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Journal of Cardiovascular Translational Research

Published in:

01-06-2010

MicroRNAs and Ultraconserved Genes as Diagnostic Markers and Therapeutic Targets in Cancer and Cardiovascular Diseases

Authors: Julianna K. Edwards, Renata Pasqualini, Wadih Arap, George A. Calin

Published in: Journal of Cardiovascular Translational Research | Issue 3/2010

Abstract

MicroRNAs (miRNAs), approximately 19–25 nucleotides in length, are posttranscriptional regulators of protein expression that target and inhibit translation of messenger (m) RNAs. Recent research on miRNAs has produced a plethora of new material on the role of miRNAs in disease. Deregulation or ablation of miRNA expression has led to major pathologies including heart disease and cancer. Signatures of differential miRNA expression have been uncovered for nearly every disease. Recent research has focused on exploitation of the selectivity of these signatures as markers of disease and for therapeutic applications. The significance of additional mechanisms of abnormal posttranscriptional regulation, such as ultraconserved genes (UCGs), has recently been recognized. This review focuses on the identification of aberrant posttranscriptional regulators (miRNAs and UCGs) in cancer and cardiovascular disease and addresses the applications of this work towards diagnosis and therapy.

Bagga, S., Bracht, J., Hunter, S., Massirer, K., Holtz, J., Eachus, R., et al. (2005). Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell, 122(4), 553–563.CrossRefPubMed

Wang, Y., Liang, Y., & Lu, Q. (2008). MicroRNA epigenetic alterations: Predicting biomarkers and therapeutic targets in human diseases. Clinical Genetics, 74(4), 307–315.CrossRefPubMed

Borchert, G. M., Lanier, W., & Davidson, B. L. (2006). RNA polymerase III transcribes human microRNAs. Nature Structural & Molecular Biology, 13(12), 1097–1101.CrossRef

Gregory, R. I., Yan, K. P., Amuthan, G., Chendrimada, T., Doratotaj, B., Cooch, N., et al. (2004). The Microprocessor complex mediates the genesis of microRNAs. Nature, 432(7014), 235–40.CrossRefPubMed

Hutvágner, G., & Zamore, P. D. (2002). A microRNA in a multiple-turnover RNAi enzyme complex. Science, 297(5589), 2056–2060.CrossRefPubMed

Bejerano, G., Pheasant, M., Makunin, I., Stephen, S., Kent, W. J., Mattick, J. S., et al. (2004). Ultraconserved elements in the human genome. Science, 304(5675), 1321–1325.CrossRefPubMed

Mattick, J. S. (2009). The genetic signatures of noncoding RNAs. PLoS Genet, 5(4), e1000459.CrossRefPubMed

Calin, G. A., Liu, C. G., Ferracin, M., Hyslop, T., Spizzo, R., Sevignani, C., et al. (2007). Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas. Cancer Cell, 12(3), 215–229.CrossRefPubMed

Strong, K., Mathers, C., Leeder, S., & Beaglehole, R. (2005). Preventing chronic diseases: How many lives can we save? Lancet, 366(9496), 1578–1582.CrossRefPubMed

10.

Lloyd-Jones, D., Adams, R. J., Brown, T. M., Carnethon, M., Dai, S., De Simone, G., Ferguson, T. B., Ford, E., Furie, K., Gillespie, C., Go, A., Greenlund, K., Haase, N., Hailpern, S., Ho, P. M., Howard, V., Kissela, B., Kittner, S., Lackland, D., Lisabeth, L., Marelli, A., McDermott, M. M., Meigs, J., Mozaffarian, D., Mussolino, M., Nichol, G., Roger, V., Rosamond, W., Sacco, R, Sorlie, P., Stafford, R., Thom, T., Wasserthiel-Smoller, S., Wong, N. D., Wylie-Rosett, J., on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. (2009) Heart disease and stroke statistics—2010 update. A report from the American Heart Association. Circulation.

11.

Jemal, A., Siegel, R., Ward, E., Murray, T., Xu, J., & Thun, M. J. (2007). Cancer statistics, 2007. CA: A Cancer Journal for Clinicians, 57(1), 43–66.CrossRef

12.

