表明，miR-21可不仅通过抑制程序性细胞死亡因子4 这一凋亡因子的表达，也可通过下调SPRY2进而激活原癌基因Ras下游的MEK/ERK，最终引起miR-21自身转录从而抑制凋亡，促进增殖。 3.3.miR-92b与肿瘤
有研究者发现miR-92b定位于染色体13q31.3。miR-92b能够抑制PRMT的表达，一种甲基化转移酶，进而导致一些抗肿瘤基因表观遗传学的改变，从而有利于肿瘤发生，同时其在脑肿瘤中的高表达也暗示其有利于肿瘤的发生[21]。Nass等[22]发现miRNA-92b在原发性脑部肿瘤中表达较高，可以用来区分转移性脑肿瘤和原发灶。Haug等[23]使用miRNA的靶基因预测软件，发现一些MYCN基因调控miRNA可能的靶标是miRNA-92b。 3.4.miR-155与肿瘤
人们最初发现，BIC基因与淋巴瘤发生有关，之后发现在C基因保守区域内包含miR-155的miRNA前体。miR-155的表达水平在Burkitt淋巴瘤中增高约100倍，在霍杰金淋巴瘤和弥漫性大B细胞淋巴瘤中表达水平也显著增高[24]。miR-155 由BIC基因编码，是最早发现的致癌miRNA之一，最初发现其在儿童Burkitt' s( 伯基特)淋巴瘤中表达上调，在进行了miR-155转基因培育的小鼠中miR-155 可以诱导B细胞淋巴瘤的发生[25]，目前众多研究表明其在霍奇金病、cLL、急性髓性白血病、肺癌、乳腺癌以及胰腺癌等肿瘤中均高表达，且起着致癌基因的作用。机制研究表明，miR-155 通过下调Ship和c/EBPβ的表达导致一系列连锁反应，最终导致前B细胞的蓄积以及急性淋巴细胞性白血病的形成[26] 。Rai等[27]也发现在弥漫性大B细胞淋巴瘤中42种基因的下调都与miR-155的高表达相关，预测其中的9个基因为miR-155的靶基因，这些靶基因中一些涉及到免疫系统和致癌作用。SHIP1就是其中的一个靶基因，TNF-α拮抗剂可以有效的降低miR-155 的表达，恢复SHIP1表达水平抑制肿瘤细胞增殖3.5.miR-224与肿瘤
有研究对肝细胞癌组织和正常组织miRNAs表达谱进行分析，发现miR-224在肝癌组织中较正常组织表达明显升高。参与调节肝癌细胞的增殖与凋亡、迁移与侵袭等生物学过程，对肝癌细胞的迁移和侵袭力有明显的促进作用，并且发现miR-224与PAK4和MMP-9等肿瘤迁移侵袭相关分子的表达具有明显的相关性[29]。
[28]
。
Lee等[30]发现miR-224通过负性调控靶基因凋亡抑制剂-5(API-5)的表达，参与肝癌细胞凋亡的调节。以上研究表明异常表达的miR-224可能参与肝癌细胞的凋亡、增殖等生物学过程。
从miRNA与肿瘤的关系中可以看出，miRNA主要扮演了两种角色：肿瘤促进因子和肿瘤抑制因子。目前已知的人类的miRNA有300多条，随着对miRNA研究的深入将会发现更多的与肿瘤相关的miRNA，并以此为基础研究治疗肿瘤的新方法。
4.总结与展望
随着对miRNA实验技术和生物信息学的发展，会有越来越多的miRNA被发现，miRNA与肿瘤之间的关系也会被进一步揭示。miRNA的实验技术和生物信息学研究将在肿瘤的治疗中发挥不可估量的作用。但是已被证实的和已明确功能的miRNA 的数量还是很少。由于miRNA靶基因的多样性以及研究手段的限制，对于miRNA作用于肿瘤细胞的机制还尚未清楚，还有待进一步的研究，但从目前的研究成果来看，运用miRNA治疗肿瘤并非是天方夜谭。
参考文献
[1].Lee RC,Feinbaum RL,Ambros V.The C.elegans heterochronic gene lin-4 encods small RNAs with antisense complementarity to lin-4[J].Cell,1993,75:843-854.
[2].Reinhart BJ,Slack BJ,Basson M,et a1.The 21 nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans[J].Nature,2000,403(6772):901-906. [3].Yi R,Poy MN,Stoffel M, et al. A skin microRNA promotes differentiation byrepressing 'stemness'[J]. Nature,2008,452:225-229.
[4].Ambros V , Lee R C , Lavanway A , et al . MicroRNAs and other tiny endogenous RNAs in C. elegans [J].Curr Biol,2003,13(10):807-818.
[5]. Meister G, Landthaler M, Dorsett Y, et al . Sequence-specific inhibition of microRNA- and siRNA-induced RNA silencing[J].RNA,2004,10: 544-550.
[6].Reuland SN,Smith SM,Bemis LT,et al.MicroRNA-26a Is Strongly Downregulated in
Melanoma and Induces Cell Death through Repression of Silencer of Death Domains (SODD)[J].Journal of Investigative Dermatology,2012,doi:10.1038/jid.2012.400. [7].Zeng Y, Cai X, Cullen BR,et al.Use of RNA polymerase Ⅱ to transcribe artificial microRNAs [J].Methods Enzymol,2005,392:371-380.
