AJMB

Noncoding RNAs and Cancer

PDF - Export to EndNote - PubMed Central XML format - PubMed Central XML format - PubMed Central XML format
PMID: 23407615 (PubMed) - PMCID: PMC3558126 - View online: PubReader
Volume 1, Issue 2, July-September , Page 55 to 70
Monday, August 10, 2009 :Received , Thursday, September 10, 2009 :Accepted

  • Corresponding author Ph.D., Reproductive Bio-technology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran, P.O. Box: 19615-1177, Tel: +98 21 22432020, Fax: +98 21 22432021, E-mail: Ardekani@avicenna.ac.ir
    - Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR , Tehran, Iran

Abstract: The eukaryotic complexity involves the expression and regulation of genes via RNA-DNA, RNA-RNA, DNA-protein and RNA-protein interactions. Recently, the role of RNA molecules in the regulation of genes in higher organisms has become more evident, especially with the discovery that about 97% of the transcriptional output in higher organisms are represented as noncoding RNAs: rRNA, snoRNAs, tRNA, transposable elements, 5' and 3' untranslated regions, introns, intergenic regions and microRNAs. MicroRNAs function by negatively regulating gene expression via degradation or translational inhibition of their target mRNAs and thus participate in a wide variety of physiological and pathological cellular processes including: development, cell proliferation, differentiation, and apoptosis pathways. MicroRNA expression profiles in many types of cancers have been identified. Recent reports have revealed that the expression profiles of microRNAs change in various human cancers and appear to function as oncogenes or tumor suppressors. Abnormal microRNA expression has increasingly become a common feature of human cancers. In this review, we summarize the latest progress on the involvement of microRNAs in different types of cancer and their potential use as potential diagnostic and prognostic tumor biomarkers in the future.

 

 

Introduction :
Ambros et al found lin-4, a gene which controls the timing of larval development of Caenorhabditis elegans (C. elegans) in 1993. But, the product of this gene was not any protein; instead it produced a pair of small RNAs (1). The longer RNA is 70 nucleotides (nt) that can shape a stem-loop structure and is the precursor of the shorter RNA (22 nt) that is now known as a member of the class of microRNA genes (2). MicroRNAs (miRNAs) are a novel class of endogenous small, non-coding RNAs (ncRNAs) that control gene expression by targeting specific mRNAs for degradation and/or translational repression (3). At the time it appeared that lin-4 was restric-ted to C. elegans because of lack of homology with other species. However, when the second miRNA gene (let-7) with its target miRNA gene (lin-41), was discovered in 2000, it became clear that these miRNA genes are conserved in many species (4). After that, a great number of microRNAs have been identified in mammals (5).
Many members of ncRNAs are part of the functional classes such as miRNAs and small nucleolar RNAs (snoRNAs) that are well conserved in various species. This is because: a) RNAs in both classes function by hybridi-zation to other nucleic acids b) many of the miRNAs have different cellular targets (6) that confine their chance for sequence co-variation and tendency to evolution. Regarding snoRNAs, they encode sequences and struc-tures that mediate binding of compatible RNA-modifying enzymes to the snoRNA tar-get RNA complex, and this further limits se-quence change (7).
miRNAs along with a large set of ncRNAs are known as ‘‘gene regulators’’ that include: Air, H19, Ipw, NTT, Tsix and XIST in mammals and have various functions from potential involvement in the imprinting pro-cess to X-chromosome inactivation in mam-mals (8). Multiple steps and specific cellular machinery are involved in the biogenesis of miRNAs (9). The miRNAs are encoded as short inverted repeats having a double-stranded RNA (dsRNA) stem loop about 70 bp long and are found in both introns and intergenic clusters in the genome (9). The introns and exons of both protein-coding and non coding transcripts are synthesized by RNA polymerase II from where miRNAs are derived (10). In the nucleus, miRNAs are transcribed as primary pri miRNA transcripts, and then they are processed to shape the precursor pre-miRNA stem loop structure and then is transported to the cytoplasm by RanGTP and Exportin 5 where they are cleaved by the Dicer RNAase III endonuclease and produce mature miRNA (21-23 nt) (11).