Chen, J. F., Murchison, E. P., Tang, R., Callis, T. E., Tatsuguchi, M., Deng, Z., et al. (2008). Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure. Proceedings of the National Academy of Sciences of the United States of America, 105(6), 2111–2116.CrossRefPubMed

13.

Zhao, Y., Ransom, J. F., Li, A., Vedantham, V., von Drehle, M., Muth, A. N., et al. (2007). Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell, 129(2), 303–317.CrossRefPubMed

14.

Thum, T., Galuppo, P., Wolf, C., Fiedler, J., Kneitz, S., van Laake, L. W., et al. (2007). MicroRNAs in the human heart: A clue to fetal gene reprogramming in heart failure. Circulation, 116(3), 258–267.CrossRefPubMed

15.

van Rooij, E., Sutherland, L. B., Liu, N., Williams, A. H., McAnally, J., Gerard, R. D., et al. (2006). A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proceedings of the National Academy of Sciences of the United States of America, 103(48), 18255–18260.CrossRefPubMed

16.

Hunter, J. J., & Chien, K. R. (1999). Signaling pathways for cardiac hypertrophy and failure. New England Journal of Medicine, 341(17), 1276–1283.CrossRefPubMed

17.

Sayed, D., Hong, C., Chen, I. Y., Lypowy, J., & Abdellatif, M. (2007). MicroRNAs play an essential role in the development of cardiac hypertrophy. Circulation Research, 100(3), 416–424.CrossRefPubMed

18.

Carè, A., Catalucci, D., Felicetti, F., Bonci, D., Addario, A., Gallo, P., et al. (2007). MicroRNA-133 controls cardiac hypertrophy. Nature Medicine, 13(5), 613–618.CrossRefPubMed

19.

Xu, C., Lu, Y., Pan, Z., Chu, W., Luo, X., Lin, H., et al. (2007). The muscle-specific microRNAs miR-1 and miR-133 produce opposing effects on apoptosis by targeting HSP60, HSP70 and caspase-9 in cardiomyocytes. Journal of Cell Science, 120(Pt 17), 3045–3052.CrossRefPubMed

20.

Xiao, J., Luo, X., Lin, H., Zhang, Y., Lu, Y., Wang, N., et al. (2007). MicroRNA miR-133 represses HERG K+channel expression contributing to QT prolongation in diabetic hearts. Journal of Biological Chemistry, 282(17), 12363–12367.CrossRefPubMed

21.

Chan, J. A., Krichevsky, A. M., & Kosik, K. S. (2005). MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Research, 65(14), 6029–6033.CrossRefPubMed

22.

Si, M. L., Zhu, S., Wu, H., Lu, Z., Wu, F., & Mo, Y. Y. (2007). miR-21-mediated tumor growth. Oncogene, 26(19), 2799–2803.CrossRefPubMed

23.

Cheng, Y., Ji, R., Yue, J., Yang, J., Liu, X., Chen, H., et al. (2007). MicroRNAs are aberrantly expressed in hypertrophic heart: Do they play a role in cardiac hypertrophy? American Journal of Pathology, 170(6), 1831–1840.CrossRefPubMed

24.

Tatsuguchi, M., Seok, H. Y., Callis, T. E., Thomson, J. M., Chen, J. F., Newman, M., et al. (2007). Expression of microRNAs is dynamically regulated during cardiomyocyte hypertrophy. Journal of Molecular and Cellular Cardiology, 42(6), 1137–1141.CrossRefPubMed

25.

Thum, T., Gross, C., Fiedler, J., Fischer, T., Kissler, S., Bussen, M., et al. (2008). MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature, 456(7224), 980–984.CrossRefPubMed

26.

Calin, G. A., & Croce, C. M. (2009). Chronic lymphocytic leukemia: Interplay between noncoding RNAs and protein-coding genes. Blood, 114(23), 4761–4770.CrossRefPubMed

27.

Liu, C. G., Spizzo, R., Calin, G. A., & Croce, C. M. (2008). Expression profiling of microRNA using oligo DNA arrays. Methods, 44(1), 22–30.CrossRefPubMed

28.

