MicroRNAs and cancer therapeutics

Pharmaceutical Research

Volumn 28, Issue 12, 2011, Pages 3043-3049

  Yeung, Man Lung ^a   Jeang, Kuan Teh ^b  

^a UNIVERSITY OF HONG KONG   (Hong Kong)

^b NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES   (United States)

Author keywords

HTLV 1; leukemia; microRNA; nanoparticles; oncomiRs

Indexed keywords

CYCLODEXTRIN; LET 7; LIPID; MACROGOL; MICRORNA; MIR 10B; MIR 122; MIR 132; MIR 16; MIR 17 3P; MIR 191; MIR 21; MIR 221; MIR 222; MIR 26A; MIR 34A; NANOPARTICLE; PARVOVIRUS VECTOR; SHORT HAIRPIN RNA; SMALL INTERFERING RNA; TRANSFERRIN; UNCLASSIFIED DRUG; VIRUS VECTOR;

ANTINEOPLASTIC ACTIVITY; ARTICLE; BREAST CANCER; CANCER GENE THERAPY; CARCINOGENESIS; DRUG SAFETY; GENE EXPRESSION; GENE SILENCING; HEPATITIS; HUMAN; HYDRODYNAMICS BASED TRANSFECTION; IMMUNE RESPONSE; IN VIVO GENE TRANSFER; LIPOSOMAL GENE DELIVERY SYSTEM; LIVER CANCER; LIVER FIBROSIS; LUNG CANCER; LUNG TUMOR; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROSTATE CANCER; PROSTATE TUMOR; TONGUE CANCER; VIRAL GENE DELIVERY SYSTEM;

ANIMALS; GENE EXPRESSION REGULATION, NEOPLASTIC; GENE THERAPY; HUMANS; MICRORNAS; NANOPARTICLES; NEOPLASMS; ONCOGENES; RNA INTERFERENCE;

EID: 83455206025     PISSN: 07248741     EISSN: 1573904X     Source Type: Journal    
DOI: 10.1007/s11095-011-0526-2     Document Type: Article

References (73)

