Therapeutic MicroRNA Strategies in Human Cancer

MicroRNAs (miRNAs) are ~22 nucleotide long, noncoding, endogenous RNA molecules which exert their functions by base pairing with messenger RNAs (mRNAs), thereby regulate protein-coding gene expression. In eukaryotic cells, miRNAs play important roles in regulating biological processes such as proliferation, differentiation, apoptosis, and stem cell self-renewal. The human genome may contain as many as 1,000 miRNAs, and more than 700 of them have been identified. miRNAs are predicted to target up to one third of mRNAs. Each miRNA can target hundreds of transcripts directly or indirectly, while more than one miRNA can converge on a single transcript target. Therefore, the potential regulatory circuitry afforded by miRNA is enormous. Recently, mounting evidence implicates miRNAs as a new class of modulator for human tumor initiation and progression. Therefore, it has been proposed that manipulating miRNA activity and miRNA biogenesis may be a novel avenue for developing efficient therapies against cancer.

[1]  F. Slack,et al.  Oncomirs — microRNAs with a role in cancer , 2006, Nature Reviews Cancer.

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

[3]  R. Sachidanandam,et al.  A role for microRNAs in maintenance of mouse mammary epithelial progenitor cells , 2007 .

[4]  Michael Q. Zhang,et al.  The Argonaute family: tentacles that reach into RNAi, developmental control, stem cell maintenance, and tumorigenesis. , 2002, Genes & development.

[5]  C. Croce,et al.  MicroRNA signatures in human cancers , 2006, Nature Reviews Cancer.

[6]  Yvonne Tay,et al.  MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation , 2009, Nature.

[7]  B. Davidson,et al.  RNA polymerase III transcribes human microRNAs , 2006, Nature Structural &Molecular Biology.

[8]  Ralph Weissleder,et al.  MicroRNA-21 knockdown disrupts glioma growth in vivo and displays synergistic cytotoxicity with neural precursor cell delivered S-TRAIL in human gliomas. , 2007, Cancer research.

[9]  F. Slack,et al.  The let-7 family of microRNAs. , 2008, Trends in cell biology.

[10]  C. Croce,et al.  SnapShot: MicroRNAs in Cancer , 2009, Cell.

[11]  Robert Langer,et al.  A combinatorial library of lipid-like materials for delivery of RNAi therapeutics , 2008, Nature Biotechnology.

[12]  Henry Mirsky,et al.  RNA editing of a miRNA precursor. , 2004, RNA.

[13]  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.

[14]  T. Mikkelsen,et al.  Altered adenosine-to-inosine RNA editing in human cancer. , 2007, Genome research.

[15]  D. Spector,et al.  A Human Cytomegalovirus-Encoded microRNA Regulates Expression of Multiple Viral Genes Involved in Replication , 2007, PLoS pathogens.

[16]  James M. Pipas,et al.  SV40-encoded microRNAs regulate viral gene expression and reduce susceptibility to cytotoxic T cells , 2005, Nature.

[17]  P. Jung,et al.  Inducible microRNA expression by an all-in-one episomal vector system , 2006, Nucleic acids research.

[18]  S. Kauppinen,et al.  LNA-mediated microRNA silencing in non-human primates , 2008, Nature.

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

[20]  Joel Greshock,et al.  MicroRNA microarray identifies Let-7i as a novel biomarker and therapeutic target in human epithelial ovarian cancer. , 2008, Cancer research.

[21]  Judy Lieberman,et al.  Micromanagers of immune cell fate and function. , 2009, Advances in immunology.

[22]  Hanah Margalit,et al.  Host Immune System Gene Targeting by a Viral miRNA , 2007, Science.

[23]  D. Bartel,et al.  MicroRNAs in the Hox network: an apparent link to posterior prevalence , 2008, Nature Reviews Genetics.

[24]  A. Judge,et al.  Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA , 2005, Nature Biotechnology.

[25]  Phillip A Sharp,et al.  Suppression of non-small cell lung tumor development by the let-7 microRNA family , 2008, Proceedings of the National Academy of Sciences.

