MicroRNAs: Control and Loss of Control in Human Physiology and Disease

Analysis of the human genome indicates that a large fraction of the genome sequences are RNAs that do not encode any proteins, also known as non-coding RNAs. MicroRNAs (miRNAs) are a group of small non-coding RNA molecules 20–22 nucleotides (nt) in length that are predicted to control the activity of approximately 30% of all protein-coding genes in mammals. miRNAs play important roles in many diseases, including cancer, cardiovascular disease, and immune disorders. The expression of miRNAs can be regulated by epigenetic modification, DNA copy number change, and genetic mutations. miRNAs can serve as a valuable therapeutic target for a large number of diseases. For miRNAs with oncogenic capabilities, potential therapies include miRNA silencing, antisense blocking, and miRNA modifications. For miRNAs with tumor suppression functions, overexpression of those miRNAs might be a useful strategy to inhibit tumor growth. In this review, we discuss the current progress of miRNA research, regulation of miRNA expression, prediction of miRNA targets, and regulatory role of miRNAs in human physiology and diseases, with a specific focus on miRNAs in pancreatic cancer, liver cancer, colorectal cancer, cardiovascular disease, the immune system, and infectious disease. This review provides valuable information for clinicians and researchers who want to recognize the newest advances in this new field and identify possible lines of investigation in miRNAs as important mediators in human physiology and diseases.

[1]  C. Fauquet,et al.  MicroRNA-binding viral protein interferes with Arabidopsis development. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[2]  B. Evers,et al.  RNA interference: mechanisms of action and therapeutic consideration. , 2006, Surgery.

[3]  T. Beaty,et al.  A genome-wide search for quantitative trait loci contributing to variation in seasonal pollen reactivity. , 2006, The Journal of allergy and clinical immunology.

[4]  R. Hruban,et al.  K-ras, p53, and DPC4 (MAD4) alterations in fine-needle aspirates of the pancreas: a molecular panel correlates with and supplements cytologic diagnosis. , 2002, American journal of clinical pathology.

[5]  J Philip McCoy,et al.  Hematopoietic-specific microRNA expression in human cells. , 2006, Leukemia research.

[6]  Y. Yatabe,et al.  Reduced Expression of the let-7 MicroRNAs in Human Lung Cancers in Association with Shortened Postoperative Survival , 2004, Cancer Research.

[7]  Anton J. Enright,et al.  Requirement of bic/microRNA-155 for Normal Immune Function , 2007, Science.

[8]  M. Amarzguioui,et al.  Approaches for chemically synthesized siRNA and vector‐mediated RNAi , 2005, FEBS letters.

[9]  A. Nadin,et al.  Catalytic Site-Directed γ-Secretase Complex Inhibitors Do Not Discriminate Pharmacologically between Notch S3 and β-APP Cleavages , 2003 .

[10]  S. Spivack,et al.  Overexpression of the microRNA hsa-miR-200c leads to reduced expression of transcription factor 8 and increased expression of E-cadherin. , 2007, Cancer research.

[11]  D. Baltimore,et al.  NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses , 2006, Proceedings of the National Academy of Sciences.

[12]  T. Tuschl,et al.  RNA interference is mediated by 21- and 22-nucleotide RNAs. , 2001, Genes & development.

[13]  S. Goodman,et al.  K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. , 1993, The American journal of pathology.

[14]  D. Eide,et al.  A Histidine-rich Cluster Mediates the Ubiquitination and Degradation of the Human Zinc Transporter, hZIP4, and Protects against Zinc Cytotoxicity* , 2007, Journal of Biological Chemistry.

[15]  P. Meltzer Cancer genomics: Small RNAs with big impacts , 2005, Nature.

[16]  M. Lindsay,et al.  Rapid Changes in MicroRNA-146a Expression Negatively Regulate the IL-1β-Induced Inflammatory Response in Human Lung Alveolar Epithelial Cells1 , 2008, The Journal of Immunology.

[17]  M. Lindsay,et al.  Expression profiling in vivo demonstrates rapid changes in lung microRNA levels following lipopolysaccharide-induced inflammation but not in the anti-inflammatory action of glucocorticoids , 2007, BMC Genomics.

[18]  Muller Fabbri,et al.  Modulation of miR-155 and miR-125b Levels following Lipopolysaccharide/TNF-α Stimulation and Their Possible Roles in Regulating the Response to Endotoxin Shock1 , 2007, The Journal of Immunology.

