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US 2007005O146A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/005014.6 A1 Bentwich et al. (43) Pub. Date: Mar. 1, 2007 (54) MICRORNAS AND USES THEREOF filed on Mar. 25, 2005. Provisional application No. 60/662,742, filed on Mar. 17, 2005. Provisional appli (76) Inventors: Itzhak Bentwich, Kvutzat Shiller (IL); cation No. 60/593,329, filed on Jan. 6, 2005. Provi Amir AVniel, Givataim (IL); Yael sional application No. 60/593,081, filed on Dec. 8, Karov, Tel-Aviv (IL); Ranit Aharonov, 2004. Provisional application No. 60/522,860, filed Tel-Aviv (IL) on Nov. 15, 2004. Provisional application No. 60/522, 457, filed on Oct. 4, 2004. Provisional application No. Correspondence Address: 60/522,452, filed on Oct. 3, 2004. Provisional appli HOWREY LLP cation No. 60/522,449, filed on Oct. 3, 2004. CFO IP DOCKETING DEPARTMENT 2941 FAIRVIEW PARK DR, SUITE 200 Publication Classification FALLS CHURCH, VA 22042-2924 (US) (51) Int. Cl. (21) Appl. No.: 11/130,645 CI2O I/68 (2006.01) G06F 9/00 (2006.01) (22) Filed: May 16, 2005 C7H 2L/04 (2006.01) (52) U.S. Cl. ................................ 702/19; 435/6; 536/24.3 Related U.S. Application Data (63) Continuation of application No. PCT/US05/16986, (57) ABSTRACT filed on May 14, 2005. Continuation-in-part of application No. 10/709,577. Described herein are novel polynucleotides associated with filed on May 14, 2004. prostate and lung cancer. The polynucleotides are miRNAS Continuation-in-part of application No. 10/709,572, and miRNA precursors. Related methods and compositions filed on May 14, 2004. that can be used for diagnosis, prognosis, and treatment of those medical conditions are disclosed. Also described (60) Provisional application No. 60/666,340, filed on Mar. herein are methods that can be used to identify modulators 30, 2005. Provisional application No. 60/665,094, of prostate and lung cancer. Patent Application Publication Mar. 1, 2007 Sheet 1 of 5 US 2007/005O146 A1 FIGURE C Exogenous dsRNA, transposon, virus, ... o (7) Long dsRNA eggs e Geo P. Ot Pre-miRNA Pre-miRNA Pre-miRNA e Ges 6) 3cul Nucleus 6 P 0 Glee amo Ca Cytoplasm triticial stillEir miRNA:miRNA- duplex SETI siRNA duplexes G) RAN-GT Nucleus ASY (4) olco mo O. Cytoplasm irring (5) assage (5) immins miRNA:miRNA duplex tuitu sitti 6 ... re. (5) sits 0. s Maurent RNA within RSC es (7) (7) Matre minA within RISC Target mRNAs from loci unrelated to miRNA gene Patent Application Publication Mar. 1, 2007 Sheet 2 of 5 US 2007/005O146 A1 ZGIRLÍTÐIH Patent Application Publication Mar. 1, 2007 Sheet 3 of 5 US 2007/005014.6 A1 s3 3 3 3 3 S. s 3 3 Patent Application Publication Mar. 1, 2007 Sheet 5 of 5 US 2007/00501.46A1 FIGURE 5 A B Poly-A f1 f2 rf r2 5 ---------, 3' BOO24579 as A42 A43 BOO24418 mm BF508730 ammum AW590194 mm Expected fragments FR1 -ms- 1406 bp FR2 2616 bp FR3 - 3257 bp FR FR2 FR3 Observed fragments -- - - - -- u 21226 4.38 3S) 227 154 35 C A42 A43 mmer-b -> US 2007/005O146 A1 Mar. 1, 2007 MICRORNAS AND USES THEREOF SUMMARY OF THE INVENTION 0006 The present invention is related to an isolated CROSS REFERENCE TO RELATED nucleic acid comprising a sequence of a pri-miRNA, pre APPLICATIONS miRNA, miRNA, miRNA*, anti-miRNA, or a miRNA bind 0001. The present application is a continuation of the ing site, or a variant thereof. The nucleic acid may comprise International Application of Bentwich et al., entitled the sequence of a hairpin referred to in Table 1: the sequence “MICRORNAS AND USES THEREOF filed May 14, of sequence identifiers 6757248-6894882 of the Sequence 2005, which is a continuation-in-part of U.S. application Ser. Listing of U.S. patent application Ser. No. 10/709,572, No. 10/709,577, filed May 14, 2004, and U.S. application