Application of RNAi to cancer research and therapy.

The introduction of double-stranded RNA (dsRNA) into cells can effectively and specifically lead to the degradation of corresponding mRNAs in a gene-dependent manner, which is defined as RNA interfering (RNAi). This powerful technology has been widely employed to manipulate gene expression in mammalian and human cells, elucidate signal pathways and identify gene functions in a whole-genome scale. Simultaneously, many pharmaceutical companies are very interested in the research and development of RNAi-based drugs for various diseases, especially in cancers. In present review, we attempt to recapitulate the potential application of this breakthrough technology in many aspects of cancer gene therapy such as genome-scale screens, target identification and validation, functional analysis and animal models for diverse diseases.

[1]  M. Gottesman,et al.  Multidrug resistance in cancer: role of ATP–dependent transporters , 2002, Nature Reviews Cancer.

[2]  R. Pomerantz,et al.  RNA interference: on the road to an alternate therapeutic strategy! , 2003, Reviews in medical virology.

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

[4]  René Bernards,et al.  Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB , 2003, Nature.

[5]  Anne E Carpenter,et al.  Systematic genome-wide screens of gene function , 2004, Nature Reviews Genetics.

[6]  A. Sancar,et al.  Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. , 2004, Annual review of biochemistry.

[7]  David M Sabatini,et al.  Applications of transfected cell microarrays in high-throughput drug discovery. , 2002, Drug discovery today.

[8]  Patrick J. Paddison,et al.  An epi-allelic series of p53 hypomorphs created by stable RNAi produces distinct tumor phenotypes in vivo , 2003, Nature Genetics.

[9]  N. Dyson,et al.  Cell cycle-dependent and cell cycle-independent control of transcription by the Drosophila E2F/RB pathway. , 2003, Genes & development.

[10]  R. Silverman,et al.  Chemistry and biochemistry of 2',5'-oligoadenylate-based antisense strategy. , 2001, Current medicinal chemistry.

[11]  T. Tuschl,et al.  Analysis of gene function in somatic mammalian cells using small interfering RNAs. , 2002, Methods.

[12]  B. Suter,et al.  Xpd/Ercc2 regulates CAK activity and mitotic progression , 2003, Nature.

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

[14]  D. Barford,et al.  Crystal structure of a PIWI protein suggests mechanisms for siRNA recognition and slicer activity , 2004, The EMBO journal.

[15]  R. Agami.  RNAi and related mechanisms and their potential use for therapy. , 2002, Current opinion in chemical biology.

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

[17]  Vijay Kumar,et al.  Specific inhibition of gene expression and transactivation functions of hepatitis B virus X protein and c‐myc by small interfering RNAs , 2004, FEBS letters.

[18]  L. Lim,et al.  An Abundant Class of Tiny RNAs with Probable Regulatory Roles in Caenorhabditis elegans , 2001, Science.

[19]  D. Voskas,et al.  Inhibition of Tie-2 Signaling Induces Endothelial Cell Apoptosis, Decreases Akt Signaling and Induces Endothelial Cell Expression of the Endogenous Anti-Angiogenic Molecule, Thrombospondin-1 , 2004, Cancer biology & therapy.

[20]  Jianping Wang,et al.  siRNA agents inhibit oncogene expression and attenuate human tumor cell growth. , 2003, Journal of experimental therapeutics & oncology.

[21]  C. Schmitt.  Senescence, apoptosis and therapy — cutting the lifelines of cancer , 2003, Nature Reviews Cancer.

[22]  D. Stokoe,et al.  Direct comparison of the specificity of gene silencing using antisense oligonucleotides and RNAi. , 2005, The Biochemical journal.

[23]  W. Hahn,et al.  Modelling the molecular circuitry of cancer , 2002, Nature Reviews Cancer.

[24]  B. Reinhart,et al.  Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA , 2000, Nature.

[25]  S. Schubert,et al.  Ribozyme- and deoxyribozyme-strategies for medical applications. , 2004, Current drug targets.

[26]  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.

[27]  R. Jorgensen,et al.  Altered gene expression in plants due to trans interactions between homologous genes. , 1990, Trends in biotechnology.