Human genome and microRNAs
Development, differentiation, growth, and metabolism are regulated by miRNAs and about 500 known miRNA genes are reported to be encoded by the mammalian genome (12). It is estimated that miRNAs regulate about one third of the genes in human genome (13). How the transcription of miRNAs are regula-ted in the cell is not precisely known However, the transcription of miRNAs are known to depend on their localization within the genome and their proximity to host genes and their locations in introns of coding genes, noncoding genes and exons (14). Recent studies have shown that miRNAs are organized in clusters and share the same transcriptional regulation and if having their own promoters, miRNAs are independently expressed (15, 16).
Approximately 50% of miRNAs are trans-cribed from non-protein-coding genes, and the rest are in the introns of coding genes (12). In higher organisms, about 97% of the trans-criptional product is non-coding RNA (ncRNA) which consist of rRNA, tRNA, introns, 5’ and 3’ untranslated regions, trans-posable elements, and intergenic regions, and a large family known as microRNAs, some of which can down-regulate large numbers of target mRNAs (3, 17). Recently, a number of mammalian miRNAs have been reported to be derived from DNA repeats and transposons (18). This finding has lead to a re-evaluation of the functional role of transposons, esp

 



Figure 1. Coding and Non-coding DNA in human genome
Figure 1. Coding and Non-coding DNA in human genome




