science.1995;267:1494-8.
[99]Sato T,Irie S,Reed JC.A novel member of the TRAF family of putative signal transducing proteins binds to the cytosolic domain of CD40.FEBSLett.1995;358:113-8.
[100]Hu HM,O'Rourke K,Boguski MS,Dixit VM.A novel RING finger protein interacts with the cytoplasmic domain of CD40.J Biol Chem.1994;269:30069-72.
[101]Gedrich RW,Gilfillan MC,Duckett CS,Van Dongen JL,Thompson CB.CD30 contains two binding sites with different specificities for members of the tumor necrosis factor receptor-associated factor family of signal transducing proteins.J Biol Chem.1996;271:12852-8.
[102]Cheng G,Baltimore D.TANK,a co-inducer with TRAF2 of TNF-and CD 40L-mediated NF-kappaB activation.Genes Dev.1996;10:963-73.
[103]Lee SY,Kandala G,Liou ML,Liou HC,Choi Y.CD30/TNF receptor-associated factor interaction:NF-kappa B activation and binding specificity.Proc Natl Acad Sci USA.1996;93:9699-703.
[104]Zapata JM,Pawlowski K,Haas E,Ware CF,Godzik A,Reed JC.A diverse family of proteins containing tumor necrosis factor receptor-associated factor domains.J Biol Chem.2001;276:24242-52.
[105]Rothe M,Xiong J,Shu HB,Williamson K,Goddard A,Goeddel DV.I-TRAF is a novel TRAF-interacting protein that regulates TRAF-mediated signal transduction.Proc Natl Acad Sci U S A.1996;93:8241-6.
[106]McCarthy JV,Ni J,Dixit VM.RIP2 is a novel NF-kappaB-activating and cell death-inducing kinase./Biol Chem.1998;273:16968-75.
[107]Song HY,Rothe M,Goeddel DV.The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation.Proc Natl Acad Sci USA.1996;93:6721-5.
[108]Karin M,Liu Z,Zandi E.AP-1 function and regulation.Curr Opin Cell Biol.1997;9:240-6.
[109]Baud V,Liu ZG,Bennett B,Suzuki N,Xia Y,Karin M.Signaling by proinflammatory cytokines:oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain.Genes Dev.1999;13:1297-308.
[110]Nishitoh H,Saitoh M,Mochida Y et al.ASK1 is essential for JNK/SAPK activation by TRAF2.Mol Cell.1998;2:389-95.
[111]Hoeflich KP,Yeh WC,Yao Z,Mak TW,Woodgett JR.Mediation of TNF receptor-associated factor effector functions by apoptosis signal-regulating kinase-1 (ASK1).Oncogene.1999;18:5814-20.
[112]Yuasa T,Ohno S,Kehrl JH,Kyriakis JM.Tumor necrosis factor signaling to stress-activated protein kinase (SAPK)/Jun NH2-terminal kinase (JNK) and p38.Germinal center kinase couples TRAF2 to mitogen-activated protein kinase/ERK kinase kinase 1 and SAPK while receptor interacting protein associates with a mitogen-activated protein kinase kinase kinase upstream of MKK6 and p38.J Biol Chem.1998;273:22681-92.
[113]Shi CS,Kehrl JH.Activation of stress-activated protein kinase/c-Jun N-terminal kinase,but not NF-kappaB,by the tumor necrosis factor (TNF) receptor 1 through a TNF receptor-associated factor 2-and germinal center kinase related-dependent pathway.J Biol Chem.1997;272:32102-7.
[114]Rothe M,Pan MG,Henzel WJ,Ayres TM,Goeddel DV.The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins.Cell.1995;83:1243-52.
[115]Lee SY,Reichlin A,Santana A,Sokol KA,Nussenzweig MC,Choi Y.TRAF2 is essential for JNK but not NF-kappaB activation and regulates lymphocyte proliferation and survival.Immunity.1997;7:703-13.
[1]Zeng Y,Cullen BR.Sequence requirements for micro RNA processing and function in human cells.RNA.2003;9:112-23.
[2]He L,Hannon GJ.MicroRNAs:small RNAs with a big role in gene regulation.Nat Rev Genet.2004;5:522-31.
[3]Wu L,Fan J,Belasco JG MicroRNAs direct rapid deadenylation of mRNA.Proc Natl Acad Sci USA.2006;103:4034-9.
[4]Calin GA,Sevignani C,Dumitru CD et al.Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers.Proc Natl Acad Sci USA.2004;101:2999-3004.
[5]Calin GA,Dumitru CD,Shimizu M et al.Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia.Proc Natl Acad Sci USA.2002;99:15524-9.
[6]Lee RC,Feinbaum RL,Ambros V.The C.elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14.Cell.1993;75:843-54.
[7]Reinhart BJ,Slack FJ,Basson M et al.The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans.Nature.2000;403:901-6.
[8]Griffiths-Jones S,Saini HK,van Dongen S,Enright AJ.miRBase:tools for microRNA genomics.Nucleic Acids Res.2008;36:D154-8.
[9]Berezikov E,Guryev V,van de Belt J,Wienholds E,Plasterk RH,Cuppen E.Phylogenetic shadowing and computational identification of human microRNA genes.Cell.2005;120:21-4.
[10]Bentwich I,Avniel A,Karov Y et al.Identification of hundreds of conserved and nonconserved human microRNAs.Nat Genet.2005;37:766-70.
[11]Bartel DP.MicroRNAs:genomics,biogenesis,mechanism,and function.Cell.2004;116:281-97.
[12]Wijnhoven BP,Michael MZ,Watson DI.MicroRNAs and cancer.Br J Surg.2007;94:23-30.
[13]Brennecke J,Hipfher DR,Stark A,Russell RB,Cohen SM.bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila.Cell.2003;113:25-36.
[14]Xu P,Vernooy SY,Guo M,Hay BA.The Drosophila microRNA Mir-14 suppresses cell death and is required for normal fat metabolism.Curr Biol.2003;13:790-5.
[15]Dostie J,Mourelatos Z,Yang M,Sharma A,Dreyfuss G Numerous microRNPs in neuronal cells containing novel microRNAs.RNA.2003;9:180-6.
[16]Krichevsky AM,King KS,Donahue CP,Khrapko K,Kosik KS.A microRNA array reveals extensive regulation of microRNAs during brain development.RNA.2003;9:1274-81.
[17]Hatfield SD,Shcherbata HR,Fischer KA,Nakahara K,Carthew RW,Ruohola-Baker H.Stem cell division is regulated by the microRNApathway.Nature.2005;435:974-8.
[18]Ambros V.The functions of animal microRNAs.Nature.2004;431:350-5.
[19]Lin SL,Chang D,Wu DY,Ying SY.A novel RNA splicing-mediated gene silencing mechanism potential for genome evolution.Biochem Biophys Res Commun.2003;310:754-60.
[20]Han J,Lee Y,Yeom KH,Kim YK,Jin H,Kim VN.The Drosha-DGCR8 complex in primary microRNA processing.Genes Dev.2004;18:3016-27.
[21]Lee Y,Ahn C,Han J et al.The nuclear RNase Ⅲ Drosha initiates microRNA processing.Nature.2003;425:415-9.