1. DP Bartel 2009 MicroRNAs: target recognition and regulatory functions Cell 136 215 233 19167326 10.1016/j.cell.2009.01.002 1:CAS:528: DC%2BD1MXhs1Kiuro%3D
2. RW Carthew EJ Sontheimer 2009 Origins and mechanisms of miRNAs and siRNAs Cell 136 642 655 19239886 10.1016/j.cell.2009.01.035 1:CAS:528: DC%2BD1MXkvFGksb0%3D
3. VN Kim J Han MC Siomi 2009 Biogenesis of small RNAs in animals Nat Rev Mol Cell Biol 10 126 139 19165215 10.1038/nrm2632 1:CAS:528: DC%2BD1MXpsVCitA%3D%3D
4. P Smibert EC Lai 2008 Lessons from microRNA mutants in worms, flies and mice Cell Cycle 7 2500 2508 18719388 10.4161/cc.7.16.6454 1:CAS:528: DC%2BD1cXht1elsbvP
5. A Gatignol A Buckler-White B Berkhout KT Jeang 1991 Characterization of a human TAR RNA-binding protein that activates the HIV-1 LTR Science 251 1597 1600 2011739 10.1126/science.2011739 1:CAS:528:DyaK3MXlslKgs7w%3D (Pubitemid 21916930)
6. P Brodersen O Voinnet 2009 Revisiting the principles of microRNA target recognition and mode of action Nat Rev Mol Cell Biol 10 141 148 19145236 10.1038/nrm2619 1:CAS:528:DC%2BD1MXltFWqtg%3D%3D
7. C Shin JW Nam KK Farh HR Chiang A Shkumatava DP Bartel 2010 Expanding the microRNA targeting code: functional sites with centered pairing Mol Cell 38 789 802 20620952 10.1016/j.molcel.2010.06.005 1:CAS:528:DC%2BC3cXovVWmtb4%3D
8. H Robins WH Press 2005 Human microRNAs target a functionally distinct population of genes with AT-rich 3′ UTRs Proc Natl Acad Sci USA 102 15557 15562 16230613 10.1073/pnas.0507443102 1:CAS:528:DC%2BD2MXht1ShtrnI (Pubitemid 41528095)
9. G Sun H Li JJ Rossi 2010 Sequence context outside the target region influences the effectiveness of miR-223 target sites in the RhoB 3′UTR Nucleic Acids Res 38 239 252 19850724 10.1093/nar/gkp870 1:CAS:528: DC%2BC3cXhtF2lsA%3D%3D
10. M Wakiyama K Takimoto O Ohara S Yokoyama 2007 Let-7 microRNA-mediated mRNA deadenylation and translational repression in a mammalian cell-free system Gene Dev 21 1857 1862 17671087 10.1101/gad.1566707 1:CAS:528: DC%2BD2sXps1alsr4%3D (Pubitemid 47204925)
11. TP Chendrimada KJ Finn X Ji D Baillat RI Gregory SA Liebhaber, et al. 2007 MicroRNA silencing through RISC recruitment of eIF6 Nature 447 823 828 17507929 10.1038/nature05841 1:CAS:528:DC%2BD2sXms1Wjs7o%3D (Pubitemid 46920131)
12. MR Fabian N Sonenberg W Filipowicz 2010 Regulation of mRNA translation and stability by microRNAs Annu Rev Biochem 79 351 379 20533884 10.1146/annurev-biochem-060308-103103 1:CAS:528:DC%2BC3cXpslShtro%3D
13. L Wu J Fan JG Belasco 2006 MicroRNAs direct rapid deadenylation of mRNA Proc Natl Acad Sci USA 103 4034 4039 16495412 10.1073/pnas.0510928103 1:CAS:528:DC%2BD28XivFWitLk%3D
14. WM Merritt YG Lin LY Han AA Kamat WA Spannuth R Schmandt, et al. 2008 Dicer, Drosha, and outcomes in patients with ovarian cancer New Engl J Med 359 2641 2650 19092150 10.1056/NEJMoa0803785 1:CAS:528:DC%2BD1cXhsFaltL3O
15. Y Karube H Tanaka H Osada S Tomida Y Tatematsu K Yanagisawa, et al. 2005 Reduced expression of Dicer associated with poor prognosis in lung cancer patients Canc Sci 96 111 115 10.1111/j.1349-7006.2005.00015.x 1:CAS:528:DC%2BD2MXislOhs7g%3D (Pubitemid 40425386)
16. MA Carmell Z Xuan MQ Zhang GJ Hannon 2002 The Argonaute family: tentacles that reach into RNAi, developmental control, stem cell maintenance, and tumorigenesis Gene Dev 16 2733 2742 12414724 10.1101/gad.1026102 1:CAS:528:DC%2BD38Xos1Sju70%3D (Pubitemid 35253139)