Volinia, S., Calin, G. A., Liu, C. G., Ambs, S., Cimmino, A., Petrocca, F., et al. (2006). A microRNA expression signature of human solid tumors defines cancer gene targets. Proceedings of the National Academy of Sciences of the United States of America, 103(7), 2257–2261.CrossRefPubMed

29.

Calin, G. A., & Croce, C. M. (2006). MicroRNA signatures in human cancers. Nature ReviewsCancer, 6(11), 857–866.CrossRef

30.

Esquela-Kerscher, A., & Slack, F. J. (2006). Oncomirs-microRNAs with a role in cancer. Nature ReviewsCancer, 6(4), 259–269.CrossRef

31.

Calin, G. A., Dumitru, C. D., Shimizu, M., Bichi, R., Zupo, S., Noch, E., et al. (2002). Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proceedings of the National Academy of Sciences of the United States of America, 99(24), 15524–15529.CrossRefPubMed

32.

Aqeilan, R. I., Calin, G. A., & Croce, C. M. (2010). miR-15a and miR-16-1 in cancer: Discovery, function and future perspectives. Cell Death and Differentiation, 17(2), 215–220.CrossRefPubMed

33.

Nicoloso, M. S., Spizzo, R., Shimizu, M., Rossi, S., & Calin, G. A. (2009). MicroRNAs—The micro steering wheel of tumour metastases. Nature ReviewsCancer, 9(4), 293–302.CrossRef

34.

Schetter, A. J., Leung, S. Y., Sohn, J. J., Zanetti, K. A., Bowman, E. D., Yanaihara, N., et al. (2008). MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA, 299(4), 425–436.CrossRefPubMed

35.

Reinhart, B. J., Slack, F. J., Basson, M., Pasquinelli, A. E., Bettinger, J. C., Rougvie, A. E., et al. (2000). The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature, 403(6772), 901–906.CrossRefPubMed

36.

Takamizawa, J., Konishi, H., Yanagisawa, K., Tomida, S., Osada, H., Endoh, H., et al. (2004). Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Research, 64(11), 3753–3756.CrossRefPubMed

37.

Johnson, S. M., Grosshans, H., Shingara, J., Byrom, M., Jarvis, R., Cheng, A., et al. (2005). RAS is regulated by the let-7 microRNA family. Cell, 120(5), 635–647.CrossRefPubMed

38.

Eccles, S. A., & Welch, D. R. (2007). Metastasis: Recent discoveries and novel treatment strategies. Lancet, 369(9574), 1742–1757.CrossRefPubMed

39.

Tavazoie, S. F., Alarcón, C., Oskarsson, T., Padua, D., Wang, Q., Bos, P. D., et al. (2008). Endogenous human microRNAs that suppress breast cancer metastasis. Nature, 451(7175), 147–152.CrossRefPubMed

40.

Wang, S., Aurora, A. B., Johnson, B. A., Qi, X., McAnally, J., Hill, J. A., et al. (2008). The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Developments Cell, 15(2), 261–271.CrossRef

41.

Wang, S., & Olson, E. N. (2009). AngiomiRs—Key regulators of angiogenesis. Current Opinion in Genetics and Development, 19(3), 205–211.CrossRefPubMed

42.

Fish, J. E., Santoro, M. M., Morton, S. U., Yu, S., Yeh, R. F., Wythe, J. D., et al. (2008). miR-126 regulates angiogenic signaling and vascular integrity. Developments Cell, 15(2), 272–284.CrossRef

43.

Ullah, M. F., & Aatif, M. (2009). The footprints of cancer development: Cancer biomarkers. Cancer Treatment Reviews, 35(3), 193–200.CrossRefPubMed

44.

Lu, J., Getz, G., Miska, E. A., Alvarez-Saavedra, E., Lamb, J., Peck, D., et al. (2005). MicroRNA expression profiles classify human cancers. Nature, 435(7043), 834–838.CrossRefPubMed

45.

Rosenfeld, N., Aharonov, R., Meiri, E., Rosenwald, S., Spector, Y., Zepeniuk, M., et al. (2008). MicroRNAs accurately identify cancer tissue origin. Nature Biotechnology, 26(4), 462–469.CrossRefPubMed

46.