[22]Gregory RI,Yan KP,Amuthan G et al.The Microprocessor complex mediates the genesis of microRNAs.Nature.2004;432:235-40.
[23]Ohrt T,Merkle D,Birkenfeld K,Echeverri CJ,Schwille P.In situ fluorescence analysis demonstrates active siRNA exclusion from the nucleus by Exportin 5.Nucleic Acids Res.2006;34:1369-80.
[24]Zeng Y,Cullen BR.Structural requirements for pre-microRNA binding and nuclear export by Exportin 5.Nucleic Acids Res.2004;32:4776-85.
[25]Ketting RF,Fischer SE,Bernstein E,Sijen T,Hannon GJ,Plasterk RH.Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C.elegans.Genes Dev.2001;15:2654-9.
[26]Lim LP,Lau NC,Weinstein EG et al.The microRNAs of Caenorhabditis elegans.Genes Dev.2003;17:991-1008.
[27]Okamura K,Ishizuka A,Siomi H,Siomi MC.Distinct roles for Argonaute proteins in small RNA-directed RNA cleavage pathways.Genes Dev.2004;18:1655-66.
[28]Michael MZ,SM OC,van Hoist Pellekaan NQ Young GP,James RJ.Reduced accumulation of specific microRNAs in colorectal neoplasia.Mol Cancer Res.2003;1:882-91.
[29]Wang H,Ach RA,Curry B.Direct and sensitive miRNA profiling from low-input total RNA.RNA.2007;13:151-9.
[30]Chan JA,Krichevsky AM,Kosik KS.MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells.Cancer Res.2005;65:6029-33.
[31]Takamizawa J,Konishi H,Yanagisawa K et al.Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival.Cancer Res.2004;64:3753-6.
[32]Eis PS,Tam W,Sun L et al.Accumulation of miR-155 and BIC RNA in human β cell lymphomas.Proc Natl Acad Sci USA.2005;102:3627-32.
[33]Tam W,Hughes SH,Hayward WS,Besmer P.Avian bic,a gene isolated from a common retroviral site in avian leukosis virus-induced lymphomas that encodes a noncoding RNA,cooperates with c-myc in lymphomagenesis and erythroleukemogenesis.J Virol.2002;76:4275-86.
[34]Costinean S,Zanesi N,Pekarsky Yet al.Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice.Proc Natl Acad Sci U S A.2006;103:7024-9.
[35]Voorhoeve PM,le Sage C,Schrier M et al.A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors.Cell.2006;124:1169-81.
[36]Felli N,Fontana L,Pelosi E et al.MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation.Proc Natl Acad Sci U S A.2005;102:18081-6.
[37]He H,Jazdzewski K,Li W et al.The role of microRNA genes in papillary thyroid carcinoma.Proc Natl Acad Sci USA.2005;102:19075-80.
[38]Nicholson DW.Caspase structure,proteolytic substrates,and function during apoptotic cell death.Cell Death Differ.1999;6:1028-42.
[39]He L,Thomson JM,Hemann MT et al.A microRNA polycistron as a potential human oncogene.Nature.2005;435:828-33.
[40]O'Dormell KA,Wentzel EA,Zeller KI,Dang CV,Mendell JT.c-Myc-regulated microRNAs modulate E2F1 expression.Nature.2005;435:839-43.
[41]Woods K,Thomson JM,Hammond SM.Direct regulation of an oncogenic micro-RNA cluster by E2F transcription factors.J Biol Chem.2007;282:2130-4.
[42]Hayashita Y,Osada H,Tatematsu Yet al.A polycistronic microRNA cluster,miR-17-92,is overexpressed in human lung cancers and enhances cell proliferation.Cancer Res.2005;65:9628-32.
[43]Matsubara H,Takeuchi T,Nishikawa E et al.Apoptosis induction by antisense oligonucleotides against miR-17-5p and miR-20a in lung cancers overexpressing miR-17-92.Oncogene.2007;26:6099-105.
[44]Cheng AM,Byrom MW,Shelton J,Ford LP.Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis.Nucleic Acids Res.2005;33:1290-7.
[45]Calin GA,Croce CM.MicroRNA signatures in human cancers.Nat Rev Cancer.2006;6:857-66.
[46]Brueckner B,Stresemann C,Kuner R et al.The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function.Cancer Res.2007;67:1419-23.
[47]Mayr C,Hemann MT,Bartel DP.Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation.Science.2007;315:1576-9.
[48]Lee YS,Dutta A.The tumor suppressor microRNA let-7 represses the HMGA2 oncogene.Genes Dev.2007;21:1025-30.
[49]Hebert C,Norris K,Scheper MA,Nikitakis N,Sauk JJ.High mobility group A2 is a target for miRNA-98 in head and neck squamous cell carcinoma..Mol Cancer.2007;6:5.
[50]Akao Y,Nakagawa Y,Naoe T.let-7 microRNA functions as a potential growth suppressor in human colon cancer cells.Biol Pharm Bull.2006;29:903-6.
[51]Johnson SM,Grosshans H,Shingara J et al.RAS is regulated by the let-7 microRNA family.Cell.2005;120:635-47.
[52]Meng F,Henson R,Wehbe-Janek H,Smith H,Ueno Y,Patel T.The MicroRNA let-7a modulates interleukin-6-dependent STAT-3 survival signaling in malignant human cholangiocytes.J Biol Chem.2007;282:8256-64.
[53]Bottoni A,Piccin D,Tagliati F,Luchin A,Zatelli MC,degli Uberti EC.miR-15a and miR-16-1down-regulation in pituitary adenomas.J Cell Physiol.2005;204:280-5.
[54]Cimmino A,Calin GA,Fabbri Met al.miR-15 and miR-16 induce apoptosis by targeting BCL2.Proc Natl Acad Sci USA.2005;102:13944-9.
[55]Garzon R,Pichiorri F,Palumbo T et al.MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukemia.Oncogene.2007;26:4148-57.
[56]Ciafre SA,Galardi S,Mangiola Aet al.Extensive modulation of a set of microRNAs in primary glioblastoma.Biochem Biophys Res Commun.2005;334:1351-8.
[57]Pekarsky Y,Santanam U,Cimmino Aet al.Tcll expression in chronic lymphocytic leukemia is regulated by miR-29 and miR-181.Cancer Res.2006;66:11590-3.
[58]Mott JL,Kobayashi S,Bronk SF,Gores GJ.mir-29 regulates Mcl-1 protein expression and apoptosis.Oncogene.2007;26:6133-40.
[59]Bandres E,Cubedo E,Agirre X et al.Identification by Real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues.Mol Cancer.2006;5:29.
[60]Akao Y,Nakagawa Y,Naoe T.MicroRNAs 143 and 145 are possible common onco-microRNAs in human cancers.Oncol Rep.2006;16:845-50.
[61]Laneve P,Di Marcotullio L,Gioia U et al.The interplay between microRNAs and the neurotrophin receptor tropomyosin-related kinase C controls proliferation of human neuroblastoma cells.Proc Natl Acad Sci USA.2007;104:7957-62.
[62]Chen Y,Stallings RL.Differential patterns of microRNA expression in neuroblastoma are correlated with prognosis,differentiation,and apoptosis.Cancer Res.2007;67:976-83.