which is incorporated herein by reference; the sequence of Ser. No. 10/709,572, filed May 14, 2004, and which claims sequence identifiers 1-6318 or 18728-18960 of the Sequence the benefit of U.S. Provisional Application No. 60/666,340, Listing of U.S. Provisional Patent Application No. 60/655, filed Mar. 30, 2005, U.S. Provisional Application No. 094, which is incorporated herein by reference; the sequence 60/665,094, filed Mar. 25, 2005, U.S. Provisional Applica of a miRNA referred to in Table 1: the sequence of sequence tion No. 60/662,742, filed Mar. 17, 2005, U.S. Provisional identifiers 1-117750 or 6894883-10068.177 of the Sequence Application No. 60/593,329, filed Jan. 6, 2005, U.S. Provi Listing of U.S. patent application Ser. No. 10/709,572, sional Application No. 60/593,081, filed Dec. 8, 2004, U.S. which is incorporated herein by reference; the sequence of Provisional Application No. 60/522,860, filed Nov. 15, sequence identifiers 6319-18727 or 18961-19401 of the 2004, U.S. Provisional Application No. 60/522.457, filed Sequence Listing of U.S. Provisional Patent Application No. Oct. 4, 2004, U.S. Provisional Application No. 60/522,452, 60/655,094, which is incorporated herein by reference; the filed Oct. 3, 2004, and U.S. Provisional Application No. sequence of a target gene binding site referred to in Table 4; 60/522,449, filed Oct. 3, 2004, the contents of which are the sequence of sequence identifiers 117751-6757247 of the incorporated herein by reference. Sequence Listing of U.S. patent application Ser. No. 10/709, 572, which is incorporated herein by reference; a comple FIELD OF THE INVENTION ment thereof, or a sequence comprising at least 12 contigu ous nucleotides at least 60% identical thereto. The isolated 0002 The invention relates in general to microRNA nucleic acid may be from 5-250 nucleotides in length. molecules as well as various nucleic acid molecules relating 0007. The present invention is also related to a probe thereto or derived therefrom. comprising the nucleic acid. The probe may comprise at least 8-22 contiguous nucleotides complementary to a BACKGROUND OF THE INVENTION miRNA referred to in Table 2 as differentially expressed in 0003 MicroRNAs (miRNAs) are short RNA oligonucle prostate cancer or lung cancer. otides of approximately 22 nucleotides that are involved in 0008. The present invention is also related to a plurality gene regulation. MicroRNAS regulate gene expression by of the probes. The plurality of probes may comprise at least targeting mRNAS for cleavage or translational repression. one probe complementary to each miRNA referred to in Although miRNAS are present in a wide range of species Table 2 as differentially expressed in prostate cancer. The including C. elegans, Drosophilla and humans, they have plurality of probes may also comprise at least one probe only recently been identified. More importantly, the role of complementary to each miRNA referred to in Table 2 as miRNAS in the development and progression of disease has differentially expressed in lung cancer. only recently become appreciated. 0009. The present invention is also related to a compo 0004 As a result of their small size, miRNAs have been sition comprising a probe or plurality of probes. difficult to identify using standard methodologies. A limited 0010. The present invention is also related to a biochip number of miRNAs have been identified by extracting large comprising a solid Substrate, said Substrate comprising a quantities of RNA. MiRNAs have also been identified that plurality of probes. Each of the probes may be attached to contribute to the presentation of visibly discernable pheno the substrate at a spatially defined address. The biochip may types. Expression array data shows that miRNAs are comprise probes that are complementary to a miRNA expressed in different developmental stages or in different referred to in Table 2 as differentially expressed in prostate tissues. The restriction of miRNAs to certain tissues or at cancer. The biochip may also comprise probes that are limited developmental stages indicates that the miRNAs complementary to a miRNA referred to in Table 2 as identified to date are likely only a small fraction of the total differentially expressed in lung cancer. miRNAs. 