Mercer, T. R., Dinger, M. E., & Mattick, J. S. (2009). Long non-coding RNAs: Insights into functions. Nature Reviews Genetics, 10(3), 155–159.CrossRefPubMed

47.

Reis, E. M., Nakaya, H. I., Louro, R., Canavez, F. C., Flatschart, A. V., Almeida, G. T., et al. (2004). Antisense intronic non-coding RNA levels correlate to the degree of tumor differentiation in prostate cancer. Oncogene, 23(39), 6684–6692.CrossRefPubMed

48.

Calin, G. A., Ferracin, M., Cimmino, A., Di Leva, G., Shimizu, M., Wojcik, S. E., et al. (2005). A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. New England Journal of Medicine, 353(17), 1793–1801. Erratum in: N Engl J Med355(5):533.CrossRefPubMed

49.

Girard, A., Sachidanandam, R., Hannon, G. J., & Carmell, M. A. (2006). A germline-specific class of small RNAs binds mammalian Piwi proteins. Nature, 442(7099), 199–202.PubMed

50.

Aravin, A., Gaidatzis, D., Pfeffer, S., Lagos-Quintana, M., Landgraf, P., Iovino, N., et al. (2006). A novel class of small RNAs bind to MILI protein in mouse testes. Nature, 442(7099), 203–207.PubMed

51.

Saito, K., Nishida, K. M., Mori, T., Kawamura, Y., Miyoshi, K., Nagami, T., et al. (2006). Specific association of Piwi with rasiRNAs derived from retrotransposon and heterochromatic regions in the Drosophila genome. Genes and Development, 20(16), 2214–2222.CrossRefPubMed

52.

O’Donnell, K. A., & Boeke, J. D. (2007). Mighty Piwis defend the germline against genome intruders. Cell, 129(1), 37–44.CrossRefPubMed

53.

Klattenhoff, C., & Theurkauf, W. (2008). Biogenesis and germline functions of piRNAs. Development, 135(1), 3–9.CrossRefPubMed

54.

Lau, N. C., Seto, A. G., Kim, J., Kuramochi-Miyagawa, S., Nakano, T., Bartel, D. P., et al. (2006). Characterization of the piRNA complex from rat testes. Science, 313(5785), 363–367.CrossRefPubMed

55.

Gunawardane, L. S., Saito, K., Nishida, K. M., Miyoshi, K., Kawamura, Y., Nagami, T., et al. (2007). A slicer-mediated mechanism for repeat-associated siRNA 5′ end formation in Drosophila. Science, 315(5818), 1587–1590.CrossRefPubMed

56.

Wurdinger, T., & Costa, F. F. (2007). Molecular therapy in the microRNA era. Pharmacogenomics Journal, 7(5), 297–304.CrossRefPubMed

57.

Aravin, A., & Tuschl, T. (2005). Identification and characterization of small RNAs involved in RNA silencing. FEBS Letters, 579(26), 5830–5840.CrossRefPubMed

58.

Rossi, S., Sevignani, C., Nnadi, S. C., Siracusa, L. D., & Calin, G. A. (2008). Cancer-associated genomic regions (CAGRs) and noncoding RNAs: Bioinformatics and therapeutic implications. Mammalian Genome, 19(7–8), 526–540.CrossRefPubMed

59.

Weiler, J., Hunziker, J., & Hall, J. (2006). Anti-miRNA oligonucleotides (AMOs): Ammunition to target miRNAs implicated in human disease? Gene Therapy, 13(6), 496–502.CrossRefPubMed

60.

Krützfeldt, J., Rajewsky, N., Braich, R., Rajeev, K. G., Tuschl, T., Manoharan, M., et al. (2005). Silencing of microRNAs in vivo with ‘antagomirs’. Nature, 438(7068), 685–689.CrossRefPubMed

61.

Martinez, J., Patkaniowska, A., Urlaub, H., Lührmann, R., & Tuschl, T. (2002). Single-stranded antisense siRNAs guide target RNA cleavage in RNAi. Cell, 110(5), 563–574.CrossRefPubMed

62.