[63]Welch C,Chen Y,Stallings RL.MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells.Oncogene.2007;26:5017-22.
[64]Chang TC,Wentzel EA,Kent OA et al.Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis.Mol Cell.2007;26:745-52.
[65]Nervi C,Fazi F,Rosa A,Fatica A,Bozzoni I.Emerging role for microRNAs in acute promyelocytic leukemia.Curr Top Microbiol Immunol.2007;313:73-84.
[66]Wu L,Belasco JG Micro-RNA regulation of the mammalian lin-28 gene during neuronal differentiation of embryonal carcinoma cells.Mol Cell Biol.2005;25:9198-208.
[67]Lee YS,Kim HK,Chung S,Kim KS,Dutta A.Depletion of human micro-RNA miR-125b reveals that it is critical for the proliferation of differentiated cells but not for the down-regulation of putative targets during differentiation.J Biol Chem.2005;280:16635-41.
[68]Moss EG,Tang L.Conservation of the heterochronic regulator Lin-28,its developmental expression and microRNA complementary sites.Dev Biol.2003;258:432-42.
[69]Lowery AJ,Miller N,McNeill RE,Kerin MJ.MicroRNAs as prognostic indicators and therapeutic targets:potential effect on breast cancer management.Clin Cancer Res.2008;14:360-5.
[70]Adams BD,Guttilla IK,White BA.Involvement of microRNAs in breast cancer.Semin Reprod Med.2008;26:522-36.
[71]Iorio MV,Casalini P,Tagliabue E,Menard S,Croce CM.MicroRNA profiling as a tool to understand prognosis,therapy response and resistance in breast cancer.Eur J Cancer.2008;44:2753-9.
[72]Gabriely G,Wurdinger T,Kesari S et al.MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators.Mol Cell Biol.2008;28:5369-80.
[73]Yanaihara N,Caplen N,Bowman E et al.Unique microRNA molecular profiles in lung cancer diagnosis and prognosis.Cancer Cell.2006;9:189-98.
[74]Venturini L,Battmer K,Castoldi M et al.Expression of the miR-17-92 polycistron in chronic myeloid leukemia (CML) CD34+ cells.Blood.2007;109:4399-405.
[75]Iorio MV,Ferracin M,Liu CG et al.MicroRNA gene expression deregulation in human breast cancer.Cancer Res.2005;65:7065-70.
[76]Lu J,Getz G,Miska EA et al.MicroRNA expression profiles classify human cancers.Nature.2005;43S:834-8.
[77]Nelson PT,Baldwin DA,Kloosterman WP,Kauppinen S,Plasterk RH,Mourelatos Z.RAKE and LNA-ISH reveal microRNA expression and localization in archival human brain.RNA.2006;12:187-91.
[78]Chen CZ.MicroRNAs as oncogenes and tumor suppressors.NEngl JMed.2005;353:1768-71.
[79]Weiler J,Hunziker J,Hall J.Anti-miRNA oligonucleotides(AMOs):ammunition to target miRNAs implicated in human disease? Gene Ther.2006;13:496-502.
[80]Esau CC,Monia BP.Therapeutic potential for microRNAs.Adv Drug Deliv Rev.2007;59:101-14.
[81]Esau CC.Inhibition of microRNA with antisense oligonucleotides.Methods.2008;44:55-60.
[82]Shen Y.Advances in the development of siRNA-based therapeutics for cancer.IDrugs.2008;11:572-8.
[83]Devi GR.siRNA-based approaches in cancer therapy.Cancer Gene Ther.2006;13:819-29.
[84]Maher EA,Furnari FB,Bachoo RM et al.Malignant glioma:genetics and biology of a grave matter.Genes Dev.2001;15:1311-33.
[85]Fumari FB,Fenton T,Bachoo RM et al.Malignant astrocytic glioma:genetics,biology,and paths to treatment.Genes Dev.2007;21:2683-710.
[86]Ohgaki H.Epidemiology of brain tumors.Methods Mol Biol.2009;472:323-42.
[87]Medina R,Zaidi SK,Liu CG et al.MicroRNAs 221 and 222 bypass quiescence and compromise cell survival.Cancer Res.2008;68:2773-80.
[88]Gillies JK,Lorimer IA.Regulation of p27Kipl by miRNA 221/222 in glioblastoma.Cell Cycle.2007;ti:2005-9.
[89]Silber J,Lim DA,Petritsch C et al.miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells.BMCMed.2008;6:14.
[90]Kefas B,Godlewski J,Comeau L et al.microRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma.Cancer Res.2008;68:3566-72.
[91]Reddy SD,Ohshiro K,Rayala SK,Kumar R.MicroRNA-7,a homeobox D10 target,inhibits p21-activated kinase 1 and regulates its functions.Cancer Res.2008;68:8195-200.
[92]Godlewski J,Nowicki MO,Bronisz Aet al.Targeting of the Bmi-1 oncogene/stem cell renewal factor by microRNA-128 inhibits glioma proliferation and self-renewal.Cancer Res.2008;68:9125-30.
[93]Zhang Y,Chao T,Li R et al.MicroRNA-128 inhibits glioma cells proliferation by targeting transcription factor E2F3a.JMol Med.2009;87:43-51.
[94]Shi L,Cheng Z,Zhang Jet al.hsa-mir-181a and hsa-mir-181b function as tumor suppressors in human glioma cells.Brain Res.2008;1236:185-93.
[95]Corsten MF,Miranda R,Kasmieh R,Krichevsky AM,Weissleder R,Shah K.MicroRNA-21 knockdown disrupts glioma growth in vivo and displays synergistic cytotoxicity with neural precursor cell delivered S-TRAIL in human gliomas.Cancer Res.2007;67:8994-9000.
[2]Louis DN,Gusella JE A tiger behind many doors:multiple genetic pathways to malignant glioma.Trends Genet.1995;11:412-5.
[3]Hochberg FH,Pruitt A.Assumptions in the radiotherapy of glioblastoma.Neurology.1980;30:907-11.
[4]Stupp R,Mason WP,van den Bent MJ et al.Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.N EnglJMed.2005;352:987-96.
[5]Shu HK,Kim MM,Chen P,Furman F,Julin CM,Israel MA.The intrinsic radioresistance of glioblastoma-derived cell lines is associated with a failure of p53 to induce p21(BAX) expression.Proc NatlAcad Sci USA.1998;95:14453-8.
[6]Bandres E,Andion E,Escalada Aet al.Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression.JNeurooncol.2005;73:189-98.
[7]Gupta M,Brewer G.MicroRNAs:new players in an old game.Proc Natl Acad Sci U S A.2006;103:3951-2.
[8]Poy MN,Eliasson L,Krutzfeldt Jet al.A pancreatic islet-specific microRNA regulates insulin secretion.Nature.2004;432:226-30.
[9]Lee Y,Kim M,Han Jet al.MicroRNA genes are transcribed by RNA polymerase II.EMBO J.2004;23:4051-60.
[10]Cai X,Hagedorn CH,Cullen BR.Human microRNAs are processed from capped,polyadenylated transcripts that can also function as mRNAs.RNA.2004;10:1957-66.