0011. The present invention is also related to a method of 0005 Computational approaches have recently been detecting differential expression of a disease-associated developed to identify the remainder of miRNAs in the miRNA. A biological sample may be provide and the level genome. Tools such as MiRscan and MiRseeker have iden of a nucleic acid measured that is at least 70% identical to tified miRNAs that were later experimentally confirmed. a sequence of a miRNA referred to in Table 1: the sequence Based on these computational tools, it has been estimated of sequence identifiers 1-117750 or 6894883-10068.177 of that the human genome contains 200-255 miRNA genes. the Sequence Listing of U.S. patent application Ser. No. These estimates are based on an assumption, however, that 10/709,572, which is incorporated herein by reference; the the miRNAs remaining to be identified will have the same sequence of sequence identifiers 6319-18727 or 18961 properties as those miRNAs already identified. Based on the 19401 of the Sequence Listing of U.S. Provisional Patent fundamental importance of miRNAS in mammalian biology Application No. 60/655,094, which is incorporated herein and disease, the art needs to identify unknown miRNAs. The by reference; or variants thereof. A difference in the level of present invention satisfies this need and provides a signifi the nucleic acid compared to a control is indicative of cant number of miRNAs and uses therefore.
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  • TUMOR Weight Pvalue LLID Unigene Clone ID Gene Name Clone Title

    TUMOR Weight Pvalue LLID Unigene Clone ID Gene Name Clone Title

    TUMOR Weight pValue LLID UniGene Clone ID Gene Name Clone Title DFSP 21.995618 0.000001 22901 Hs.279937 767289 KIAA1001 KIAA1001 protein (arylsulfatase G ) DFSP 20.640497 0.000001 22901 Hs.279937 767289 KIAA1001 KIAA1001 protein (arylsulfatase G ) DFSP 16.808706 0.000001 115207 Hs.109438 491519 LOC115207 hypothetical protein BC013764 Potassium channel tetramerisation domain containing 12 (KCTD12) DFSP 16.762566 0.000001 6241 Hs.75319 624627 RRM2 ribonucleotide reductase M2 polypeptide DFSP 15.336772 0.000001 26960 Hs.3821 32273 NBEA neurobeachin DFSP 15.292698 0.000001 3956 Hs.227751 2911117 LGALS1 lectin, galactoside-binding, soluble, 1 (galectin 1) DFSP 14.971929 0.000001 4853 Hs.8121 855336 NOTCH2 Notch homolog 2 (Drosophila) DFSP 14.461723 0.000001 2012 Hs.79368 1589468 EMP1 epithelial membrane protein 1 DFSP 14.2439 0.000001 10253 Hs.18676 813698 SPRY2 sprouty homolog 2 (Drosophila) DFSP 14.096623 0.000001 1306 Hs.83164 809901 COL15A1 collagen, type XV, alpha 1 DFSP 13.865339 0.000001 192137 Hs.239870 138929 HCC-4 cervical cancer oncogene 4 DFSP 13.84257 0.000001 10184 Hs.79299 1469377 LHFPL2 lipoma HMGIC fusion partner-like 2 DFSP 13.022625 0.000001 124540 Hs.173179 244227 MSI2 musashi homolog 2 (Drosophila) DFSP 12.98912 0.000001 64216 Hs.7395 897576 TFB2M transcription factor B2, mitochondrial DFSP 12.551832 0.000001 8829 Hs.69285 489535 NRP1 neuropilin 1 DFSP 12.417664 0.000001 26471 Hs.8603 80484 P8 p8 protein (candidate of metastasis 1) DFSP 12.344255 0.000001 10577 Hs.119529 854644 NPC2 Niemann-Pick disease, type C2 DFSP 12.260815