[19]  J. Thomison,et al.  Fine tuning , 2020, Catalysis from A to Z.

[20]  M. Walsh,et al.  TRAF‐Mediated TNFR‐Family Signaling , 2002, Current protocols in immunology.

[21]  Doron Betel,et al.  The microRNA.org resource: targets and expression , 2007, Nucleic Acids Res..

[22]  O. Kent,et al.  A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes , 2006, Oncogene.

[23]  S. Akira,et al.  Toll-like receptors. , 2003, Annual review of immunology.

[24]  A. Hatzigeorgiou,et al.  A combined computational-experimental approach predicts human microRNA targets. , 2004, Genes & development.

[25]  C. Burge,et al.  Prediction of Mammalian MicroRNA Targets , 2003, Cell.

[26]  Timothy K Starr,et al.  Positive and negative selection of T cells. , 2003, Annual review of immunology.

[27]  Shuang Huang,et al.  Involvement of MicroRNA in AU-Rich Element-Mediated mRNA Instability , 2005, Cell.

[28]  C. Sander,et al.  A Mammalian microRNA Expression Atlas Based on Small RNA Library Sequencing , 2007, Cell.

[29]  Susan M. Kaech,et al.  Molecular and Functional Profiling of Memory CD8 T Cell Differentiation , 2002, Cell.

[30]  K. Kosik,et al.  MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. , 2005, Cancer research.

[31]  S. Asurmendi,et al.  Infection and coaccumulation of tobacco mosaic virus proteins alter microRNA levels, correlating with symptom and plant development , 2007, Proceedings of the National Academy of Sciences.

[32]  C. Mayr,et al.  miR-150, a microRNA expressed in mature B and T cells, blocks early B cell development when expressed prematurely , 2007, Proceedings of the National Academy of Sciences.

[33]  M. Toyota,et al.  Epigenetic silencing of microRNA-34b/c and B-cell translocation gene 4 is associated with CpG island methylation in colorectal cancer. , 2008, Cancer research.

[34]  B. Williams,et al.  Induction of T cell-mediated immunity using a c-Myb DNA vaccine in a mouse model of colon cancer , 2008, Cancer Immunology, Immunotherapy.

[35]  Hiroyuki Tagawa,et al.  Identification and characterization of a novel gene, C13orf25, as a target for 13q31-q32 amplification in malignant lymphoma. , 2004, Cancer research.

[36]  P. Schuster,et al.  From sequences to shapes and back: a case study in RNA secondary structures , 1994, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[37]  C. Croce,et al.  MiR-15a and miR-16-1 cluster functions in human leukemia , 2008, Proceedings of the National Academy of Sciences.

[38]  W. Tam,et al.  miR‐155/BIC as an oncogenic microRNA , 2006, Genes, chromosomes & cancer.

[39]  J. Lorens,et al.  RNAi screening for therapeutic targets in human malignancies. , 2007, Current pharmaceutical biotechnology.

[40]  E. Vigorito,et al.  Regulation of B- and T-cell differentiation by a single microRNA. , 2008, Biochemical Society transactions.

[41]  G. Kelsoe,et al.  Inflammation and the reciprocal production of granulocytes and lymphocytes in bone marrow , 2005, The Journal of experimental medicine.

[42]  N. Rajewsky,et al.  MiR-150 Controls B Cell Differentiation by Targeting the Transcription Factor c-Myb , 2007, Cell.

[43]  Shuomin Zhu,et al.  MicroRNA-21 Targets the Tumor Suppressor Gene Tropomyosin 1 (TPM1)* , 2007, Journal of Biological Chemistry.

[44]  Kwang-Soo Kim,et al.  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* , 2005, Journal of Biological Chemistry.

[45]  W. Filipowicz,et al.  Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? , 2008, Nature Reviews Genetics.

[46]  Thomas D. Schmittgen,et al.  Methylation mediated silencing of MicroRNA-1 gene and its role in hepatocellular carcinogenesis. , 2008, Cancer research.

[47]  George E. Sandusky,et al.  Dicer Is Required for Embryonic Angiogenesis during Mouse Development* , 2005, Journal of Biological Chemistry.