[28]  J. Krol,et al.  Structural Features of MicroRNA (miRNA) Precursors and Their Relevance to miRNA Biogenesis and Small Interfering RNA/Short Hairpin RNA Design* , 2004, Journal of Biological Chemistry.

[29]  G. Rainaldi,et al.  Synthetic hammerhead ribozymes as therapeutic tools to control disease genes. , 2005, Current gene therapy.

[30]  G. Hannon,et al.  Processing of primary microRNAs by the Microprocessor complex , 2004, Nature.

[31]  M. Nakajima,et al.  Identification of genes involved in cell invasion by using a library of randomized hybrid ribozymes , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Thomas Tuschl,et al.  RISC is a 5' phosphomonoester-producing RNA endonuclease. , 2004, Genes & development.

[33]  David P. Bartel,et al.  MicroRNAs: At the Root of Plant Development?1 , 2003, Plant Physiology.

[34]  Y. Lazebnik,et al.  Confirming Specificity of RNAi in Mammalian Cells , 2002, Science's STKE.

[35]  V. Erdmann,et al.  RNA cleaving '10-23' DNAzymes with enhanced stability and activity. , 2003, Nucleic acids research.

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

[37]  Eric Westhof,et al.  Single Processing Center Models for Human Dicer and Bacterial RNase III , 2004, Cell.

[38]  A. Hengstermann,et al.  siRNA targeting of the viral E6 oncogene efficiently kills human papillomavirus-positive cancer cells , 2003, Oncogene.

[39]  V. Ambros,et al.  MicroRNAs and Other Tiny Endogenous RNAs in C. elegans , 2003, Current Biology.

[40]  Michael R. Green,et al.  Nonspecific, concentration-dependent stimulation and repression of mammalian gene expression by small interfering RNAs (siRNAs). , 2004, RNA.

[41]  R. Ramos,et al.  RNAi reveals doublecortin is required for radial migration in rat neocortex , 2003, Nature Neuroscience.

[42]  Reuven Agami,et al.  A large-scale RNAi screen in human cells identifies new components of the p53 pathway , 2004, Nature.

[43]  F. Hoppe-Seyler,et al.  Induction of apoptosis in tumor cells by siRNA-mediated silencing of the livin/ML-IAP/KIAP gene , 2003, Oncogene.

[44]  R. Gaynor,et al.  Identification of NF-κB-regulated genes induced by TNFα utilizing expression profiling and RNA interference , 2003, Oncogene.

[45]  Phillip A Sharp,et al.  siRNAs can function as miRNAs , 2003 .

[46]  S. Raguz,et al.  Complete reversal of multidrug resistance by stable expression of small interfering RNAs targeting MDR1 , 2004, Gene Therapy.

[47]  Matthias John,et al.  Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs , 2004, Nature.

[48]  E. Sahai,et al.  ERK-MAPK signaling coordinately regulates activity of Rac1 and RhoA for tumor cell motility. , 2003, Cancer cell.

[49]  A. Aguzzi,et al.  IL-6 is required for glioma development in a mouse model , 2004, Oncogene.

[50]  Phillip A. Sharp,et al.  The RNAi revolution , 2004, Nature.

[51]  M. Amarzguioui,et al.  Tolerance for mutations and chemical modifications in a siRNA. , 2003, Nucleic acids research.

[52]  E. Lesnik,et al.  Pharmacokinetic properties of 2'-O-(2-methoxyethyl)-modified oligonucleotide analogs in rats. , 2001, The Journal of pharmacology and experimental therapeutics.

[53]  R. Cardiff.  Mouse models of human breast cancer. , 2003, Comparative medicine.

[54]  T. Tuschl,et al.  New microRNAs from mouse and human. , 2003, RNA.

[55]  M. Vasconcelos,et al.  Specific downregulation of bcl-2 and xIAP by RNAi enhances the effects of chemotherapeutic agents in MCF-7 human breast cancer cells , 2004, Cancer Gene Therapy.

[56]  Robert M Sears,et al.  Local gene knockdown in the brain using viral-mediated RNA interference , 2003, Nature Medicine.