Cimmino, A., Calin, G. A., Fabbri, M., Iorio, M. V., Ferracin, M., Shimizu, M., et al. (2005). miR-15 and miR-16 induce apoptosis by targeting BCL2. Proceedings of the National Academy of Sciences of the United States of America, 102(39), 13944–13949.CrossRefPubMed

63.

Calin, G. A., Cimmino, A., Fabbri, M., Ferracin, M., Wojcik, S. E., Shimizu, M., et al. (2008). miR-15a and miR-16-1 cluster functions in human leukemia. Proceedings of the National Academy of Sciences of the United States of America, 105(13), 5166–5171.CrossRefPubMed

64.

Weidhaas, J. B., Babar, I., Nallur, S. M., Trang, P., Roush, S., Boehm, M., et al. (2007). MicroRNAs as potential agents to alter resistance to cytotoxic anticancer therapy. Cancer Research, 67(23), 11111–11116.CrossRefPubMed

65.

Duisters, R. F., Tijsen, A. J., Schroen, B., Leenders, J. J., Lentink, V., van der Made, I., et al. (2009). miR-133 and miR-30 regulate connective tissue growth factor: Implications for a role of microRNAs in myocardial matrix remodeling. Circulation Research, 104(2), 170–178. 6p following 178.CrossRefPubMed

66.

van Rooij, E., Sutherland, L. B., Qi, X., Richardson, J. A., Hill, J., & Olson, E. N. (2007). Control of stress-dependent cardiac growth and gene expression by a microRNA. Science, 316(5824), 575–579.CrossRefPubMed

67.

Meng, F., Henson, R., Wehbe-Janek, H., Ghoshal, K., Jacob, S. T., & Patel, T. (2007). MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology, 133(2), 647–658.CrossRefPubMed

68.

Asangani, I. A., Rasheed, S. A., Nikolova, D. A., Leupold, J. H., Colburn, N. H., Post, S., et al. (2008). MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene, 27(15), 2128–2136.CrossRefPubMed

69.

Zhu, S., Si, M. L., Wu, H., & Mo, Y. Y. (2007). MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). Journal of Biological Chemistry, 282(19), 14328–14336.CrossRefPubMed

70.

Iorio, M. V., Ferracin, M., Liu, C. G., Veronese, A., Spizzo, R., Sabbioni, S., et al. (2005). MicroRNA gene expression deregulation in human breast cancer. Cancer Research, 65(16), 7065–7070.CrossRefPubMed

71.

Gironella, M., Seux, M., Xie, M. J., Cano, C., Tomasini, R., Gommeaux, J., et al. (2007). Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development. Proceedings of the National Academy of Sciences of the United States of America, 104(41), 16170–16175.CrossRefPubMed

72.

Harris, T. A., Yamakuchi, M., Ferlito, M., Mendell, J. T., & Lowenstein, C. J. (2008). MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proceedings of the National Academy of Sciences of the United States of America, 105(5), 1516–1521.CrossRefPubMed

73.

Ma, L., Teruya-Feldstein, J., & Weinberg, R. A. (2007). Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature, 449(7163), 682–688.CrossRefPubMed

74.

He, L., Thomson, J. M., Hemann, M. T., Hernando-Monge, E., Mu, D., Goodson, S., et al. (2005). A microRNA polycistron as a potential human oncogene. Nature, 435(7043), 828–833.CrossRefPubMed

75.

Dews, M., Homayouni, A., Yu, D., Murphy, D., Sevignani, C., Wentzel, E., et al. (2006). Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. Nature Genetics, 38(9), 1060–1065.CrossRefPubMed

76.

Bonauer, A., Carmona, G., Iwasaki, M., Mione, M., Koyanagi, M., Fischer, A., et al. (2009). MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science, 324(5935), 1710–1713.CrossRefPubMed

Title: MicroRNAs and Ultraconserved Genes as Diagnostic Markers and Therapeutic Targets in Cancer and Cardiovascular Diseases
Authors: Julianna K. Edwards
Renata Pasqualini
Wadih Arap
George A. Calin
Publication date: 01-06-2010
Publisher: Springer US
Published in: Journal of Cardiovascular Translational Research / Issue 3/2010
Print ISSN: 1937-5387
Electronic ISSN: 1937-5395
DOI: https://doi.org/10.1007/s12265-010-9179-5

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