17. J Sun SL Zheng F Wiklund SD Isaacs G Li KE Wiley, et al. 2009 Sequence variants at 22q13 are associated with prostate cancer risk Canc Res 69 10 15 10.1158/0008-5472.CAN-08-3464 1:CAS:528:DC%2BD1MXmvFeh
18. Y Horikawa CG Wood H Yang H Zhao Y Ye J Gu, et al. 2008 Single nucleotide polymorphisms of microRNA machinery genes modify the risk of renal cell carcinoma Clin Canc Res 14 7956 7962 10.1158/1078-0432.CCR-08-1199 1:CAS:528:DC%2BD1cXhsVegt7%2FK
19. H Yang CP Dinney Y Ye Y Zhu HB Grossman X Wu 2008 Evaluation of genetic variants in microRNA-related genes and risk of bladder cancer Canc Res 68 2530 2537 10.1158/0008-5472.CAN-07-5991 1:CAS:528:DC%2BD1cXktV2jsLs%3D (Pubitemid 351521830)
20. Y Ye KK Wang J Gu H Yang J Lin JA Ajani, et al. 2008 Genetic variations in microRNA-related genes are novel susceptibility loci for esophageal cancer risk Cancer Prev Res (Phila) 1 460 469 10.1158/1940-6207.CAPR-08-0135 1:CAS:528:DC%2BC3cXptVyqsrg%3D
21. J Clague SM Lippman H Yang MA Hildebrandt Y Ye JJ Lee, et al. 2010 Genetic variation in MicroRNA genes and risk of oral premalignant lesions Mol Carcinog 49 183 189 19851984 1:CAS:528:DC%2BC3cXhvFSjsrc%3D
22. GA Calin CD Dumitru M Shimizu R Bichi S Zupo E Noch, et al. 2002 Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia Proc Natl Acad Sci USA 99 15524 15529 12434020 10.1073/pnas.242606799 1:CAS:528:DC%2BD3sXjvVOl (Pubitemid 35403967)
23. J Lu G Getz EA Miska E Alvarez-Saavedra J Lamb D Peck, et al. 2005 MicroRNA expression profiles classify human cancers Nature 435 834 838 15944708 10.1038/nature03702 1:CAS:528:DC%2BD2MXkvVGgsLc%3D (Pubitemid 40839735)
24. Y Xi R Shalgi O Fodstad Y Pilpel J Ju 2006 Differentially regulated micro-RNAs and actively translated messenger RNA transcripts by tumor suppressor p53 in colon cancer Clin Canc Res 12 2014 2024 10.1158/1078-0432.CCR-05-1853 1:CAS:528:DC%2BD28XjtlCiu7w%3D
25. KA O'Donnell EA Wentzel KI Zeller CV Dang JT Mendell 2005 c-Myc-regulated microRNAs modulate E2F1 expression Nature 435 839 843 15944709 10.1038/nature03677 (Pubitemid 40839736)
26. MV Iorio R Visone G Di Leva V Donati F Petrocca P Casalini, et al. 2007 MicroRNA signatures in human ovarian cancer Canc Res 67 8699 8707 10.1158/0008-5472.CAN-07-1936 1:CAS:528:DC%2BD2sXhtVCit7vN (Pubitemid 47437445)
27. GA Calin M Ferracin A Cimmino G Di Leva M Shimizu SE Wojcik, et al. 2005 A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia New Engl J Med 353 1793 1801 16251535 10.1056/NEJMoa050995 1:CAS:528:DC%2BD2MXhtFKrtLbJ (Pubitemid 41549891)
28. MV Iorio M Ferracin CG Liu A Veronese R Spizzo S Sabbioni, et al. 2005 MicroRNA gene expression deregulation in human breast cancer Canc Res 65 7065 7070 10.1158/0008-5472.CAN-05-1783 1:CAS:528:DC%2BD2MXns1WrtL8%3D (Pubitemid 41161233)
29. V Fulci S Chiaretti M Goldoni G Azzalin N Carucci S Tavolaro, et al. 2007 Quantitative technologies establish a novel microRNA profile of chronic lymphocytic leukemia Blood 109 4944 4951 17327404 10.1182/blood-2006-12-062398 1:CAS:528:DC%2BD2sXmt1Onsr4%3D (Pubitemid 46827793)
30. CH Lawrie S Soneji T Marafioti CD Cooper S Palazzo JC Paterson, et al. 2007 MicroRNA expression distinguishes between germinal center B cell-like and activated B cell-like subtypes of diffuse large B cell lymphoma Int J Canc 121 1156 1161 10.1002/ijc.22800 1:CAS:528:DC%2BD2sXhtFGhu7nP (Pubitemid 47101656)