[11]Lee Y,Jeon K,Lee JT,Kim S,Kim VN.MicroRNA maturation:stepwise processing and subcellular localization.EMBO J.2002;21:4663-70.
[12]Lee Y,Ahn C,Han Jet al.The nuclear RNase III Drosha initiates microRNA processing.Nature.2003;425:415-9.
[13]Denli AM,Tops BB,Plasterk RH,Ketting RF,Hannon GJ.Processing of primary microRNAs by the Microprocessor complex.Nature.2004;432:231-5.
[14]Gregory RI,Yan KP,Amuthan G et al.The Microprocessor complex mediates the genesis of microRNAs.Nature.2004;432:235-40.
[15]Han J,Lee Y,Yeom KH,Kim YK,Jin H,Kim VN.The Drosha-DGCR8 complex in primary microRNA processing.Genes Dev.2004;18:3016-27.
[16]Landthaler M,Yalcin A,Tuschl T.The human DiGeorge syndrome critical region gene 8 and Its D.melanogaster homolog are required for miRNA biogenesis.Curr Biol.2004;14:2162-7.
[17]Lund E,Guttinger S,Calado A,Dahlberg JE,Kutay U.Nuclear export of microRNA precursors.Science.2004;303:95-8.
[18]Yi R,Qin Y,Macara IG,Cullen BR.Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs.Genes Dev.2003;17:3011-6.
[19]Bohnsack MT,Czaplinski K,Gorlich D.Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs.RNA.2004;10:185-91.
[20]Hutvagner G,McLachlan J,Pasquinelli AE,Balint E,Tuschl T,Zamore PD.A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA.Science.2001;293:834-8.
[21]Grishok A,Pasquinelli AE,Conte D et al.Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C.elegans developmental timing.Cell.2001;106:23-34.
[22]Ketting RF,Fischer SE,Bernstein E,Sijen T,Hannon GJ,Plasterk RH.Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C.elegans.Genes Dev.2001;15:2654-9.
[23]Khvorova A,Reynolds A,Jayasena SD.Functional siRNAs and miRNAs exhibit strand bias.Cell.2003;115:209-16.
[24]Hampton JK.Long-term effects of hemodialysis in diabetic patients with end stage renal disease.ANNA J.1992;19:455-6.
[25]Hutvagner G Small RNA asymmetry in RNAi:function in RISC assembly and gene regulation.FEBS Lett.2005;579:5850-7.
[26]Hutvagner G,Zamore PD.A microRNA in a multiple-turnover RNAi enzyme complex.Science.2002;297:2056-60.
[27]Meister G,Landthaler M,Dorsett Y,Tuschl T.Sequence-specific inhibition of microRNA-and siRNA-induced RNA silencing.RNA.2004;10:544-50.
[28]Reinhart BJ,Slack FJ,Basson M et al.The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans.Nature.2000;403:901-6.
[29]Lewis BP,Burge CB,Bartel DP.Conserved seed pairing,often flanked by adenosines,indicates that thousands of human genes are microRNA targets.Cell.2005;120:15-20.
[30]Ma L,Teruya-Feldstein J,Weinberg RA.Tumour invasion and metastasis initiated by microRNA-10b in breast cancer.Nature.2007;449:682-8.
[31]Scherr M,Venrurini L,Battmer K et al.Lentivirus-mediated antagomir expression for specific inhibition of miRNA function.Nucleic Acids Res.2007;35:e149.
[32]Lee YS,Kim HK,Chung S,Kim KS,Dutta A.Depletion of human micro-RNA miR-125b reveals that it is critical for the proliferation of differentiated cells but not for the down-regulation of putative targets during differentiation.J Biol Chem.2005;280:16635-41.
[33]Lee RC,Feinbaum RL,Ambros V.The C.elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14.Cell.1993;75:843-54.
[34]Johnston RJ,Hobert O.A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans.Nature.2003;426:845-9.
[35]Lai EC.microRNAs:runts of the genome assert themselves.Curr Biol.2003;13:R925-36.
[36]Ambros V,Lee RC,Lavanway A,Williams PT,Jewell D.MicroRNAs and other tiny endogenous RNAs in C.elegans.CurrBiol.2003;13:807-18.
[37]Lagos-Quintana M,Rauhut R,Meyer J,Borkhardt A,Tuschl T.New microRNAs from mouse and human.RNA.2003;9:175-9.
[38]Lagos-Quintana M,Rauhut R,Yalcin A,Meyer J,Lendeckel W,Tuschl T.Identification of tissue-specific microRNAs from mouse.Curr Biol.2002;12:735-9.
[39]Kim J,Krichevsky A,Grad Y et al.Identification of many microRNAs that copurify with polyribosomes in mammalian neurons.Proc Natl Acad Sci USA.2004;101:360-5.
[40]Mourelatos Z,Dostie J,Paushkin S et al.miRNPs:a novel class of ribonucleoproteins containing numerous microRNAs.Genes Dev.2002;16:720-8.
[41]Miska EA,Alvarez-Saavedra E,Townsend M et al.Microarray analysis of microRNA expression in the developing mammalian brain.Genome Biol.2004;5:R68.
[42]Houbaviy HB,Murray MF,Sharp PA.Embryonic stem cell-specific MicroRNAs.Dev Cell.2003;5:351-8.
[43]Suh MR,Lee Y,Kim JY et al.Human embryonic stem cells express a unique set of microRNAs.Dev Biol.2004;270:488-98.
[44]Watanabe T,Takeda A,Mise K et al.Stage-specific expression of microRNAs during Xenopus development.FEBS Lett.2005;579:318-24.
[45]Pfeffer S,Sewer A,Lagos-Quintana M et al.Identification of microRNAs of the herpesvirus family.Nat Methods.2005;2:269-76.
[46]Lim LP,Glasner ME,Yekta S,Burge CB,Bartel DP.Vertebrate microRNA genes.Science.2003;299:1540.
[47]Lim LP,Lau NC,Weinstein EG et al.The microRNAs of Caenorhabditis elegans.Genes Dev.2003;17:991-1008.
[48]Ohler U,Yekta S,Lim LP,Bartel DP,Burge CB.Patterns of flanking sequence conservation and a characteristic upstream motif for microRNA gene identification.RNA.2004;10:1309-22.
[49]Grad Y,Aach J,Hayes GD et al.Computational and experimental identification of C.elegans microRNAs.Mol Cell.2003;11:1253-63.
[50]Okamura K,Ishizuka A,Siomi H,Siomi MC.Distinct roles for Argonaute proteins in small RNA-directed RNA cleavage pathways.Genes Dev.2004;18:1655-66.
[51]Brennecke J,Hipmer DR,Stark A,Russell RB,Cohen SM.bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila.Cell.2003;113:25-36.
[52]Zeng Y,Cullen BR.Sequence requirements for micro RNA processing and function in human cells.RNA.2003;9:112-23.
[53]Krichevsky AM,King KS,Donahue CP,Khrapko K,Kosik KS.A microRNA array reveals extensive regulation of microRNAs during brain development.RNA.2003;9:1274-81.
[54]Michael MZ,SM OC,van Hoist Pellekaan NG,Young GP,James RJ.Reduced accumulation of specific microRNAs in colorectal neoplasia.Mol Cancer Res.2003;1:882-91.