[57]  R. Gaynor,et al.  Identification and Validation of Genes Involved in the Pathogenesis of Colorectal Cancer Using cDNA Microarrays and RNA Interference 1 , 2003 .

[58]  Y. Wan,et al.  RNA-mediated gene regulation system: now and the future (Review). , 2002, International journal of molecular medicine.

[59]  E. Sontheimer,et al.  Argonaute Journeys into the Heart of RISC , 2004, Science.

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

[61]  Jianzhu Chen,et al.  Use of siRNAs to prevent and treat influenza virus infection. , 2004, Virus research.

[62]  F. Rosselli,et al.  The DNA crosslink‐induced S‐phase checkpoint depends on ATR–CHK1 and ATR–NBS1–FANCD2 pathways , 2004, The EMBO journal.

[63]  James R Beasley,et al.  Miniaturized, ultra-high throughput screening of tyrosine kinases using homogeneous, competitive fluorescence immunoassays. , 2004, Assay and drug development technologies.

[64]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[65]  H. Lage,et al.  Modulation of the classical multidrug resistance (MDR) phenotype by RNA interference (RNAi) , 2003, FEBS letters.

[66]  V. Ambros.  The functions of animal microRNAs , 2004, Nature.

[67]  岡村 勝友.  Distinct roles for Argonaute proteins in small RNA-directed RNA cleavage pathways , 2004 .

[68]  V. Kim,et al.  MicroRNA maturation: stepwise processing and subcellular localization , 2002, The EMBO journal.

[69]  N. Caplen,et al.  Defining and assaying RNAi in mammalian cells. , 2005, Molecular cell.

[70]  Serge Batalov,et al.  Identification of modulators of TRAIL-induced apoptosis via RNAi-based phenotypic screening. , 2003, Molecular cell.

[71]  D. Dykxhoorn,et al.  Killing the messenger: short RNAs that silence gene expression , 2003, Nature Reviews Molecular Cell Biology.

[72]  Lawrence Lum,et al.  The Hedgehog Response Network: Sensors, Switches, and Routers , 2004, Science.

[73]  Neff Walker,et al.  A MicroRNA as a Translational Repressor of APETALA2 in Arabidopsis Flower Development , 2004 .

[74]  Patrick J. Paddison,et al.  Short hairpin activated gene silencing in mammalian cells. , 2004, Methods in molecular biology.

[75]  H. Vornlocher,et al.  Inhibition of bcr-abl gene expression by small interfering RNA sensitizes for imatinib mesylate (STI571). , 2003, Blood.

[76]  C. Gondi,et al.  Inhibition of cathepsin B and MMP-9 gene expression in glioblastoma cell line via RNA interference reduces tumor cell invasion, tumor growth and angiogenesis , 2004, Oncogene.

[77]  G. Hannon,et al.  Crystal Structure of Argonaute and Its Implications for RISC Slicer Activity , 2004, Science.

[78]  H. Liber,et al.  Silencing expression of the catalytic subunit of DNA-dependent protein kinase by small interfering RNA sensitizes human cells for radiation-induced chromosome damage, cell killing, and mutation. , 2002, Cancer research.

[79]  A. Borkhardt,et al.  Killing of leukemic cells with a BCR/ABL fusion gene by RNA interference (RNAi) , 2002, Oncogene.

[80]  J. Adams.  The proteasome: a suitable antineoplastic target , 2004, Nature Reviews Cancer.

[81]  L. Vassilev,et al.  In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2 , 2004, Science.

[82]  M. Kizaki,et al.  In vitro and in vivo growth suppression of human papillomavirus 16-positive cervical cancer cells by E6 siRNA. , 2003, Molecular therapy : the journal of the American Society of Gene Therapy.

[83]  A. Klippel,et al.  Structural variations and stabilising modifications of synthetic siRNAs in mammalian cells. , 2003, Nucleic acids research.

[84]  Gary Ruvkun,et al.  A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity , 2003, Nature Genetics.

[85]  Ronald W. Davis,et al.  Quantitative phenotypic analysis of yeast deletion mutants using a highly parallel molecular bar–coding strategy , 1996, Nature Genetics.

[86]  M. Strasberg-Rieber,et al.  Induction of tumor cell apoptosis and chemosensitization by antisense strategies. , 2005, Methods in molecular medicine.