[48]  N. Rajewsky,et al.  Silencing of microRNAs in vivo with ‘antagomirs’ , 2005, Nature.

[49]  Shangqin Guo,et al.  MicroRNA-mediated control of cell fate in megakaryocyte-erythrocyte progenitors. , 2008, Developmental cell.

[50]  N. Iizuka,et al.  Differential gene expression in distinct virologic types of hepatocellular carcinoma: association with liver cirrhosis , 2003, Oncogene.

[51]  Khalid S. A. Khabar,et al.  Rapid transit in the immune cells: the role of mRNA turnover regulation , 2007, Journal of leukocyte biology.

[52]  Yuriy Gusev,et al.  Computational analysis of biological functions and pathways collectively targeted by co-expressed microRNAs in cancer , 2007, BMC Bioinformatics.

[53]  C. Croce,et al.  Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma. , 2007, Cancer research.

[54]  H. Chi,et al.  Innate recognition of non-self nucleic acids , 2008, Genome Biology.

[55]  Grace X. Y. Zheng,et al.  Dynamic regulation of miRNA expression in ordered stages of cellular development. , 2007, Genes & development.

[56]  Lin Zhang,et al.  MicroRNAs: A New Insight into Cancer Genome , 2006, Cell cycle.

[57]  C. Morrison,et al.  MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B , 2007, Proceedings of the National Academy of Sciences.

[58]  L. Lim,et al.  Transcripts Targeted by the MicroRNA-16 Family Cooperatively Regulate Cell Cycle Progression , 2007, Molecular and Cellular Biology.

[59]  K. Gunsalus,et al.  Combinatorial microRNA target predictions , 2005, Nature Genetics.

[60]  Phillip A. Sharp,et al.  miRNA Profiling of Naïve, Effector and Memory CD8 T Cells , 2007, PloS one.

[61]  D. Bartel,et al.  MicroRNAs Modulate Hematopoietic Lineage Differentiation , 2004, Science.

[62]  Brian S. Roberts,et al.  The colorectal microRNAome. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[63]  W. S. Hayward,et al.  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 , 2002, Journal of Virology.

[64]  Tushar Patel,et al.  Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines. , 2006, Gastroenterology.

[65]  J. Parrillo Pathogenetic mechanisms of septic shock. , 1993, The New England journal of medicine.

[66]  Oliver Hobert,et al.  Perfect seed pairing is not a generally reliable predictor for miRNA-target interactions , 2006, Nature Structural &Molecular Biology.

[67]  O. Singh,et al.  High-dimensional biology to comprehend hepatocellular carcinoma , 2008, Expert review of proteomics.

[68]  K. Calame MicroRNA-155 function in B Cells. , 2007, Immunity.

[69]  Yvonne Tay,et al.  A Pattern-Based Method for the Identification of MicroRNA Binding Sites and Their Corresponding Heteroduplexes , 2006, Cell.

[70]  S. Lowe,et al.  A microRNA polycistron as a potential human oncogene , 2005, Nature.

[71]  Christopher P Evans,et al.  An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells , 2007, Proceedings of the National Academy of Sciences.

[72]  Nikolaus Rajewsky,et al.  Computational identification of microRNA targets , 2004, Genome Biology.

[73]  O. Kirak,et al.  Regulation of progenitor cell proliferation and granulocyte function by microRNA-223 , 2008, Nature.

[74]  C. Burant,et al.  Identification of a putative tumor suppressor gene Rap1GAP in pancreatic cancer. , 2006, Cancer research.

[75]  G. Ruvkun,et al.  A uniform system for microRNA annotation. , 2003, RNA.

[76]  Zihua Hu,et al.  MicroRNA targets in immune genes and the Dicer/Argonaute and ARE machinery components. , 2008, Molecular immunology.

[77]  Laura Mariani,et al.  MicroRNAs modulate the angiogenic properties of HUVECs. , 2006, Blood.

[78]  Shuomin Zhu,et al.  miR-21-mediated tumor growth , 2007, Oncogene.

[79]  A. Saïb,et al.  A Cellular MicroRNA Mediates Antiviral Defense in Human Cells , 2005, Science.

[80]  M. Buendia,et al.  Integration of woodchuck hepatitis and N‐myc rearrangement determine size and histologic grade of hepatic tumors , 2004, Hepatology.