[55]Desmeules M,Mikkelsen T,Mao Y.Increasing incidence of primary malignant brain tumors:influence of diagnostic methods.J Natl Cancer Inst.1992;84:442-5.
[56]McKinley BP,Michalek AM,Fenstermaker RA,Plunkett RJ.The impact of age and sex on the incidence of glial tumors in New York state from 1976 to 1995.J Neurosurg.2000;93:932-9.
[57]Bartel DP.MicroRNAs:genomics,biogenesis,mechanism,and function.Cell.2004;116:281-97.
[58]He L,Thomson JM,Hemann MT et al.A microRNA polycistron as a potential human oncogene.Nature.2005;435:828-33.
[59]Iorio MV,Ferracin M,Liu CG et al.MicroRNA gene expression deregulation in human breast cancer.Cancer Res.2005;65:7065-70.
[60]Si ML,Zhu S,Wu H,Lu Z,Wu F,Mo YY.miR-21-mediated tumor growth.Oncogene.2007;26:2799-803.
[61]Zhu S,Si ML,Wu H,Mo YY.MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1).J Biol Chem.2007;282:14328-36.
[62]Tran N,McLean T,Zhang X et al.MicroRNA expression profiles in head and neck cancer cell lines.Biochem Biophys Res Commun.2007;358:12-7.
[63]Fulci V,Chiaretti S,Goldoni M et al.Quantitative technologies establish a novel microRNA profile of chronic lymphocytic leukemia.Blood.2007;109:4944-51.
[64]Ciafre SA,Galardi S,Mangiola A et al.Extensive modulation of a set of microRNAs in primary glioblastoma.Biochem Biophys Res Commun.2005;334:1351-8.
[65]Chan JA,Krichevsky AM,Kosik KS.MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells.Cancer Res.2005;65:6029-33.
[66]Corsten MF,Miranda R,Kasmieh R,Krichevsky AM,Weissleder R,Shah K.MicroRNA-21 knockdown disrupts glioma growth in vivo and displays synergistic cytotoxicity with neural precursor cell delivered S-TRAIL in human gliomas.Cancer Res.2007;67:8994-9000.
[67]Chen Y,Liu W,Chao T et al.MicroRNA-21 down-regulates the expression of tumor suppressor PDCD4 in human glioblastoma cell T98G.Cancer Lett.2008;272:197-205.
[68]Gabriely G,Wurdinger T,Kesari S et al.MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators.Mol Cell Biol.2008;28:5369-80.
[69]Blower PE,Verducci JS,Lin S et al.MicroRNA expression profiles for the NCI-60 cancer cell panel.Mol Cancer Ther.2007;6:1483-91.
[70]Fojo T.Multiple paths to a drug resistance phenotype:mutations,translocations,deletions and amplification of coding genes or promoter regions,epigenetic changes and microRNAs.Drug Resist Updat.2007;10:59-67.
[71]Mishra PJ,Humeniuk R,Longo-Sorbello GS,Banerjee D,Bertino JR.A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance.Proc Natl Acad Sci USA.2007;104:13513-8.
[72]Biedler JL,Spengler BA.A novel chromosome abnormality in human neuroblastoma and antifolate-resistant Chinese hamster cell lives in culture.J Natl Cancer Inst.1976;57:683-95.
[73]Schimke RT,Kaufman RJ,Alt FW,Kellems RF.Gene amplification and drug resistance in cultured murine cells.Science.1978;202:1051-5.
[74]Roninson IB,Abelson HT,Housman DE,Howell N,Varshavsky A.Amplification of specific DNA sequences correlates with multi-drug resistance in Chinese hamster cells.Nature.1984;309:626-8.
[75]Fojo AT,Whang-Peng J,Gottesman MM,Pastan I.Amplification of DNA sequences in human multidrug-resistant KB carcinoma cells.Proc Natl Acad Sci USA.1985;82:7661-5.
[76]Van der Bliek AM,Van der Velde-Koerts T,Ling V,Borst P.Overexpression and amplification of five genes in a multidrug-resistant Chinese hamster ovary cell line.Mol Cell Biol.1986;6:1671-8.
[77]Carlson RW,Moench SJ,Hammond ME et al.HER2 testing in breast cancer:NCCN Task Force report and recommendations.J Natl Compr Cane Netw.2006;4 Suppl 3:Sl-22;quiz S3-4.
[78]Campbell LJ,Patsouris C,Rayeroux KC,Somana K,Januszewicz EH,Szer J.BCR/ABL amplification in chronic myelocytic leukemia blast crisis following imatinib mesylate administration.Cancer Genet Cytogenet.2002;139:30-3.
[79]Lievre A,Bachet JB,Le Corre D et al.KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer.Cancer Res.2006;66:3992-5.
[80]Pegoraro L,Palumbo A,Erikson J et al.A 14;18 and an 8;14 chromosome translocation in a cell line derived from an acute B-cell leukemia.Proc Natl Acad Sci USA.1984;81:7166-70.
[81]Mashima T,Tsuruo T.Defects of the apoptotic pathway as therapeutic target against cancer.Drug Resist Updat.2005;8:339-43.
[82]Huff LM,Lee JS,Robey RW,Fojo T.Characterization of gene rearrangements leading to activation of MDR-1.J Biol Chem.2006;281:36501-9.
[83]Rozovskaia T,Ravid-Amir O,Tillib S et al.Expression profiles of acute lymphoblastic and myeloblastic leukemias with ALL-1 rearrangements.Proc Natl Acad Sci USA.2003;100:7853-8.
[84]Glasspool RM,Teodoridis JM,Brown R.Epigenetics as a mechanism driving polygenic clinical drug resistance.Br J Cancer.2006;94:1087-92.
[85]Meng F,Henson R,Lang M et al.Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines.Gastroenterology.2006;130:2113-29.
[86]Miklos GL,De Couet HG The mutations previously designated as flightless-I3,flightless-02 and standby are members of the W-2 lethal complementation group at the base of the X-chromosome of Drosophila melanogaster.JNeurogenet.1990;6:133-51.
[87]Campbell HD,Schimansky T,Claudianos C et al.The Drosophila melanogaster flightless-I gene involved in gastrulation and muscle degeneration encodes gelsolin-like and leucine-rich repeat domains and is conserved in Caenorhabditis elegans and humans.Proc Natl Acad Sci USA.1993;90:11386-90.
[88]Liu YT,Yin HL.Identification of the binding partners for flightless I,A novel protein bridging the leucine-rich repeat and the gelsolin superfamilies.J Biol Chem.1998;273:7920-7.
[89]Wilson SA,Brown EC,Kingsman AJ,Kingsman SM.TRIP:a novel double stranded RNA binding protein which interacts with the leucine rich repeat of flightless I.Nucleic Acids Res.1998;26:3460-7.
[90]Lee SY,Choi Y.TRAF-interacting protein (TRIP):a novel component of the tumor necrosis factor receptor (TNFR)-and CD30-TRAF signaling complexes that inhibits TRAF2-mediated NF-kappaB activation.J Exp Med.1997;185:1275-85.