Table 1. Cancer-related miRNAs
Table 1. Cancer-related miRNAs




Table 2. Cancer-related miRNAs
Table 2. Cancer-related miRNAs




References :
  1. 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 (5):843-854.
  2. Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. Identification of novel genes coding for small expressed RNAs. Science 2001;294(5543): 853-858.
  3. Cinzia Sevignani,George A. Calin, Linda D. Siracusa, Carlo M. Croce. Mammalian micro RNAs: a small world for fine-tuning gene expres-sion. Mamm Genome 2006;17(3):189-202.
  4. Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kuroda MI, Maller B, et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 2000;408 (6808):86-89.
  5. Zhang C. MicroRNAs: role in cardiovascular boil-ogy and disease. Clin Sci 2008;114(12):699-706.
  6. Mattick JS, Makunin IV. Small regulatory RNAs in mammals. Hum Mol Genet 2005;14:R121-R132.
  7. Pang KC, Frith MC, Mattick JS. Rapid evolution of noncoding RNAs: lack of conservation does not mean lack of function. Trends Genet 2006;22(1):1-5.
  8. Mattick JS, Makunin IV. Non-coding RNA. Hum Mol Genet 2006;15:R17-R29.
  9. Hastings ML, Krainer AR. Pre-mRNA splicing in the new millennium. Curr Opin Cell Biol 2001;13 (3):302-309.
  10. Morey C, Avner P. Employment opportunities for non-coding RNAs. FEBS Lett 2004;567(1):27-34
  11. Bilen J, Liu N, Bonini NM. A new role for microRNA pathways: modulation of degeneration induced by pathogenic human disease proteins. Cell Cycle 2006;5(24):2835-2838.
  12. Saini HK, Griffiths-Jones S, Enright AJ. Genomic analysis of human microRNA transcripts. Proc Natl Acad Sci USA 2007;104(45):17719-17724.
  13. Urbich C, Kuehbacher A, Dimmeler S. Role of microRNAs in vascular diseases, inflammation, and angiogenesis. Cardiovasc Res 2008;79(4):581-588.
  14. Baskerville S, Bartel DP. Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes. RNA 2005; 11(3):241-247.
  15. Lee Y, Kim M, Han J, Yeom KH, Lee S, Baek SH, et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J 2004;23(20):4051-4060.
  16. Altuvia Y, Landgraf P, Lithwick G, Elefant N, Pfeffer S, Aravin A, et al. Clustering and conserva-tion patterns of human microRNAs. Nucleic Acids Res 2005;33(8):2697-2706.
  17. Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, et al. Microarray analysis shows that some microRNAs down-regulate large numbers of target mRNAs. Nature 2005;433 (7027):769-773.
  18. Smalheiser NR, Torvik VI. Mammalian miRNAs derived from genomic repeats. Trends Genet 2005; 21(6):322-326.
  19. Whitelaw E, Martin DI. Retrotransposons as epi-genetic mediators of phenotypic variation in mam-mals. Nat Genet 2001;27(4):361-365.
  20. Peaston AE, Evsikov AV, Graber JH, de Vries WN, Holbrook AE, Solter D, et al. Retro-transposons regulate host genes in mouse oocytes and preimplantation embryos. Dev Cell 2004;7(4): 597-606.
  21. Devor EJ. Primate microRNAs miR-220 and miR-492 lie within processed pseudogenes. J Hered 2006;97(2):186-190.
  22. A Herbert. The four Rs of RNA-directed evolu-tions. Nat Genet 2004;36(1):19-25.
  23. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. Initial sequencing and analysis of the human genome. Nature 2001;409 (6822):860-921.
  24. Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, et al. The sequence of the human genome. Science 2001;291(5507):1304-1351.
  25. Szymanski M, Barciszewska MZ, Erdmann VA, Barciszewski J. A new frontier for molecular medicine: Noncoding RNAs. Biochim Biophys Acta 2005;1756(1):65-75.
  26. Bartel D. MicroRNAs: genomics, biogenesis, mechanism, function. Cell 2004;116(2):281-297.
  27. Griffiths-Jones S, Saini HK, van Dongen S, Enright AJ. miRBase: tools for microRNA genom-ics. Nucleic Acids Res 2008;36:D154-D158.
  28. AE Erson, EM Petty. MicroRNAs in development and disease. Clin Genet 2008;74(4):296-306.
  29. Aukerman MJ, Sakai H. Regulation of flowering time and floral organ identity by a microRNA and its APETALA2-like target genes. Plant Cell 2003; 15(11):2730-2741.
  30. Chen CZ, Li L, Lodish HF, Bartel DP. MicroRNAs modulate hematopoietic lineage differentiation. Science 2004;303(5654):83-86.
  31. Lagos-Quintana M, Rauhut R, Meyer J, Borkhardt A, Tuschl T. New microRNAs from mouse and human. RNA 2003;9(2):175-179.
  32. Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, 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(24):15524-15529.
  33. Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, 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.
  34. Lynam-Lennon N, Maher SG, Reynolds JV. Reynolds. The roles of microRNA in cancer and apoptosis. Biol Rev Camb Philos Soc 2009;84(1): 55-71.