[81]  J. Mattick,et al.  Non-coding RNA. , 2006, Human molecular genetics.

[82]  L. Lim,et al.  MicroRNA targeting specificity in mammals: determinants beyond seed pairing. , 2007, Molecular cell.

[83]  Yoko Fukuda,et al.  An Evolutionarily Conserved Mechanism for MicroRNA-223 Expression Revealed by MicroRNA Gene Profiling , 2007, Cell.

[84]  C. Croce,et al.  MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. , 2007, JAMA.

[85]  George A Calin,et al.  MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. , 2008, JAMA.

[86]  M. Washington,et al.  Epigenetic silencing of the intronic microRNA hsa-miR-342 and its host gene EVL in colorectal cancer , 2008, Oncogene.

[87]  Anton J. Enright,et al.  microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells. , 2007, Immunity.

[88]  Peter A. Jones,et al.  Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. , 2006, Cancer cell.

[89]  Lin He,et al.  MicroRNAs: small RNAs with a big role in gene regulation , 2004, Nature reviews genetics.

[90]  George A Calin,et al.  MicroRNAs and cancer: Profile, profile, profile , 2007, International journal of cancer.

[91]  Peter A. Jones,et al.  Epigenetic Activation of Tumor Suppressor MicroRNAs in Human Cancer Cells , 2006, Cell cycle.

[92]  J. Lupski,et al.  The complete genome of an individual by massively parallel DNA sequencing , 2008, Nature.

[93]  T. Davison,et al.  MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma , 2007, Oncogene.

[94]  Huan Yang,et al.  MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. , 2008, Cancer research.

[95]  Keiichiro Nishida,et al.  Expression of microRNA-146 in rheumatoid arthritis synovial tissue. , 2008, Arthritis and rheumatism.

[96]  Mark M. Davis,et al.  miR-181a Is an Intrinsic Modulator of T Cell Sensitivity and Selection , 2007, Cell.

[97]  James G. Krueger,et al.  Pathogenesis and therapy of psoriasis , 2007, Nature.

[98]  B. Reinhart,et al.  The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans , 2000, Nature.

[99]  R. Aharonov,et al.  Identification of hundreds of conserved and nonconserved human microRNAs , 2005, Nature Genetics.

[100]  E. Lai Micro RNAs are complementary to 3′ UTR sequence motifs that mediate negative post-transcriptional regulation , 2002, Nature Genetics.

[101]  Y. Pekarsky,et al.  Tcl1 expression in chronic lymphocytic leukemia is regulated by miR-29 and miR-181. , 2006, Cancer research.

[102]  George A. Calin,et al.  Mammalian microRNAs: a small world for fine-tuning gene expression , 2006, Mammalian Genome.

[103]  V. Ambros,et al.  The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 , 1993, Cell.

[104]  H. Osada,et al.  MicroRNAs in biological processes and carcinogenesis. , 2007, Carcinogenesis.

[105]  Ian A. White,et al.  An IL-4-independent and CD25-mediated function of c-maf in promoting the production of Th2 cytokines , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[106]  Naoto Tsuchiya,et al.  Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells , 2007, Proceedings of the National Academy of Sciences.

[107]  C. Sen,et al.  Evidence for the Involvement of miRNA in Redox Regulated Angiogenic Response of Human Microvascular Endothelial Cells , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[108]  P. Sarnow,et al.  Modulation of Hepatitis C Virus RNA Abundance by a Liver-Specific MicroRNA , 2005, Science.

[109]  P. Janson,et al.  MicroRNAs: Novel Regulators Involved in the Pathogenesis of Psoriasis? , 2007, PloS one.

[110]  Stefano Volinia,et al.  MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[111]  A. Munnich,et al.  miR-122, a paradigm for the role of microRNAs in the liver. , 2008, Journal of hepatology.

[112]  Phillip D Zamore,et al.  Sequence-Specific Inhibition of Small RNA Function , 2004, PLoS biology.

[113]  Margaret S. Ebert,et al.  MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells , 2007, Nature Methods.

[114]  M. Emi,et al.  Down-regulation of a novel gene, DRLM, in human liver malignancy from 4q22 that encodes a NAP-like protein. , 2002, Gene.

[115]  A. van den Berg,et al.  High expression of B‐cell receptor inducible gene BIC in all subtypes of Hodgkin lymphoma , 2002, Genes, chromosomes & cancer.