[91]Smith CA,Farrah T,Goodwin RG The TNF receptor superfamily of cellular and viral proteins:activation,costimulation,and death.Cell.1994;76:959-62.
[92]Tartaglia LA,Ayres TM,Wong GH,Goeddel DV.A novel domain within the 55 kd TNF receptor signals cell death.Cell.1993;74:845-53.
[93]Itoh N,Nagata S.A novel protein domain required for apoptosis.Mutational analysis of human Fas antigen.J Biol Chem.1993;268:10932-7.
[94]Stanger BZ,Leder P,Lee TH,Kim E,Seed B.RIP:a novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death.Cell.1995;81:513-23.
[95]Muzio M,Chinnaiyan AM,Kischkel FC et al.FLICE,a novel FADD-homologous ICE/CED-3-like protease,is recruited to the CD95 (Fas/APO-1) death—inducing signaling complex.Cell.1996;85:817-27.
[96]Boldin MP,Goncharov TM,Goltsev YV,Wallach D.Involvement of MACH,a novel MORTl/FADD-interacting protease,in Fas/APO-1-and TNF receptor-induced cell death.Cell.1996;85:803-15.
[97]Rothe M,Wong SC,Henzel WJ,Goeddel DV.A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor.Cell.1994;78:681-92.
[98]Cheng G,Cleary AM,Ye ZS,Hong DI,Lederman S,Baltimore D.Involvement of CRAF1,a relative of TRAF,in CD40 signaling.Science.1995;267:1494-8.
[99]Sato T,Irie S,Reed JC.A novel member of the TRAF family of putative signal transducing proteins binds to the cytosolic domain of CD40.FEBSLett.1995;358:113-8.
[100]Hu HM,O'Rourke K,Boguski MS,Dixit VM.A novel RING finger protein interacts with the cytoplasmic domain of CD40.J Biol Chem.1994;269:30069-72.
[101]Gedrich RW,Gilfillan MC,Duckett CS,Van Dongen JL,Thompson CB.CD30 contains two binding sites with different specificities for members of the tumor necrosis factor receptor-associated factor family of signal transducing proteins.J Biol Chem.1996;271:12852-8.
[102]Cheng G,Baltimore D.TANK,a co-inducer with TRAF2 of TNF-and CD 40L-mediated NF-kappaB activation.Genes Dev.1996;10:963-73.
[103]Lee SY,Kandala G,Liou ML,Liou HC,Choi Y.CD30/TNF receptor-associated factor interaction:NF-kappa B activation and binding specificity.Proc Natl Acad Sci USA.1996;93:9699-703.
[104]Zapata JM,Pawlowski K,Haas E,Ware CF,Godzik A,Reed JC.A diverse family of proteins containing tumor necrosis factor receptor-associated factor domains.J Biol Chem.2001;276:24242-52.
[105]Rothe M,Xiong J,Shu HB,Williamson K,Goddard A,Goeddel DV.I-TRAF is a novel TRAF-interacting protein that regulates TRAF-mediated signal transduction.Proc Natl Acad Sci U S A.1996;93:8241-6.
[106]McCarthy JV,Ni J,Dixit VM.RIP2 is a novel NF-kappaB-activating and cell death-inducing kinase./Biol Chem.1998;273:16968-75.
[107]Song HY,Rothe M,Goeddel DV.The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation.Proc Natl Acad Sci USA.1996;93:6721-5.
[108]Karin M,Liu Z,Zandi E.AP-1 function and regulation.Curr Opin Cell Biol.1997;9:240-6.
[109]Baud V,Liu ZG,Bennett B,Suzuki N,Xia Y,Karin M.Signaling by proinflammatory cytokines:oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain.Genes Dev.1999;13:1297-308.
[110]Nishitoh H,Saitoh M,Mochida Y et al.ASK1 is essential for JNK/SAPK activation by TRAF2.Mol Cell.1998;2:389-95.
[111]Hoeflich KP,Yeh WC,Yao Z,Mak TW,Woodgett JR.Mediation of TNF receptor-associated factor effector functions by apoptosis signal-regulating kinase-1 (ASK1).Oncogene.1999;18:5814-20.
[112]Yuasa T,Ohno S,Kehrl JH,Kyriakis JM.Tumor necrosis factor signaling to stress-activated protein kinase (SAPK)/Jun NH2-terminal kinase (JNK) and p38.Germinal center kinase couples TRAF2 to mitogen-activated protein kinase/ERK kinase kinase 1 and SAPK while receptor interacting protein associates with a mitogen-activated protein kinase kinase kinase upstream of MKK6 and p38.J Biol Chem.1998;273:22681-92.
[113]Shi CS,Kehrl JH.Activation of stress-activated protein kinase/c-Jun N-terminal kinase,but not NF-kappaB,by the tumor necrosis factor (TNF) receptor 1 through a TNF receptor-associated factor 2-and germinal center kinase related-dependent pathway.J Biol Chem.1997;272:32102-7.
[114]Rothe M,Pan MG,Henzel WJ,Ayres TM,Goeddel DV.The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins.Cell.1995;83:1243-52.
[115]Lee SY,Reichlin A,Santana A,Sokol KA,Nussenzweig MC,Choi Y.TRAF2 is essential for JNK but not NF-kappaB activation and regulates lymphocyte proliferation and survival.Immunity.1997;7:703-13.
[1]Zeng Y,Cullen BR.Sequence requirements for micro RNA processing and function in human cells.RNA.2003;9:112-23.
[2]He L,Hannon GJ.MicroRNAs:small RNAs with a big role in gene regulation.Nat Rev Genet.2004;5:522-31.
[3]Wu L,Fan J,Belasco JG MicroRNAs direct rapid deadenylation of mRNA.Proc Natl Acad Sci USA.2006;103:4034-9.
[4]Calin GA,Sevignani C,Dumitru CD et al.Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers.Proc Natl Acad Sci USA.2004;101:2999-3004.
[5]Calin GA,Dumitru CD,Shimizu M et al.Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia.Proc Natl Acad Sci USA.2002;99:15524-9.
[6]Lee RC,Feinbaum RL,Ambros V.The C.elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14.Cell.1993;75:843-54.
[7]Reinhart BJ,Slack FJ,Basson M et al.The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans.Nature.2000;403:901-6.
[8]Griffiths-Jones S,Saini HK,van Dongen S,Enright AJ.miRBase:tools for microRNA genomics.Nucleic Acids Res.2008;36:D154-8.
[9]Berezikov E,Guryev V,van de Belt J,Wienholds E,Plasterk RH,Cuppen E.Phylogenetic shadowing and computational identification of human microRNA genes.Cell.2005;120:21-4.
[10]Bentwich I,Avniel A,Karov Y et al.Identification of hundreds of conserved and nonconserved human microRNAs.Nat Genet.2005;37:766-70.
[11]Bartel DP.MicroRNAs:genomics,biogenesis,mechanism,and function.Cell.2004;116:281-97.
[12]Wijnhoven BP,Michael MZ,Watson DI.MicroRNAs and cancer.Br J Surg.2007;94:23-30.
[13]Brennecke J,Hipfher DR,Stark A,Russell RB,Cohen SM.bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila.Cell.2003;113:25-36.