  35. Ruan K, Fang X, Ouyang G. MicroRNAs: Novel regulators in the hallmarks of human cancer. Cancer Lett 2009;(Epub ahead of print-available online).
  36. Zhang B, Pan X, Cobb GP, Anderson TA. Micro RNAs as oncogenes and tumor suppressors. Dev Biol 2007;302:1-12.
  37. He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang Y, et al. A microRNA component of the p53 tumor suppressor network. Nature 2007;447 (7148):1130-1134.
  38. Croce CM. Oncogenes and cancer. N Engl J Med 2008;358(5):502- 511.
  39. Bueno MJ, de Castro IP, Malumbres M. Control of cell proliferation pathways by microRNAs. Cell Cycle 2008;7(20):3143-3148.
  40. Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA 2005;102(39):13944-13949.
  41. Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 2005;120(4):513-522.
  42. Hahn WC, Weinberg RA. Modelling the molecular circuitry of cancer. Nat Rev Cancer 2002;2(5):331-341.
  43. Benetti R, Gonzalo S, Jaco I, Muñoz P, Gonzalez S, Schoeftner S, et al. A mammalian microRNA cluster controls DNA methylation and telomere recombination via Rbl2-dependent regulation of DNA methyltransferases. Nat Struct Mol Biol 2008;15(3):268-279.
  44. Lee DY, Deng Z, Wang CH, Yang BB. MicroRNA-378 promotes cell survival, tumor growth, and angiogenesis by targeting SuFu and Fus-1 expression. Proc Natl Acad Sci USA 2007; 104(51):20350-20355.
  45. Si ML, Zhu S, Wu H, Lu Z, Wu F, Mo YY. miR-21-mediated tumor growth. Oncogene 2007;26 (19):2799-2803.
  46. Yan LX, Huang XF, Shao Q, Huang MY, Deng L, Wu QL, et al. MicroRNA miR-21 over-expression in human breast cancer is associated with advanced clinical stage, lymph node metastasis and patient poor prognosis. RNA 2008;14(11):2348-2360.
  47. Zhu S, Wu H, Wu F, Nie D, Sheng S, Mo YY. MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Res 2008;18(3):350-359.
  48. Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S, et al. MicroRNA-21 (miR-21) post transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 2008;27(15):2128-2136.
  49. Huang Q, Gumireddy K, Schrier M, le Sage C, Nagel R, Nair S, et al. The microRNAs miR-373 and miR-520c promote tumor invasion and metastasis. Nat Cell Biol 2008;10(2):202-210.
  50. Tavazoie SF, Alarcón C, Oskarsson T, Padua D, Wang Q, Bos PD, et al. Endogenous human microRNAs that suppress breast cancer metastasis. Nature 2008;451(7175):147-152.
  51. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100(1):57-70.
  52. Pickering MT, Stadler BM, Kowalik TF. miR-17 and miR-20a temper an E2F1-induced G1 check point to regulate cell cycle progression. Oncogene 2009;28(1):140-145.
  53. Sevignani C, Calin GA, Nnadi SC, Shimizu M, Davuluri RV, Hyslop T, et al. MicroRNA genes are frequently located near mouse cancer suscepti-bility loci. Proc Natl Acad Sci USA 2007;104(19): 8017-8022.
  54. Sorlie T. Molecular portraits of breast cancer: tumour subtypes as distinct disease entities. Eur J Cancer 2004;40(18):2667-2675.
  55. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, et al. Race, breast cancer subtypes and survival in the Carolina Breast Cancer Study. JAMA 2006;295(21):2492-2502.
  56. Sempere LF, Christensen M, Silahtaroglu A, Bak M, Heath CV, Schwartz G, et al. Altered micro RNA expression confined to specific epithelial cell subpopulations in breast cancer. Cancer Res 2007;67(24):11612-11620.
  57. Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, et al. MicroRNA gene expression deregulation in human breast cancer. Cancer Res 2005;65(16):7065-7070.
  58. Negrini M, Rasio D, Hampton GM, Sabbioni S, Rattan S, Carter SL, et al. Definition and refine-ment of chromosome 11 regions of LOH in breast cancer: identification of a new region at 11q23-q24. Cancer Res 1995;55(14):3003-3007.
  59. Cannistra SA. Cancer of the ovary. N Engl J Med 2004;351(24):2519-2529.
  60. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics. CA Cancer J Clin 2001;51(1): 15-36.
  61. Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P, et al. MicroRNA signatures in human ovarian cancer. Cancer Res 2007;67(18): 8699-8707.
  62. Zhang L, Huang J, Yang N, Greshock J, Megraw MS, Giannakakis A, et al. MicroRNAs exhibit high frequency genomic alterations in human cancer. Proc Natl Acad Sci USA 2006;103(24):9136-9141.
  63. Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, et al. MicroRNA signatures in human ovarian cancer. Cancer Res 2007;67(18):8699-8707.
  64. Yang H, Kong W, He L, Zhao JJ, O’Donnell JD, Wang J, et al. MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Res 2008;68(2):425-433.
  65. Dahiya N, Sherman-Baust CA, Wang TL, Davidson B, Shih IeM, Zhang Y, Wood W 3rd, et al. MicroRNA expression and identification of putative miRNA targets in ovarian cancer. PloS One 2008;3(6):e2436.