[26]  P. Seeburg,et al.  Liver Disintegration in the Mouse Embryo Caused by Deficiency in the RNA-editing Enzyme ADAR1* , 2004, Journal of Biological Chemistry.

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

[28]  K. Nishikura,et al.  Requirement of the RNA editing deaminase ADAR1 gene for embryonic erythropoiesis. , 2000, Science.

[29]  Kathryn A. O’Donnell,et al.  c-Myc-regulated microRNAs modulate E2F1 expression , 2005, Nature.

[30]  Anton J. Enright,et al.  Identification of Virus-Encoded MicroRNAs , 2004, Science.

[31]  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.

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

[33]  J. Visvader,et al.  Cancer stem cells in solid tumours: accumulating evidence and unresolved questions , 2008, Nature Reviews Cancer.

[34]  F. Slack,et al.  The let-7 microRNA reduces tumor growth in mouse models of lung cancer , 2008, Cell cycle.

[35]  Mihaela Zavolan,et al.  Virus-encoded microRNAs: novel regulators of gene expression. , 2006, Trends in microbiology.

[36]  Sean J. Morrison,et al.  Hmga2 Promotes Neural Stem Cell Self-Renewal in Young but Not Old Mice by Reducing p16Ink4a and p19Arf Expression , 2008, Cell.

[37]  K. Roemer,et al.  Epstein–Barr virus-encoded microRNA miR-BART2 down-regulates the viral DNA polymerase BALF5 , 2007, Nucleic acids research.

[38]  V. Kim,et al.  Biogenesis of small RNAs in animals , 2009, Nature Reviews Molecular Cell Biology.

[39]  Reuven Agami,et al.  A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. , 2006, Cell.

[40]  F. Slack,et al.  let-7 microRNAs in development, stem cells and cancer. , 2008, Trends in molecular medicine.

[41]  E. Moss,et al.  Two genetic circuits repress the Caenorhabditis elegans heterochronic gene lin-28 after translation initiation. , 2002, Developmental biology.

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

[43]  Yanjie Lu,et al.  Retracted: Novel approaches for gene‐specific interference via manipulating actions of microRNAs: Examination on the pacemaker channel genes HCN2 and HCN4 , 2007, Journal of cellular physiology.

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

[45]  I. Bozzoni,et al.  Primary microRNA transcripts are processed co-transcriptionally , 2008, Nature Structural &Molecular Biology.

[46]  Yukio Kawahara,et al.  RNA editing of the microRNA‐151 precursor blocks cleavage by the Dicer–TRBP complex , 2007, EMBO reports.

[47]  J. Lieberman,et al.  let-7 Regulates Self Renewal and Tumorigenicity of Breast Cancer Cells , 2007, Cell.

[48]  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.

[49]  R. Stephens,et al.  Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. , 2006, Cancer cell.

[50]  David P. Bartel,et al.  Supporting Online Material Materials and Methods Fig. S1 Tables S1 and S2 References Database S1 Disrupting the Pairing between Let-7 and Hmga2 Enhances Oncogenic Transformation , 2022 .

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

[52]  R. Plasterk,et al.  MicroRNA function in animal development , 2005, FEBS letters.

[53]  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.

[54]  F. Slack,et al.  RAS Is Regulated by the let-7 MicroRNA Family , 2005, Cell.

[55]  A. Schier,et al.  Target Protectors Reveal Dampening and Balancing of Nodal Agonist and Antagonist by miR-430 , 2007, Science.

[56]  T. Golub,et al.  Impaired microRNA processing enhances cellular transformation and tumorigenesis , 2007, Nature Genetics.

[57]  Kathryn A. O’Donnell,et al.  Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model , 2009, Cell.

[58]  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.

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

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

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

[62]  N. Zhang,et al.  Electroporation-mediated transfer of plasmids to the lung results in reduced TLR9 signaling and inflammation , 2007, Gene Therapy.

[63]  E. Sontheimer,et al.  Origins and Mechanisms of miRNAs and siRNAs , 2009, Cell.