31. T Greither LF Grochola A Udelnow C Lautenschlager P Wurl H Taubert 2010 Elevated expression of microRNAs 155, 203, 210 and 222 in pancreatic tumors is associated with poorer survival Int J Canc 126 73 80 10.1002/ijc.24687 1:CAS:528:DC%2BD1MXhsVamtL7I
32. N Habbe JB Koorstra JT Mendell GJ Offerhaus JK Ryu G Feldmann, et al. 2009 MicroRNA miR-155 is a biomarker of early pancreatic neoplasia Canc Biol Ther 8 340 346 10.4161/cbt.8.4.7338 1:CAS:528:DC%2BD1MXotV2qtLs%3D
33. A Rodriguez E Vigorito S Clare MV Warren P Couttet DR Soond, et al. 2007 Requirement of bic/microRNA-155 for normal immune function Science 316 608 611 17463290 10.1126/science.1139253 1:CAS:528:DC%2BD2sXksFeksbg%3D (Pubitemid 46683148)
34. V Nair M Zavolan 2006 Virus-encoded microRNAs: novel regulators of gene expression Trends Microbiol 14 169 175 16531046 10.1016/j.tim.2006.02.007 1:CAS:528:DC%2BD28Xjs1Gltrk%3D
35. E Gottwein N Mukherjee C Sachse C Frenzel WH Majoros JT Chi, et al. 2007 A viral microRNA functions as an orthologue of cellular miR-155 Nature 450 1096 1099 18075594 10.1038/nature05992 1:CAS:528:DC%2BD2sXhsVaqtrjK (Pubitemid 350273603)
36. Watashi K, Yeung ML, Starost MF, Hosmane RS, Jeang KT. Identification of small molecules that suppress microRNA function and reverse tumorigenesis. J Biol Chem. 2010;285:24707-24716.
37. ML Yeung J Yasunaga Y Bennasser N Dusetti D Harris N Ahmad, et al. 2008 Roles for microRNAs, miR-93 and miR-130b, and tumor protein 53-induced nuclear protein 1 tumor suppressor in cell growth dysregulation by human T-cell lymphotrophic virus 1 Canc Res 68 8976 8985 10.1158/0008-5472.CAN-08-0769 1:CAS:528:DC%2BD1cXhtlSkurzJ
38. S Ma KH Tang YP Chan TK Lee PS Kwan A Castilho, et al. 2010 miR-130b Promotes CD133(+) liver tumor-initiating cell growth and self-renewal via tumor protein 53-induced nuclear protein 1 Cell Stem Cell 7 694 707 21112564 10.1016/j.stem.2010.11.010 1:CAS:528:DC%2BC3cXhsVygs7rF
39. ML Si S Zhu H Wu Z Lu F Wu YY Mo 2007 miR-21-mediated tumor growth Oncogene 26 2799 2803 17072344 10.1038/sj.onc.1210083 1:CAS:528: DC%2BD2sXksF2rsb4%3D (Pubitemid 46663837)
40. L He X He LP Lim E de Stanchina Z Xuan Y Liang, et al. 2007 A microRNA component of the p53 tumour suppressor network Nature 447 1130 1134 17554337 10.1038/nature05939 1:CAS:528:DC%2BD2sXmvFKmu7c%3D (Pubitemid 47014436)
41. Q Ji X Hao Y Meng M Zhang J Desano D Fan, et al. 2008 Restoration of tumor suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheres BMC Canc 8 266 10.1186/1471-2407-8-266
42. WCS Cho 2010 MicroRNAs in cancer-from research to therapy Biochim Biophys Acta Rev Canc 1805 209 217 1:CAS:528:DC%2BC3cXjt1Kqsrc%3D
43. E Elyakim E Sitbon A Faerman S Tabak E Montia L Belanis, et al. 2010 hsa-miR-191 is a candidate oncogene target for hepatocellular carcinoma therapy Canc Res 70 8077 8087 10.1158/0008-5472.CAN-10-1313 1:CAS:528:DC%2BC3cXht1yqs7bE
44. MS Kumar SJ Erkeland RE Pester CY Chen MS Ebert PA Sharp, et al. 2008 Suppression of non-small cell lung tumor development by the let-7 microRNA family Proc Natl Acad Sci USA 105 3903 3908 18308936 10.1073/pnas.0712321105 1:CAS:528:DC%2BD1cXjs1Ohs7s%3D (Pubitemid 351723497)