  66. Poliseno L, Tuccoli A, Mariani L, Evangelista M, Citti L, Woods K, et al. MicroRNAs modulate the angiogenic properties of HUVECs. Blood 2006; 108(9):3068-3071.
  67. le Sage C, Nagel R, Egan DA, Schrier M, Mesman E, Mangiola A, et al. Regulation of the p27 (Kip1) tumor suppressor by miR-221 and miR-222 pro-motes cancer cell proliferation. EMBO J 2007;26 (15):3699-3708.
  68. Nam EJ, Yoon H, Kim SW, Kim H, Kim YT, Kim JH, et al. MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res 2008;14(9): 2690-2695.
  69. Faber C, Kirchner T, Hlubek F. The impact of microRNAs on colorectal cancer. Virchows Arch 2009;454(4):359-367.
  70. Hermeking H. p53 enters the microRNA world. Cancer Cell 2007;12(5):414-418.
  71. Powell SM, Zilz N, Beazer-Barclay Y, Bryan TM, Hamilton SR, Thibodeau SN, et al. APC mutations occur early during colorectal tumorigenesis. Nature 1992;359(6392):235-237.
  72. Nagel R, le Sage C, Diosdado B, van der Waal M, Oude Vrielink JA, Bolijn A, et al. Regulation of the adenomatous polyposis coli gene by the miR-135 family in colorectal cancer. Cancer Res 2008;68(14):5795-5802.
  73. Spaderna S, Schmalhofer O, Hlubek F, Berx G, Eger A, Merkel S, et al. A transient, EMT-linked loss of basement membranes indicates metastasis and poor survival in colorectal cancer. Gastro-enterology 2006;131(3):830-840.
  74. Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S, et al. A reciprocal repress-sion between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep 2006;9(6):582-589.
  75. Michael MZ, O' Connor SM, van Holst Pellekaan NG, Young GP, James RJ. Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res 2003;1(12):882-891.
  76. Bandrés E, Cubedo E, Agirre X, Malumbres R, Zárate R, Ramirez N, 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
  77. Guo C, Sah JF, Beard L, Willson JK, Markowitz SD, Guda K. The noncoding RNA, miR- 126, suppresses the growth of neoplastic cells by tar-geting phosphatidylinositol 3-kinase signaling and is frequently lost in colon cancers. Genes Chrom-osomes Cancer 2008;47(11):939-946.
  78. Schetter AJ, Leung SY, Sohn JJ, Zanetti KA, Bowman ED, Yanaihara N, et al. MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 2008;299(4):425-436.
  79. Xi Y, Formentini A, Chien M, Weir DB, Russo JJ, Ju J, et al. Prognostic values of microRNAs in colorectal cancer. Biomark Insights 2006;2:113-121.
  80. Tenen DG. Disruption of differentiation in human cancer: AML shows the way. Nat Rev Cancer 2003;3(2):89-101.
  81. Dixon-McIver A, East P, Mein CA, Cazier JB, Molloy G, Chaplin T, et al. Distinctive patterns of microRNA expression associated with karyotype in acute myeloid leukemia. PloS One 2008;3(5): e2141.
  82. Debernardi S, Skoulakis S, Molloy G, Chaplin T, Dixon-McIver A, Young BD. .MicroRNA miR-181a correlates with morphological sub-class of acute myeloid leukemia and the expression of its target genes in global genome-wide analysis. Leukemia 2007;21(5):912-916.
  83. Garzon R, Garofalo M, Martelli MP, Briesewitz R, Wang L, Fernandez-Cymering C, et al. Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin. Proc Natl Acad Sci USA 2008;105(10):3945-3950.
  84. Costa A, Osório C, Dias S. MicroRNA expression profiling in bone marrow: Implications in hemato-logical malignancies. Biotechnol J 2009;4(1):88-97.
  85. Pui CH, Jeha S. New therapeutic strategies for the treatment of acute lymphoblastic leukemia. Nat Rev Drug Discov 2007;6(2):149-165.
  86. O'Connell RM, Rao DS, Chaudhuri AA, Boldin MP, Taganov KD, Nicoll J, et al. Sustained expres-sion of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. Exp Med 2008;205(3):585-594.
  87. Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, Xue Y, et al. Regulation of the germinal center response by microRNA-155. Science 2007;316 (5824):604-608.
  88. Mi S, Lu J, Sun M, Li Z, Zhang H, Neilly MB, et al. MicroRNA expression signatures accurately discriminate acute lymphoblastic leukemia from acute myeloid leukemia.Proc Natl Acad Sci USA 2007;104(50):19971-19976.
  89. Melo JV, Barnes DJ. Chronic myeloid leukemia as a model of disease evolution in human cancer. Nat Rev Cancer 2007;7(6):441-453.
  90. Rowley JD. Letter: Deletions of chromosome 7 in haematological disorders. Lancet 1973;2(7842): 1385-1386.
  91. Venturini L, Battmer K, Castoldi M, Schultheis B, Hochhaus A, Muckenthaler MU, et al. Expression of the miR-17-92 polycistron in chronic myeloid leukemia (CML) CD34+ cells. Blood 2007;109 (10):4399-4405.
  92. Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med 2005;352: 804-815.
  93. Calin GA, Liu CG, Sevignani C, Ferracin M, Felli N, Dumitru CD, et al. MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proc Natl Acad Sci USA 2004;101 (32):11755-11760.