[116]  Meredith Wadman,et al.  James Watson's genome sequenced at high speed , 2008, Nature.

[117]  A. Fire,et al.  Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans , 1998, Nature.

[118]  Aadel A. Chaudhuri,et al.  Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder , 2008, The Journal of experimental medicine.

[119]  Stefanie Dimmeler,et al.  Role of Dicer and Drosha for Endothelial MicroRNA Expression and Angiogenesis , 2007, Circulation research.

[120]  Bryan R. Cullen,et al.  Analysis of the Interaction of Primate Retroviruses with the Human RNA Interference Machinery , 2007, Journal of Virology.

[121]  C. Benz,et al.  Rapid alteration of microRNA levels by histone deacetylase inhibition. , 2006, Cancer research.

[122]  Y. Akao,et al.  MicroRNA-143 and -145 in colon cancer. , 2007, DNA and cell biology.

[123]  A. Hatzigeorgiou,et al.  TarBase: A comprehensive database of experimentally supported animal microRNA targets. , 2005, RNA.

[124]  Tara L. Naylor,et al.  microRNAs exhibit high frequency genomic alterations in human cancer. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[125]  R. Weinberg,et al.  Tumour invasion and metastasis initiated by microRNA-10b in breast cancer , 2007, Nature.

[126]  Chris Sander,et al.  MicroRNA profiling of the murine hematopoietic system , 2005, Genome Biology.

[127]  Michael Z Michael,et al.  Reduced accumulation of specific microRNAs in colorectal neoplasia. , 2003, Molecular cancer research : MCR.

[128]  David Baltimore,et al.  MicroRNA-155 is induced during the macrophage inflammatory response , 2007, Proceedings of the National Academy of Sciences.

[129]  P. Foster,et al.  Regulation of microRNA by antagomirs: a new class of pharmacological antagonists for the specific regulation of gene function? , 2007, American journal of respiratory cell and molecular biology.

[130]  I. Kockum,et al.  Susceptibility loci for atopic dermatitis on chromosome 21 in a Swedish population , 2006, Allergy.

[131]  Arndt Borkhardt,et al.  High expression of precursor microRNA‐155/BIC RNA in children with Burkitt lymphoma , 2004, Genes, chromosomes & cancer.

[132]  Stefano Volinia,et al.  Interferon modulation of cellular microRNAs as an antiviral mechanism , 2007, Nature.

[133]  G. Fu,et al.  Insight into hepatocellular carcinogenesis at transcriptome level by comparing gene expression profiles of hepatocellular carcinoma with those of corresponding noncancerous liver , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[134]  Mark Graham,et al.  miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. , 2006, Cell metabolism.

[135]  V. Velculescu,et al.  Implications of micro-RNA profiling for cancer diagnosis , 2006, Oncogene.

[136]  C. Burge,et al.  The microRNAs of Caenorhabditis elegans. , 2003, Genes & development.

[137]  Chunxiang Zhang,et al.  MicroRNA Expression Signature and Antisense-Mediated Depletion Reveal an Essential Role of MicroRNA in Vascular Neointimal Lesion Formation , 2007, Circulation research.

[138]  C. Croce,et al.  Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[139]  Alessandro Fatica,et al.  A Minicircuitry Comprised of MicroRNA-223 and Transcription Factors NFI-A and C/EBPα Regulates Human Granulopoiesis , 2005, Cell.

[140]  Rork Kuick,et al.  Molecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancer. , 2003, Cancer research.

[141]  Q. Yao,et al.  Small interfering RNA therapy in cancer: mechanism, potential targets, and clinical applications. , 2008, Expert opinion on therapeutic targets.

[142]  Muller Fabbri,et al.  A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. , 2005, The New England journal of medicine.

[143]  Lin Zhang,et al.  The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis , 2008, Nature Cell Biology.

[144]  C. Burge,et al.  Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA Targets , 2005, Cell.

[145]  K. Rajewsky,et al.  Aberrant T cell differentiation in the absence of Dicer , 2005, The Journal of experimental medicine.

[146]  T. Tuschl,et al.  Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells , 2001, Nature.

[147]  G. Wakabayashi,et al.  Downregulation of miR‐138 is associated with overexpression of human telomerase reverse transcriptase protein in human anaplastic thyroid carcinoma cell lines , 2008, Cancer science.