45. L Ma F Reinhardt E Pan J Soutschek B Bhat EG Marcusson, et al. 2010 Therapeutic silencing of miR-10b inhibits metastasis in a mouse mammary tumor model Nat Biotechnol 28 341 347 20351690 10.1038/nbt.1618 1:CAS:528: DC%2BC3cXjvFars74%3D
46. XP Zhang A Ladd E Dragoescu WT Budd JL Ware ZE Zehner 2009 MicroRNA-17-3p is a prostate tumor suppressor in vitro and in vivo, and is decreased in high grade prostate tumors analyzed by laser capture microdissection Clin Exp Metastas 26 965 979 10.1007/s10585-009-9287-2 1:CAS:528:DC%2BD1MXhsVWlsrbF
47. Mercatelli N, Coppola V, Bonci D, Miele F, Costantini A, Guadagnoli M, et al. The inhibition of the highly expressed miR-221 and miR-222 impairs the growth of prostate carcinoma xenografts in mice. Plos One 2008;3:e4029.
48. F Takeshita L Patrawala M Osaki R Takahashi Y Yamamoto N Kosaka, et al. 2010 Systemic delivery of synthetic MicroRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell-cycle genes Mol Ther 18 181 187 19738602 10.1038/mt.2009.207 1:CAS:528:DC%2BD1MXhtV2qt7rI
49. JS Li HZ Huang LJ Sun M Yang CB Pan WL Chen, et al. 2009 MiR-21 indicates poor prognosis in tongue squamous cell carcinomas as an apoptosis inhibitor Clin Canc Res 15 3998 4008 10.1158/1078-0432.CCR-08-3053 1:CAS:528: DC%2BD1MXntlOis7s%3D
50. J Kota RR Chivukula KA O'Donnell EA Wentzel CL Montgomery HW Hwang, et al. 2009 Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model Cell 137 1005 1017 19524505 10.1016/j.cell.2009.04.021 1:CAS:528:DC%2BD1MXps1eiurg%3D
51. S Anand BK Majeti LM Acevedo EA Murphy R Mukthavaram L Scheppke, et al. 2010 MicroRNA-132-mediated loss of p120RasGAP activates the endothelium to facilitate pathological angiogenesis Nat Med 16 909 914 20676106 10.1038/nm.2186 1:CAS:528:DC%2BC3cXpsFWku7k%3D
52. YC Chen XD Zhu XJ Zhang B Liu L Huang 2010 Nanoparticles modified with tumor-targeting scFv deliver siRNA and miRNA for cancer therapy Mol Ther 18 1650 1656 20606648 10.1038/mt.2010.136 1:CAS:528:DC%2BC3cXosVKiu7k%3D
53. CL Jopling 2008 Regulation of hepatitis C virus by microRNA-122 Biochem Soc Trans 36 1220 1223 19021529 10.1042/BST0361220 1:CAS:528:DC%2BD1cXhsVCgsLfK
54. CL Jopling M Yi AM Lancaster SM Lemon P Sarnow 2005 Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA Science 309 1577 1581 16141076 10.1126/science.1113329 1:CAS:528:DC%2BD2MXpsFWisr8%3D (Pubitemid 41266486)
55. RE Lanford ES Hildebrandt-Eriksen A Petri R Persson M Lindow ME Munk, et al. 2010 Therapeutic silencing of MicroRNA-122 in primates with chronic hepatitis C virus infection Science 327 198 201 19965718 10.1126/science.1178178 1:CAS:528:DC%2BC3cXht1egsA%3D%3D
56. E Song SK Lee J Wang N Ince N Ouyang J Min, et al. 2003 RNA interference targeting Fas protects mice from fulminant hepatitis Nat Med 9 347 351 12579197 10.1038/nm828 1:CAS:528:DC%2BD3sXhsFGgs7Y%3D (Pubitemid 36362792)
57. D De Paula MV Bentley RI Mahato 2007 Hydrophobization and bioconjugation for enhanced siRNA delivery and targeting RNA 13 431 456 17329355 10.1261/rna.459807 (Pubitemid 46509424)
58. S Hacein-Bey-Abina C Von Kalle M Schmidt MP McCormack N Wulffraat P Leboulch, et al. 2003 LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1 Science 302 415 419 14564000 10.1126/science.1088547 1:CAS:528:DC%2BD3sXotV2isb4%3D (Pubitemid 37296260)