  94. Akao Y, Nakagawa Y, Kitade Y, Kinoshita T, Naoe T. Downregulation of microRNAs-143 and 145 in B-cell malignancies. Cancer Sci 2007;98 (12):1914-1920.
  95. Fulci V, Chiaretti S, Goldoni M, Azzalin G, Carucci N, Tavolaro S, et al. Quantitative technol-ogies establish a novel microRNA profile of chronic lymphocytic leukemia. Blood 2007;109 (11):4944-4951.
  96. Marton S, Garcia MR, Robello C, Persson H, Trajtenberg F, Pritsch O, et al. Small RNAs analysis in CLL reveals a deregulation of miRNA expression and novel miRNA candidates of putative relevance in CLL pathogenesis. Leukemia 2008;22(2):330-338.
  97. Zhang H, Chen Y. New insight into the role of miRNAs in leukemia. Sci China C Life Sci 2009; 52(3):224-231.
  98. Yang L, Parkin DM, Whelan S, Zhang S, Chen Y, Lu F, et al. Statistics on cancer in China: cancer registration in 2002. Eur J Cancer Prev 2005;14 (4):329-335.
  99. Pecorelli S, Pasinetti B, Angioli R, Favalli G, Odicino F. Systemic therapy for gynecological neoplasms: ovary, cervix and endometrium. Cancer Chemother Bio Response Modif 2005;22:515-544.
  100. Wu W, Lin Z, Zhuang Z, Liang X. Expression profile of mammalian microRNAs in endometrioid adenocarcinoma. Eur J Cancer Prev 2009;18(1):50-55.
  101. Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Can-cer Inst 2005;97(2):142-146.
  102. Kamangar F, Malekzadeh R, Dawsey SM, Saidi F. Esophageal cancer in northeastern Iran. Arch Iran Med 2007;10(1):70-82.
  103. Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic gastroesophageal refluxes as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999;340(11):825-31.
  104. Feber A, Xi L, Luketich JD, Pennathur A, Landreneau RJ, Wu M, et al. MicroRNA expres-sion profiles of esophageal cancer. J Thorac Cardiovasc Surg 2008;135(2):255-260.
  105. Saito Y, Suzuki H, Hibi T. The role of microRNAs in gastrointestinal cancers. J Gastro-enterol 2009;44(Suppl 19):18-22.
  106. Xia L, Zhang D, Du R, Pan Y, Zhao L, Sun S, et al. miR-15b and miR-16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells. Int J Cancer 2008;123(2):372-9.
  107. Petrocca F, Visone R, Onelli MR, Shah MH, Nicoloso MS, de Martino I, et al. E2F1-regulated microRNAs impair TGF-beta dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell 2008;13(3):272-86.
  108. Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC, ed. World Health Organization Classification of Tumors, Pathology and Genetics: Tumors of the Lung, Pleura, Thymus and Heart. Lyon: IARC Press;2004:12-15.
  109. Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 2006;9(3):189-198.
  110. Karube Y, Tanaka H, Osada H, Tomida S, Tatematsu Y, Yanagisawa K, et al. Reduced expression of Dicer associated with poor prognosis in lung cancer patients. Cancer Sci 2005;96(2): 111-115.
  111. Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, et al. RAS is regulated by the let-7 microRNA family. Cell 2005;120(5):635-647.
  112. Hayashita Y, Osada H, Tatematsu Y, Yamada H, Yanagisawa K, Tomida S, et al. A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell prolifer-ation. Cancer Res 2005;65(21):9628-9632.
  113. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58(2):71-96.
  114. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55 (2):74-108.
  115. Gottardo F, Liu CG, Ferracin M, Calin GA, Fassan M, Bassi P, et al. Micro-RNA profiling in kidney and bladder cancers. Urol Oncol 2007;25 (5):387-392.
  116. Wang G, Zhan H, He H , Tong W , Wang B , Liao G , et al. Up-regulation of microRNA in blad-der tumor tissue is not common. Int Urol Nephrol 2009; (Epub ahead of print).
  117. Ichimi T, Enokida H, Okuno Y, Kunimoto R, Chiyomaru T, Kawamoto K, et al. Identification of novel microRNA targets based on microRNA signatures in bladder cancer. Int J Cancer 2009;125 (2):345-352.
  118. Nikiforova MN, Chiosea SI, Nikiforov YE. MicroRNA expression profiles in thyroid tumors. Endocr Pathol 2009;20(2):85-91.
  119. Nikiforova MN, Tseng GC, Steward D, Diorio D, Nikiforov YE. MicroRNA expression profiling of thyroid tumors: biological significance and diag-nostic utility. J Clin Endocrinol Metab 2008;93(5): 1600-1608.
  120. Visone R, Pallante P, Vecchione A, Cirombella R, Ferracin M, Ferraro A, et al. Specific microRNAs are downregulated in human thyroid anaplastic carcinomas. Oncogene 2007;26 (54):7590-7595.
  121. Thum T, Catalucci D, Bauersachs J. Micro RNAs: novel regulators in cardiac development and disease. Cardiovas Res 2008;79(4):562-570.
  122. Hutvágner G, Simard MJ, Mello CC, Zamore PD. Sequence specific inhibition of small RNA function. PLoS Biol 2004;2(4):E98.
  123. Meister G, Landthaler M, Dorsett Y, Tuschl T. Sequence-specific inhibition of microRNA and siRNA-induced RNA silencing. RNA 2004;10(3): 544-550.