[87]  T. Jovin,et al.  Small interfering RNAs suppress the expression of endogenous and GFP-fused epidermal growth factor receptor (erbB1) and induce apoptosis in erbB1-overexpressing cells. , 2003, Experimental cell research.

[88]  P. Sharp,et al.  RNA interference--2001. , 2001, Genes & development.

[89]  E. Dougherty,et al.  RNAi microarray analysis in cultured mammalian cells. , 2003, Genome research.

[90]  Andrew G Fraser,et al.  Identification of genes that protect the C. elegans genome against mutations by genome-wide RNAi. , 2003, Genes & development.

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

[92]  C. Cepko,et al.  Electroporation and RNA interference in the rodent retina in vivo and in vitro , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[93]  R. Bernards,et al.  Stable suppression of tumorigenicity by virus-mediated RNA interference. , 2002, Cancer cell.

[94]  G. Hannon,et al.  RNase III enzymes and the initiation of gene silencing , 2004, Nature Structural &Molecular Biology.

[95]  H. Paulson,et al.  RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia , 2004, Nature Medicine.

[96]  Jay Z. Parrish,et al.  Functional genomic analysis of apoptotic DNA degradation in C. elegans. , 2003, Molecular cell.

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

[98]  Lawrence Lum,et al.  Identification of Hedgehog Pathway Components by RNAi in Drosophila Cultured Cells , 2003, Science.

[99]  James R Okicki,et al.  Potent inhibition of respiratory syncytial virus by combination treatment with 2-5A antisense and ribavirin. , 2004, Antiviral research.

[100]  G. Stamatoyannopoulos,et al.  Down-regulation of CXCR4 by inducible small interfering RNA inhibits breast cancer cell invasion in vitro. , 2003, Cancer research.

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

[102]  S. Michnick,et al.  PKB/Akt modulates TGF-beta signalling through a direct interaction with Smad3. , 2004, Nature cell biology.

[103]  D. Corey,et al.  Lipid-mediated introduction of peptide nucleic acids into cells. , 2002, Methods in molecular biology.

[104]  R. Plasterk,et al.  Dicers at RISC The Mechanism of RNAi , 2004, Cell.

[105]  Anton P. McCaffrey,et al.  Inhibition of hepatitis B virus in mice by RNA interference , 2003, Nature Biotechnology.

[106]  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.

[107]  C. Mann,et al.  Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse , 2003, Nature Medicine.

[108]  Molecular biology. Argonaute journeys into the heart of RISC. , 2004, Science.

[109]  René Bernards,et al.  New tools for functional mammalian cancer genetics , 2003, Nature Reviews Cancer.

[110]  Wenwu Cui,et al.  OptiRNAi, an RNAi design tool , 2004, Comput. Methods Programs Biomed..

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

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

[113]  Hideyuki Takahashi,et al.  Caenorhabditis elegans Ce-rdh-1/rad-51 functions after double-strand break formation of meiotic recombination , 2004, Chromosome Research.

[114]  C. Rinaldo,et al.  Roles for Caenorhabditis elegans rad-51 in meiosis and in resistance to ionizing radiation during development. , 2002, Genetics.

[115]  C. Burge,et al.  Vertebrate MicroRNA Genes , 2003, Science.

[116]  R. Shao,et al.  Silencing of hdm2 oncogene by siRNA inhibits p53-dependent human breast cancer , 2004, Cancer Gene Therapy.

[117]  Jennifer A. Doudna,et al.  The chemical repertoire of natural ribozymes , 2002, Nature.

[118]  M. Eder,et al.  RNAi in functional genomics. , 2004, Current opinion in molecular therapeutics.

[119]  Michael Koutsilieris,et al.  The Akt pathway: molecular targets for anti-cancer drug development. , 2004, Current cancer drug targets.

[120]  J. Dahlberg,et al.  Molecular biology. , 1977, Science.

[121]  B. Cullen,et al.  Structural requirements for pre-microRNA binding and nuclear export by Exportin 5. , 2004, Nucleic acids research.

[122]  P. Zipperlen,et al.  Functional genomic analysis of C. elegans chromosome I by systematic RNA interference , 2000, Nature.