59. ME Davis 2009 The first targeted delivery of siRNA in humans via a self-assembling. Cyclodextrin polymer-based nanoparticle: from concept to clinic Mol Pharm 6 659 668 19267452 10.1021/mp900015y 1:CAS:528:DC%2BD1MXjvF2gsb4%3D
60. JD Heidel JYC Liu Y Yen BS Zhou BSE Heale JJ Rossi, et al. 2007 Potent siRNA inhibitors of ribonucleotide reductase subunit RRM2 reduce cell proliferation in vitro and in vivo Clin Canc Res 13 2207 2215 10.1158/1078-0432.CCR-06-2218 1:CAS:528:DC%2BD2sXjs12rtLg%3D (Pubitemid 46649891)
61. JD Heidel ZP Yu JYC Liu SM Rele YC Liang RK Zeidan, et al. 2007 Administration in non-human primates of escalating intravenous doses of targeted nanoparticles containing ribonucleotide reductase subunit M2 siRNA Proc Natl Acad Sci USA 104 5715 5721 17379663 10.1073/pnas.0701458104 1:CAS:528: DC%2BD2sXkt1KgsLY%3D (Pubitemid 47175600)
62. M Lopez-Fraga T Martinez A Jimenez 2009 RNA interference technologies and therapeutics from basic research to products BioDrugs 23 305 332 19754220 10.2165/11318190-000000000-00000 1:CAS:528:DC%2BD1MXhsVWhtbbL
63. F Mccormick 1989 Ras Gtpase activating protein - signal transmitter and signal terminator Cell 56 5 8 2535967 10.1016/0092-8674(89)90976-8 1:CAS:528:DyaL1MXhvVOrsb4%3D (Pubitemid 19033511)
64. LP Lim NC Lau P Garrett-Engele A Grimson JM Schelter J Castle, et al. 2005 Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs Nature 433 769 773 15685193 10.1038/nature03315 1:CAS:528:DC%2BD2MXhtleqsLs%3D (Pubitemid 40292988)
65. Braun A. Biosafety in handling gene transfer vectors. Curr Protoc Hum Genet. 2006, Chapter 12:Unit 12 11.
66. D Grimm KL Streetz CL Jopling TA Storm K Pandey CR Davis, et al. 2006 Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways Nature 441 537 541 16724069 10.1038/nature04791 1:CAS:528: DC%2BD28XkvVyku7g%3D (Pubitemid 44050158)
67. M van de Wetering I Oving V Muncan MT Pon Fong H Brantjes D van Leenen, et al. 2003 Specific inhibition of gene expression using a stably integrated, inducible small-interfering-RNA vector EMBO Rep 4 609 615 12776180 10.1038/sj.embor.embor865 (Pubitemid 36939953)
68. F Czauderna A Santel M Hinz M Fechtner B Durieux G Fisch, et al. 2003 Inducible shRNA expression for application in a prostate cancer mouse model Nucleic Acids Res 31 e127 14576327 10.1093/nar/gng127
69. S Kappel Y Matthess M Kaufmann K Strebhardt 2007 Silencing of mammalian genes by tetracycline-inducible shRNA expression Nat Protoc 2 3257 3269 18079726 10.1038/nprot.2007.458 1:CAS:528:DC%2BD2sXhsVejtrfJ
70. X Zhou J Ruan G Wang W Zhang 2007 Characterization and identification of microRNA core promoters in four model species PLoS Comput Biol 3 e37 17352530 10.1371/journal.pcbi.0030037 (Pubitemid 46535734)
71. Y Lee M Kim J Han KH Yeom S Lee SH Baek, et al. 2004 MicroRNA genes are transcribed by RNA polymerase II EMBO J 23 4051 4060 15372072 10.1038/sj.emboj.7600385 1:CAS:528:DC%2BD2cXotlCrsrs%3D (Pubitemid 39472426)
72. RD Morin MD O'Connor M Griffith F Kuchenbauer A Delaney AL Prabhu, et al. 2008 Application of massively parallel sequencing to microRNA profiling and discovery in human embryonic stem cells Genome Res 18 610 621 18285502 10.1101/gr.7179508 1:CAS:528:DC%2BD1cXks1alsLk%3D (Pubitemid 351482785)
73. BM Ryan AI Robles CC Harris 2010 Genetic variation in microRNA networks: the implications for cancer research Nat Rev Canc 10 389 402 10.1038/nrc2867 1:CAS:528:DC%2BC3cXmsVWmtrw%3D