[14]Xu P,Vernooy SY,Guo M,Hay BA.The Drosophila microRNA Mir-14 suppresses cell death and is required for normal fat metabolism.Curr Biol.2003;13:790-5.
[15]Dostie J,Mourelatos Z,Yang M,Sharma A,Dreyfuss G Numerous microRNPs in neuronal cells containing novel microRNAs.RNA.2003;9:180-6.
[16]Krichevsky AM,King KS,Donahue CP,Khrapko K,Kosik KS.A microRNA array reveals extensive regulation of microRNAs during brain development.RNA.2003;9:1274-81.
[17]Hatfield SD,Shcherbata HR,Fischer KA,Nakahara K,Carthew RW,Ruohola-Baker H.Stem cell division is regulated by the microRNApathway.Nature.2005;435:974-8.
[18]Ambros V.The functions of animal microRNAs.Nature.2004;431:350-5.
[19]Lin SL,Chang D,Wu DY,Ying SY.A novel RNA splicing-mediated gene silencing mechanism potential for genome evolution.Biochem Biophys Res Commun.2003;310:754-60.
[20]Han J,Lee Y,Yeom KH,Kim YK,Jin H,Kim VN.The Drosha-DGCR8 complex in primary microRNA processing.Genes Dev.2004;18:3016-27.
[21]Lee Y,Ahn C,Han J et al.The nuclear RNase Ⅲ Drosha initiates microRNA processing.Nature.2003;425:415-9.
[22]Gregory RI,Yan KP,Amuthan G et al.The Microprocessor complex mediates the genesis of microRNAs.Nature.2004;432:235-40.
[23]Ohrt T,Merkle D,Birkenfeld K,Echeverri CJ,Schwille P.In situ fluorescence analysis demonstrates active siRNA exclusion from the nucleus by Exportin 5.Nucleic Acids Res.2006;34:1369-80.
[24]Zeng Y,Cullen BR.Structural requirements for pre-microRNA binding and nuclear export by Exportin 5.Nucleic Acids Res.2004;32:4776-85.
[25]Ketting RF,Fischer SE,Bernstein E,Sijen T,Hannon GJ,Plasterk RH.Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C.elegans.Genes Dev.2001;15:2654-9.
[26]Lim LP,Lau NC,Weinstein EG et al.The microRNAs of Caenorhabditis elegans.Genes Dev.2003;17:991-1008.
[27]Okamura K,Ishizuka A,Siomi H,Siomi MC.Distinct roles for Argonaute proteins in small RNA-directed RNA cleavage pathways.Genes Dev.2004;18:1655-66.
[28]Michael MZ,SM OC,van Hoist Pellekaan NQ Young GP,James RJ.Reduced accumulation of specific microRNAs in colorectal neoplasia.Mol Cancer Res.2003;1:882-91.
[29]Wang H,Ach RA,Curry B.Direct and sensitive miRNA profiling from low-input total RNA.RNA.2007;13:151-9.
[30]Chan JA,Krichevsky AM,Kosik KS.MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells.Cancer Res.2005;65:6029-33.
[31]Takamizawa J,Konishi H,Yanagisawa K et al.Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival.Cancer Res.2004;64:3753-6.
[32]Eis PS,Tam W,Sun L et al.Accumulation of miR-155 and BIC RNA in human β cell lymphomas.Proc Natl Acad Sci USA.2005;102:3627-32.
[33]Tam W,Hughes SH,Hayward WS,Besmer P.Avian bic,a gene isolated from a common retroviral site in avian leukosis virus-induced lymphomas that encodes a noncoding RNA,cooperates with c-myc in lymphomagenesis and erythroleukemogenesis.J Virol.2002;76:4275-86.
[34]Costinean S,Zanesi N,Pekarsky Yet al.Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice.Proc Natl Acad Sci U S A.2006;103:7024-9.
[35]Voorhoeve PM,le Sage C,Schrier M et al.A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors.Cell.2006;124:1169-81.
[36]Felli N,Fontana L,Pelosi E et al.MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation.Proc Natl Acad Sci U S A.2005;102:18081-6.
[37]He H,Jazdzewski K,Li W et al.The role of microRNA genes in papillary thyroid carcinoma.Proc Natl Acad Sci USA.2005;102:19075-80.
[38]Nicholson DW.Caspase structure,proteolytic substrates,and function during apoptotic cell death.Cell Death Differ.1999;6:1028-42.
[39]He L,Thomson JM,Hemann MT et al.A microRNA polycistron as a potential human oncogene.Nature.2005;435:828-33.
[40]O'Dormell KA,Wentzel EA,Zeller KI,Dang CV,Mendell JT.c-Myc-regulated microRNAs modulate E2F1 expression.Nature.2005;435:839-43.
[41]Woods K,Thomson JM,Hammond SM.Direct regulation of an oncogenic micro-RNA cluster by E2F transcription factors.J Biol Chem.2007;282:2130-4.
[42]Hayashita Y,Osada H,Tatematsu Yet al.A polycistronic microRNA cluster,miR-17-92,is overexpressed in human lung cancers and enhances cell proliferation.Cancer Res.2005;65:9628-32.
[43]Matsubara H,Takeuchi T,Nishikawa E et al.Apoptosis induction by antisense oligonucleotides against miR-17-5p and miR-20a in lung cancers overexpressing miR-17-92.Oncogene.2007;26:6099-105.
[44]Cheng AM,Byrom MW,Shelton J,Ford LP.Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis.Nucleic Acids Res.2005;33:1290-7.
[45]Calin GA,Croce CM.MicroRNA signatures in human cancers.Nat Rev Cancer.2006;6:857-66.
[46]Brueckner B,Stresemann C,Kuner R et al.The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function.Cancer Res.2007;67:1419-23.
[47]Mayr C,Hemann MT,Bartel DP.Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation.Science.2007;315:1576-9.
[48]Lee YS,Dutta A.The tumor suppressor microRNA let-7 represses the HMGA2 oncogene.Genes Dev.2007;21:1025-30.
[49]Hebert C,Norris K,Scheper MA,Nikitakis N,Sauk JJ.High mobility group A2 is a target for miRNA-98 in head and neck squamous cell carcinoma..Mol Cancer.2007;6:5.
[50]Akao Y,Nakagawa Y,Naoe T.let-7 microRNA functions as a potential growth suppressor in human colon cancer cells.Biol Pharm Bull.2006;29:903-6.
[51]Johnson SM,Grosshans H,Shingara J et al.RAS is regulated by the let-7 microRNA family.Cell.2005;120:635-47.
[52]Meng F,Henson R,Wehbe-Janek H,Smith H,Ueno Y,Patel T.The MicroRNA let-7a modulates interleukin-6-dependent STAT-3 survival signaling in malignant human cholangiocytes.J Biol Chem.2007;282:8256-64.
[53]Bottoni A,Piccin D,Tagliati F,Luchin A,Zatelli MC,degli Uberti EC.miR-15a and miR-16-1down-regulation in pituitary adenomas.J Cell Physiol.2005;204:280-5.
[54]Cimmino A,Calin GA,Fabbri Met al.miR-15 and miR-16 induce apoptosis by targeting BCL2.Proc Natl Acad Sci USA.2005;102:13944-9.
