臨床整形外科46巻5号

2011年05月発行

最新基礎科学/知っておきたい

マイクロRNAの基礎と応用

著者： 高田修治¹

所属機関： ¹独立行政法人国立成育医療研究センター研究所システム発生・再生医学研究部ゲノム機能研究室

ページ範囲：P.418 - P.423

■はじめに

　マイクロRNA(microRNA，miRNA)は内在性の20-24塩基長程の低分子RNAで，メッセンジャーRNA(mRNA)の3'UTRに不完全ながら塩基配列特異的に認識した場合にはそのmRNAの翻訳抑制，完全一致に認識した場合にはmRNAを切断することにより機能している(図1)．本稿執筆時，ヒトにおいてはゲノム中に約1,000のマイクロRNAがデータベースに登録されている(http://www.mirbase.org/)．マイクロRNAは個体の発生や細胞の増殖，癌化，疾病への関与が明らかになってきており，診断や核酸医薬などの観点からも注目されている．本稿ではマイクロRNAの生合成や解析方法などの基礎と，炎症やリウマチへの関与と将来診断や創薬への可能性を秘めたその応用について概説する．

参考文献

1) Lee Y, Kim M, Han J, et al:MicroRNA genes are transcribed by RNA polymerase II. EMBO J 23:4051-4060, 2004

2) Lee Y, Ahn C, Han J, et al:The nuclear RNase III Drosha initiates microRNA processing. Nature 425:415-419 2003

3) Yi R, Qin Y, Macara IG, et al:Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev 17:3011-3016, 2003

4) Lund E, Guttinger S, Calado A, et al:Nuclear export of microRNA precursors. Science 303:95-98, 2004

5) Bernstein E, Caudy AA, Hammond SM, et al:Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409:363-366, 2001

6) Hutvagner G, Zamore PD:A microRNA in a multipleturnover RNAi enzyme complex. Science 297:2056-2060, 2002

7) Gregory RI, Chendrimada TP, Cooch N, et al:Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell 123:631-640, 2005

8) Bass BL:RNA editing by adenosine deaminases that act on RNA. Annu Rev Biochem 71:817-846, 2002

9) Schmauss C, Howe JR:RNA editing of neurotransmitter receptors in the mammalian brain. Sci STKE 2002:PE26, 2002

10) Liu CG, Calin GA, Meloon B, et al:An oligonucleotide microchip for genome-wide microRNA profiling in human and mouse tissues. Proc Natl Acad Sci U S A 101:9740-9744, 2004

11) Thomson JM, Parker J, Perou CM, et al:A custom microarray platform for analysis of microRNA gene expression. Nat Methods 1:47-53, 2004

12) Nelson PT, Baldwin DA, Scearce LM, et al:Microarray-based, high-throughput gene expression profiling of microRNAs. Nat Methods 1:155-161, 2004

13) Babak T, Zhang W, Morris Q, et al:Probing microRNAs with microarrays:tissue specificity and functional inference. RNA 10:1813-1819, 2004

14) Barad O, Meiri E, Avniel A, et al:MicroRNA expression detected by oligonucleotide microarrays:system establishment and expression profiling in human tissues. Genome Res 14:2486-2494, 2004

15) Lagos-Quintana M, Rauhut R, Yalcin A, et al:Identification of tissue-specific microRNAs from mouse. Curr Biol 12:735-739, 2002

16) Takada S, Berezikov E, Yamashita Y, et al:Mouse microRNA profiles determined with a new and sensitive cloning method. Nucleic Acids Res 34:e115, 2006

17) Motameny S, Wolters S, Nurnberg P, et al:Next generation sequencing of miRNAs ― strategies, resources and methods. Genes 1:70-84, 2010

18) Varallyay E, Burgyan J, Havelda Z:MicroRNA detection by northern blotting using locked nucleic acid probes. Nat Protoc 3:190-196, 2008

19) Valoczi A, Hornyik C, Varga N, et al:Sensitive and specific detection of microRNAs by northern blot analysis using LNA-modified oligonucleotide probes. Nucleic Acids Res 32:e175, 2004

20) Krutzfeldt J, Rajewsky N, Braich R, et al:Silencing of microRNAs in vivo with ‘antagomirs'. Nature 438:685-689, 2005

21) Bernstein E, Kim SY, Carmell MA, et al:Dicer is essential for mouse development. Nat Genet 35:215-217, 2003

22) Harfe BD, McManus MT, Mansfield JH, et al:The RNaseIII enzyme dicer is required for morphogenesis but not patterning of the vertebrate limb. Proc Natl Acad Sci U S A 102:10898-10903, 2005

23) Kanellopoulou C, Muljo SA, Kung AL, et al:Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. Genes Dev 19:489-501, 2005

24) Murchison EP, Partridge JF, Tam OH, et al:Characterization of Dicer-deficient murine embryonic stem cells. Proc Natl Acad Sci U S A 102:12135-12140, 2005