[123]  Steven A. Rosenberg,et al.  Adoptive-cell-transfer therapy for the treatment of patients with cancer , 2003, Nature Reviews Cancer.

[124]  B. Reinhart,et al.  Prediction of Plant MicroRNA Targets , 2002, Cell.

[125]  B. Cullen,et al.  Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. , 2003, Genes & development.

[126]  B. Li,et al.  Expression profiling reveals off-target gene regulation by RNAi , 2003, Nature Biotechnology.

[127]  Fischer L Tan,et al.  RNAi, a new therapeutic strategy against viral infection , 2004, Cell Research.

[128]  Robert H. Silverman,et al.  Activation of the interferon system by short-interfering RNAs , 2003, Nature Cell Biology.

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

[130]  R. Iggo,et al.  Induction of an interferon response by RNAi vectors in mammalian cells , 2003, Nature Genetics.

[131]  Robert Lucito,et al.  RNA interference microarrays: high-throughput loss-of-function genetics in mammalian cells. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[132]  David L. Lewis,et al.  Efficient delivery of siRNA for inhibition of gene expression in postnatal mice , 2002, Nature Genetics.

[133]  M. Manns,et al.  Caspase 8 small interfering RNA prevents acute liver failure in mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[134]  C. Croce,et al.  An oligonucleotide microchip for genome-wide microRNA profiling in human and mouse tissues. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[135]  Nick V Grishin,et al.  Biochemical identification of Argonaute 2 as the sole protein required for RNA-induced silencing complex activity. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[136]  J. M. Thomson,et al.  Argonaute2 Is the Catalytic Engine of Mammalian RNAi , 2004, Science.

[137]  Thomas Tuschl,et al.  Sequence, chemical, and structural variation of small interfering RNAs and short hairpin RNAs and the effect on mammalian gene silencing. , 2003, Antisense & nucleic acid drug development.

[138]  Andrew Fraser,et al.  RNA interference: Human genes hit the big screen , 2004, Nature.

[139]  Ricardo Macarrón.  Ultra high quality uHTS. , 2003, Drug discovery today.

[140]  T. Hubbard,et al.  A census of human cancer genes , 2004, Nature Reviews Cancer.

[141]  Thomas Tuschl,et al.  siRNAs: applications in functional genomics and potential as therapeutics , 2004, Nature Reviews Drug Discovery.

[142]  W. Hung,et al.  Histone deacetylase inhibitor up-regulates RECK to inhibit MMP-2 activation and cancer cell invasion. , 2003, Cancer research.

[143]  P. Friedl,et al.  Tumour-cell invasion and migration: diversity and escape mechanisms , 2003, Nature Reviews Cancer.

[144]  T. Giordano,et al.  RNAi: gene-silencing in therapeutic intervention. , 2002, Drug discovery today.

[145]  Gary Ruvkun,et al.  Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes , 2003, Nature.

[146]  A. Reynolds,et al.  Rational siRNA design for RNA interference , 2004, Nature Biotechnology.

[147]  K. Kinzler,et al.  Cancer genes and the pathways they control , 2004, Nature Medicine.

[148]  S. Nakajima,et al.  Functional and physical interactions between ERCC1 and MSH2 complexes for resistance to cis-diamminedichloroplatinum(II) in mammalian cells. , 2004, DNA repair.

[149]  Judy Lieberman,et al.  RNA interference targeting Fas protects mice from fulminant hepatitis , 2003, Nature Medicine.

[150]  Patrick J. Paddison,et al.  RNA interference: the new somatic cell genetics? , 2002, Cancer cell.

[151]  W. Hauswirth,et al.  Ribozyme gene therapy: applications for molecular medicine. , 2001, Trends in molecular medicine.

[152]  R. Gaynor,et al.  Identification of NF-kappa B-regulated genes induced by TNFalpha utilizing expression profiling and RNA interference. , 2003, Oncogene.

[153]  J. Heasman.  Morpholino oligos: making sense of antisense? , 2002, Developmental biology.

[154]  M. Bjornsti,et al.  The tor pathway: a target for cancer therapy , 2004, Nature Reviews Cancer.