[148]  R. Ross,et al.  Atherosclerosis is an inflammatory disease. , 1998, American heart journal.

[149]  Stijn van Dongen,et al.  miRBase: tools for microRNA genomics , 2007, Nucleic Acids Res..

[150]  R. Hartmann,et al.  Locked nucleic acid oligonucleotides: the next generation of antisense agents? , 2007, BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy.

[151]  N. Rajewsky,et al.  Regulation of the Germinal Center Response by MicroRNA-155 , 2007, Science.

[152]  F. Slack,et al.  The let-7 microRNA represses cell proliferation pathways in human cells. , 2007, Cancer research.

[153]  Wei Wang,et al.  MicroRNA-34b and MicroRNA-34c are targets of p53 and cooperate in control of cell proliferation and adhesion-independent growth. , 2007, Cancer research.

[154]  Joshua T. Mendell,et al.  MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1 , 2008, Proceedings of the National Academy of Sciences.

[155]  Sam Griffiths-Jones,et al.  The microRNA Registry , 2004, Nucleic Acids Res..

[156]  C. Croce,et al.  miR-15 and miR-16 induce apoptosis by targeting BCL2. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[157]  J. Kitzman,et al.  Determinants of targeting by endogenous and exogenous microRNAs and siRNAs. , 2007, RNA.

[158]  H. Horvitz,et al.  MicroRNA expression profiles classify human cancers , 2005, Nature.

[159]  F. J. Livesey,et al.  A role for Dicer in immune regulation , 2006, The Journal of experimental medicine.

[160]  L. O’Neill 'Fine tuning' TLR signaling , 2008, Nature Immunology.

[161]  Thomas D. Schmittgen,et al.  Expression profiling identifies microRNA signature in pancreatic cancer , 2006, International journal of cancer.

[162]  Stefano Volinia,et al.  Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[163]  Rudolf Jaenisch,et al.  Targeted Deletion Reveals Essential and Overlapping Functions of the miR-17∼92 Family of miRNA Clusters , 2008, Cell.

[164]  Nathalie Wong,et al.  MicroRNA-223 is commonly repressed in hepatocellular carcinoma and potentiates expression of Stathmin1. , 2008, Gastroenterology.

[165]  F. Alt,et al.  The expression of Vpre-B/λ5 surrogate light chain in early bone marrow precursor B cells of normal and B cell-deficient mutant mice , 1994, Cell.

[166]  J. Frampton,et al.  Hematopoietic lineage commitment: miRNAs add specificity to a widely expressed transcription factor. , 2008, Developmental Cell.

[167]  Jing Wang,et al.  Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes , 2008, Nature Immunology.

[168]  Riccardo Dalla-Favera,et al.  Germinal centres: role in B-cell physiology and malignancy , 2008, Nature Reviews Immunology.

[169]  Thomas D. Schmittgen,et al.  The Human Angiotensin II Type 1 Receptor +1166 A/C Polymorphism Attenuates MicroRNA-155 Binding* , 2007, Journal of Biological Chemistry.

[170]  B. Monia,et al.  Therapeutic potential for microRNAs. , 2007, Advanced drug delivery reviews.

[171]  S. Kauppinen,et al.  LNA-modified oligonucleotides mediate specific inhibition of microRNA function. , 2006, Gene.

[172]  Scott E. Martin,et al.  Applications of RNA interference in mammalian systems. , 2007, Annual review of genomics and human genetics.

[173]  A. Nadin,et al.  Catalytic site-directed gamma-secretase complex inhibitors do not discriminate pharmacologically between Notch S3 and beta-APP cleavages. , 2003, Biochemistry.

[174]  Yoko Fukuda,et al.  Exploration of human miRNA target genes in neuronal differentiation. , 2005, Nucleic acids symposium series.

[175]  Mauro Biffoni,et al.  The promyelocytic leukemia zinc finger-microRNA-221/-222 pathway controls melanoma progression through multiple oncogenic mechanisms. , 2008, Cancer research.

[176]  Wayne Tam,et al.  Accumulation of miR-155 and BIC RNA in human B cell lymphomas. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[177]  N. Rajewsky,et al.  Dicer Ablation Affects Antibody Diversity and Cell Survival in the B Lymphocyte Lineage , 2008, Cell.