25) Mudhasani R, Zhu Z, Hutvagner G, et al:Loss of miRNA biogenesis induces p19Arf-p53 signaling and senescence in primary cells. J Cell Biol 181:1055-1063, 2008

26) Lewis BP, Shih IH, Jones-Rhoades MW, et al:Prediction of mammalian microRNA targets. Cell 115:787-798, 2003

27) Krek A, Grun D, Poy MN, et al:Combinatorial microRNA target predictions. Nat Genet 37:495-500, 2005

28) Lu J, Getz G, Miska EA, et al:MicroRNA expression profiles classify human cancers. Nature 435:834-838, 2005

29) Esquela-Kerscher A, Slack FJ:Oncomirs ― microRNAs with a role in cancer. Nat Rev Cancer 6:259-269, 2006

30) Hebert SS, Horre K, Nicolai L, et al:Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/beta-secretase expression. Proc Natl Acad Sci U S A 105:6415-6420, 2008

31) Saba R, Goodman CD, Huzarewich RL, et al:A miRNA signature of prion induced neurodegeneration. PLoS ONE 3e:3652, 2008

32) Sayed D, Hong C, Chen IY, et al:MicroRNAs play an essential role in the development of cardiac hypertrophy. Circ Res 100:416-424, 2007

33) Thum T, Gross C, Fiedler J, et al:MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456:980-984, 2008

34) Morton SU, Scherz PJ, Cordes KR, et al:microRNA-138 modulates cardiac patterning during embryonic development. Proc Natl Acad Sci U S A 105:17830-17835, 2008

35) Poy MN, Eliasson L, Krutzfeldt J, et al:A pancreatic islet- specific microRNA regulates insulin secretion. Nature 432:226-230, 2004

36) Tang X, Tang G, Ozcan S:Role of microRNAs in diabetes. Biochim Biophys Acta 1779:697-701, 2008

37) Lovis P, Roggli E, Laybutt DR, et al:Alterations in microRNA expression contribute to fatty acid- induced pancreatic beta-cell dysfunction. Diabetes 57:2728-2736, 2008

38) Pfeffer S, Zavolan M, Grasser FA, et al:Identification of virus-encoded microRNAs. Science 304:734-736, 2004

39) Pfeffer S, Sewer A, Lagos-Quintana M, et al:Identification of microRNAs of the herpesvirus family. Nat Methods 2:269-276, 2005

40) Ghosh Z, Mallick B, Chakrabarti J:Cellular versus viral microRNAs in host- virus interaction. Nucleic Acids Res 37:1035-1048, 2009

41) Tan Z, Randall G, Fan J, et al:Allele-specific targeting of microRNAs to HLA-G and risk of asthma. Am J Hum Genet 81:829-834, 2007

42) Stanczyk J, Pedrioli DM, Brentano F, et al:Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum 58:1001-1009, 2008

43) Nakasa T, Miyaki S, Okubo A, et al:Expression of microRNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheum 58:1284-1292, 2008

44) Taganov KD, Boldin MP, Chang KJ, et al:NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A 103:12481-12486, 2006

45) Miyaki S, Nakasa T, Otsuki S, et al:MicroRNA-140 is expressed in differentiated human articular chondrocytes and modulates interleukin-1 responses. Arthritis Rheum 60:2723-2730, 2009

46) Iliopoulos D, Malizos KN, Oikonomou P, et al:Integrative microRNA and proteomic approaches identify novel osteoarthritis genes and their collaborative metabolic and inflammatory networks. PLoS One 3:e3740, 2008

47) Miyaki S, Sato T, Inoue A, et al:MicroRNA-140 plays dual roles in both cartilage development and homeostasis. Genes Dev 24:1173-1185, 2010

48) Kosaka N, Iguchi H, Ochiya T:Circulating microRNA in body fluid:a new potential biomarker for cancer diagnosis and prognosis. Cancer Sci 101:2087-2092, 2010

49) Lawrie CH, Gal S, Dunlop HM, et al:Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br J Haematol 141:672-675, 2008

50) Kosaka N, Izumi H, Sekine K, et al:microRNA as a new immune-regulatory agent in breast milk. Silence 1:7, 2010

51) Michael A, Bajracharya SD, Yuen PS, et al:Exosomes from human saliva as a source of microRNA biomarkers. Oral Dis 16:34-38, 2010

52) Chen X, Ba Y, Ma L, et al:Characterization of microRNAs in serum:a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 18:997-1006, 2008

53) Watanabe T, Totoki Y, Toyoda A, et al:Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes. Nature 453:539-543, 2008

54) Soifer HS, Rossi JJ, Strom P:MicroRNAs in disease and potential therapeutic applications. Molecular Therapy 15:2070-2079, 2007

55) Elmen J, Lindow M, Schutz S, et al:LNA-mediated microRNA silencing in non-human primates. Nature 452:896-899, 2008