[55]Garzon R,Pichiorri F,Palumbo T et al.MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukemia.Oncogene.2007;26:4148-57.
[56]Ciafre SA,Galardi S,Mangiola Aet al.Extensive modulation of a set of microRNAs in primary glioblastoma.Biochem Biophys Res Commun.2005;334:1351-8.
[57]Pekarsky Y,Santanam U,Cimmino Aet al.Tcll expression in chronic lymphocytic leukemia is regulated by miR-29 and miR-181.Cancer Res.2006;66:11590-3.
[58]Mott JL,Kobayashi S,Bronk SF,Gores GJ.mir-29 regulates Mcl-1 protein expression and apoptosis.Oncogene.2007;26:6133-40.
[59]Bandres E,Cubedo E,Agirre X et al.Identification by Real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues.Mol Cancer.2006;5:29.
[60]Akao Y,Nakagawa Y,Naoe T.MicroRNAs 143 and 145 are possible common onco-microRNAs in human cancers.Oncol Rep.2006;16:845-50.
[61]Laneve P,Di Marcotullio L,Gioia U et al.The interplay between microRNAs and the neurotrophin receptor tropomyosin-related kinase C controls proliferation of human neuroblastoma cells.Proc Natl Acad Sci USA.2007;104:7957-62.
[62]Chen Y,Stallings RL.Differential patterns of microRNA expression in neuroblastoma are correlated with prognosis,differentiation,and apoptosis.Cancer Res.2007;67:976-83.
[63]Welch C,Chen Y,Stallings RL.MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells.Oncogene.2007;26:5017-22.
[64]Chang TC,Wentzel EA,Kent OA et al.Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis.Mol Cell.2007;26:745-52.
[65]Nervi C,Fazi F,Rosa A,Fatica A,Bozzoni I.Emerging role for microRNAs in acute promyelocytic leukemia.Curr Top Microbiol Immunol.2007;313:73-84.
[66]Wu L,Belasco JG Micro-RNA regulation of the mammalian lin-28 gene during neuronal differentiation of embryonal carcinoma cells.Mol Cell Biol.2005;25:9198-208.
[67]Lee YS,Kim HK,Chung S,Kim KS,Dutta A.Depletion of human micro-RNA miR-125b reveals that it is critical for the proliferation of differentiated cells but not for the down-regulation of putative targets during differentiation.J Biol Chem.2005;280:16635-41.
[68]Moss EG,Tang L.Conservation of the heterochronic regulator Lin-28,its developmental expression and microRNA complementary sites.Dev Biol.2003;258:432-42.
[69]Lowery AJ,Miller N,McNeill RE,Kerin MJ.MicroRNAs as prognostic indicators and therapeutic targets:potential effect on breast cancer management.Clin Cancer Res.2008;14:360-5.
[70]Adams BD,Guttilla IK,White BA.Involvement of microRNAs in breast cancer.Semin Reprod Med.2008;26:522-36.
[71]Iorio MV,Casalini P,Tagliabue E,Menard S,Croce CM.MicroRNA profiling as a tool to understand prognosis,therapy response and resistance in breast cancer.Eur J Cancer.2008;44:2753-9.
[72]Gabriely G,Wurdinger T,Kesari S et al.MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators.Mol Cell Biol.2008;28:5369-80.
[73]Yanaihara N,Caplen N,Bowman E et al.Unique microRNA molecular profiles in lung cancer diagnosis and prognosis.Cancer Cell.2006;9:189-98.
[74]Venturini L,Battmer K,Castoldi M et al.Expression of the miR-17-92 polycistron in chronic myeloid leukemia (CML) CD34+ cells.Blood.2007;109:4399-405.
[75]Iorio MV,Ferracin M,Liu CG et al.MicroRNA gene expression deregulation in human breast cancer.Cancer Res.2005;65:7065-70.
[76]Lu J,Getz G,Miska EA et al.MicroRNA expression profiles classify human cancers.Nature.2005;43S:834-8.
[77]Nelson PT,Baldwin DA,Kloosterman WP,Kauppinen S,Plasterk RH,Mourelatos Z.RAKE and LNA-ISH reveal microRNA expression and localization in archival human brain.RNA.2006;12:187-91.
[78]Chen CZ.MicroRNAs as oncogenes and tumor suppressors.NEngl JMed.2005;353:1768-71.
[79]Weiler J,Hunziker J,Hall J.Anti-miRNA oligonucleotides(AMOs):ammunition to target miRNAs implicated in human disease? Gene Ther.2006;13:496-502.
[80]Esau CC,Monia BP.Therapeutic potential for microRNAs.Adv Drug Deliv Rev.2007;59:101-14.
[81]Esau CC.Inhibition of microRNA with antisense oligonucleotides.Methods.2008;44:55-60.
[82]Shen Y.Advances in the development of siRNA-based therapeutics for cancer.IDrugs.2008;11:572-8.
[83]Devi GR.siRNA-based approaches in cancer therapy.Cancer Gene Ther.2006;13:819-29.
[84]Maher EA,Furnari FB,Bachoo RM et al.Malignant glioma:genetics and biology of a grave matter.Genes Dev.2001;15:1311-33.
[85]Fumari FB,Fenton T,Bachoo RM et al.Malignant astrocytic glioma:genetics,biology,and paths to treatment.Genes Dev.2007;21:2683-710.
[86]Ohgaki H.Epidemiology of brain tumors.Methods Mol Biol.2009;472:323-42.
[87]Medina R,Zaidi SK,Liu CG et al.MicroRNAs 221 and 222 bypass quiescence and compromise cell survival.Cancer Res.2008;68:2773-80.
[88]Gillies JK,Lorimer IA.Regulation of p27Kipl by miRNA 221/222 in glioblastoma.Cell Cycle.2007;ti:2005-9.
[89]Silber J,Lim DA,Petritsch C et al.miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells.BMCMed.2008;6:14.
[90]Kefas B,Godlewski J,Comeau L et al.microRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma.Cancer Res.2008;68:3566-72.
[91]Reddy SD,Ohshiro K,Rayala SK,Kumar R.MicroRNA-7,a homeobox D10 target,inhibits p21-activated kinase 1 and regulates its functions.Cancer Res.2008;68:8195-200.
[92]Godlewski J,Nowicki MO,Bronisz Aet al.Targeting of the Bmi-1 oncogene/stem cell renewal factor by microRNA-128 inhibits glioma proliferation and self-renewal.Cancer Res.2008;68:9125-30.
[93]Zhang Y,Chao T,Li R et al.MicroRNA-128 inhibits glioma cells proliferation by targeting transcription factor E2F3a.JMol Med.2009;87:43-51.
[94]Shi L,Cheng Z,Zhang Jet al.hsa-mir-181a and hsa-mir-181b function as tumor suppressors in human glioma cells.Brain Res.2008;1236:185-93.
[95]Corsten MF,Miranda R,Kasmieh R,Krichevsky AM,Weissleder R,Shah K.MicroRNA-21 knockdown disrupts glioma growth in vivo and displays synergistic cytotoxicity with neural precursor cell delivered S-TRAIL in human gliomas.Cancer Res.2007;67:8994-9000.