[64]  Daniel B. Martin,et al.  Circulating microRNAs as stable blood-based markers for cancer detection , 2008, Proceedings of the National Academy of Sciences.

[65]  D. Leake,et al.  Double-stranded regions are essential design components of potent inhibitors of RISC function. , 2007, RNA.

[66]  Anindya Dutta,et al.  The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. , 2007, Genes & development.

[67]  Haifan Lin,et al.  MicroRNAs: key regulators of stem cells , 2009, Nature Reviews Molecular Cell Biology.

[68]  Artemis G. Hatzigeorgiou,et al.  Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer , 2008, Proceedings of the National Academy of Sciences.

[69]  Liz Y. Han,et al.  Effect of interleukin-8 gene silencing with liposome-encapsulated small interfering RNA on ovarian cancer cell growth. , 2008, Journal of the National Cancer Institute.

[70]  Vetle I. Torvik,et al.  Complications in mammalian microRNA target prediction. , 2006, Methods in molecular biology.

[71]  Jan-Fang Cheng,et al.  Dicer, Drosha, and outcomes in patients with ovarian cancer. , 2008, The New England journal of medicine.

[72]  G. Ruvkun,et al.  Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans , 1993, Cell.

[73]  Anna M. Krichevsky,et al.  miR-21: a small multi-faceted RNA , 2008, Journal of cellular and molecular medicine.

[74]  J. Weiler,et al.  Anti-miRNA oligonucleotides (AMOs): ammunition to target miRNAs implicated in human disease? , 2006, Gene Therapy.

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

[76]  Pablo Landgraf,et al.  Abnormal microRNA-16 locus with synteny to human 13q14 linked to CLL in NZB mice. , 2007, Blood.

[77]  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.

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

[79]  V. Kim,et al.  The nuclear RNase III Drosha initiates microRNA processing , 2003, Nature.

[80]  Mauro Biffoni,et al.  The miR-15a–miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities , 2008, Nature Medicine.

[81]  Qihong Huang,et al.  Small-molecule inhibitors of microrna miR-21 function. , 2008, Angewandte Chemie.

[82]  F. Slack,et al.  Small non-coding RNAs in animal development , 2008, Nature Reviews Molecular Cell Biology.

[83]  Xin Li,et al.  A microRNA Mediates EGF Receptor Signaling and Promotes Photoreceptor Differentiation in the Drosophila Eye , 2005, Cell.

[84]  L. Lim,et al.  A microRNA component of the p53 tumour suppressor network , 2007, Nature.

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

[86]  Simion I. Chiosea,et al.  Overexpression of Dicer in precursor lesions of lung adenocarcinoma. , 2007, Cancer research.

[87]  Theresa A. Storm,et al.  Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways , 2006, Nature.

[88]  M. Loda,et al.  Altered eIF6 and Dicer expression is associated with clinicopathological features in ovarian serous carcinoma patients , 2008, Modern Pathology.

[89]  R. Emeson,et al.  Altered RNA Editing in Mice Lacking ADAR2 Autoregulation , 2006, Molecular and Cellular Biology.

[90]  C. Croce,et al.  Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[91]  Praveen Sethupathy,et al.  MicroRNA target site polymorphisms and human disease. , 2008, Trends in genetics : TIG.

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

[93]  Bryan R. Cullen,et al.  A viral microRNA functions as an orthologue of cellular miR-155 , 2007, Nature.

[94]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[95]  J. Rossi,et al.  Toxicity in mice expressing short hairpin RNAs gives new insight into RNAi , 2006, Genome Biology.

[96]  Anil K Sood,et al.  Therapeutic EphA2 gene targeting in vivo using neutral liposomal small interfering RNA delivery. , 2005, Cancer research.

[97]  C. Croce,et al.  A microRNA expression signature of human solid tumors defines cancer gene targets , 2006, Proceedings of the National Academy of Sciences of the United States of America.

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

[99]  Shuta Tomida,et al.  Reduced expression of Dicer associated with poor prognosis in lung cancer patients , 2005, Cancer science.