[8].Lim LP , Glasner ME , Yekta S , et al . Vertebrate microRNA genes[J].Science, 2003, 299(5612) :1540。
[9].Wienholds E, Kloosterman WP, Miska E,et al.MicroRNA expression in zebrafish embryonic development[J].Science, 2005,309(5732):310-311.
[10].Lin L, Chen L, Xu YX, et al.MicroRNA-195 promotes apoptosis and suppresses tumorigenicity of human colorectal cancer cells [J]. Biochemical and Biophysical Research Communications,2010,400(2): 236-240.
[11].Lee KH,Goan YG, Hsiao M,et al. MicroRNA-373(miR-373) post-transcriptionally regulates large tumor suppressor,homolog 2 (LATS2) and stimulates proliferation in human esophageal cancer[J]. Experimental cell research, 2009,315(15): 2529-2538. [12].Cummins JM, He Y, Leary RJ,et al. The colorectal microRNAome [J].Proc Natl Acad Sci USA,2006,103(10):3687-3692.
[13].Calin GA, Sevignani C, Dumitru CD, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers[J]. Proc Natl Acad Sci,2004,101(9):2999-3004.
[14].Calin GA,Dutimru CD,Shmiziu M,el at.Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia[J].Proc Natl Acad Sci,2002,99(24):15524-15529.
[15]. Cimmino A,Calin GA，Fabbri M，et al．miR-15 and miR-16 induce apotosis by targeting BCL2[J].Proc Natl Acad Sci USA,2005,102(39):13944-13949.
［16].Fabbri M，Bottoni A，Shimizu M， et al． Association of a microRNA/TP53 feedback circuitry with pathogenesis and outcome of B-cell chronic lymphocytic leukemia［J］．JAMA,2011,305(1):59-67．
[17].Corsten MF,Miranda R, Kasmieh R, et al. MicroRNA-21 Knockdown Disrupts Glioma Growth In vivo and Displays Synergistic Cytotoxicity with Neural Precursor Cell–Delivered S-TRAIL in Human Gliomas [J].Can cer Res,2007,67(19) :8994- 9000. [18].Zhou X, Ren Y, Moore L, et al.Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cellsindependent of PTEN status[J].Laboratory Investigation,2010,90:144–155.
[19].Gee HE,Camps C,Buffa FM,et al. MicroRNA-10b and breast cancer metastasis[J].
Nature,2008,455: E8-E9.
[20].Hatley ME，Patrick DM，Garcia MR,et al． Modulation of K-Ras-dependent lung tumorigenesis by MicroRNA-21［J].Cancer Cell,2010,18(3):282-293．
[21].Pal S,Baiocchi RA,Byrd JC,et al.Low levels of miR-92b/96 induce PRMT5 translation and H3R8/H4R3 methylation in mantle cell lymphoma[J].The EMBO Journal ,2007, 26(15):3558–3569.
[22].Nass D,Meiri E,Gilad S,et al.MiR-92b and miR-9/9* are specifically expressed in brain primary tumors and can be used to differentiate primary from metastatic brain tumors[J].Brain Pathol,2009,19(3):375-383.
[23].Haug BH,Henriksen JR,Buechner J,et al.MYCN-regulated miRNA-92 inhibits secretion of the tumor suppressor DICKKOPF-3 (DKK3) in neuroblastoma [J].Carcinogenesis,2011,32(7):1005-1012.
[24].Metzler M,Wilda M,Busch K,et al.High expression of precursor microRA-155/BIC RNA in children with Burkitt lymphoma[J].Genes Chromosomes Cancer,2004,39(2):167- 169.
[25].Costinean S,Zanesi N,Pekarsky Y,et al.Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in Eμ-miR155 transgenic mice[J].Proc Natl Acad Sci USA, 2006,103(18): 7024-7029.
［26].Costinean S，Sandhu SK，Pedersen IM，et al．Src homology 2 domain–containing inositol-5-phosphatase and CCAAT enhancer-binding protein β are targeted by miR-155 in B cells of Eμ-MiR-155 transgenic mice [J]．Blood，2009,114(7): 1374-1382． [27].Rai D,Karanti S,Jung I, et al.Coordinated expression of microRNA-155 and predicted target genes in diffuse large B-cell lymphoma [J].Cancer Genet Cytogenet, 2008,181(1): 8-15.
[28].Pedersen IM ,Otero D,Kao E,et al.Onco-miR-155 targets SHIP1 to promote TNFa-dependent growth of B cell lymphomas[J]. EMBO Mol Med, 2009, 1(5): 288-295. [29] 李琼，王阁，杨志祥,等. MicroRNA224在HepG2细胞中高表达及其靶基因的生物学预测，中华消化外科杂志[J],2008,7(4),297-299.
[30].Wang Y,Lee AT , Ma JZ,et al . Profiling microRNA expression in hepatocelluar
carcinoma reveals microRNA-224 up-regulation and apoptosis inhibitor-5 as a microRNA-224 specific target[J].J Biol Chem,2008,283:13205-13215.