Evolution of the Mir-155 Family and Possible Targets in Cancers and the Immune System

  • Published : 2014.10.11


The mir-155 family is not only involved in a diversity of cancers, but also as a regulator of the immune system. However, the evolutionary history of this family is still unclear. The present study indicates that mir-155 evolved independently with lineage-specific gain of miRNAs. In addition, arm switching has occurred in the mir-155 family, and alternative splicing could produce two different lengths of ancestral sequences, implying the alternative splicing can also drive evolution for intragenic miRNAs. Here we screened validated target genes and immunity-related proteins, followed by analyzation of the mir-155 family function by high-throughput methods like the gene ontology (GO) and Kyoto Eneyclopedin of Genes and Genemes (KEGG) pathway enrichment analysis. The high-throughput analysis showed that the CCND1 and EGFR genes were outstanding in being significantly enriched, and the target genes cebpb and VCAM1 and the protein SMAD2 were also vital in mir-155-related immune reponse activities. Therefore, we conclude that the mir-155 family is highly conserved in evolution, and CCND1 and EGFR genes might be potential targets of mir-155 with regard to progress of cancers, while the cebpb and VCAM1 genes and the protein SMAD2 might be key factors in the mir-155 regulated immune activities.


  1. Babar IA, Cheng CJ, Booth CJ, et al (2012). Nanoparticle-based therapy in an in vivo microRNA-155 (miR-155)-dependent mouse model of lymphoma. Proc Natl Acad Sci USA, 109, 1695-704.
  2. Concepcion CP, Bonetti C, Ventura A (2012). The microRNA-17-92 family of microRNA clusters in development and disease. Cancer J, 18, 262-7.
  3. Bartel DP (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell, 116, 281-97.
  4. Bartel DP (2009). MicroRNAs: target recognition and regulatory functions. Cell, 136, 215-33.
  5. Blow MJ, Grocock RJ, van Dongen S, et al (2006). RNA editing of human microRNAs. Genome biology, 7, 27.
  6. Corsten MF, Papageorgiou A, Verhesen W, et al (2012). MicroRNA profiling identifies microRNA-155 as an adverse mediator of cardiac injury and dysfunction during acute viral myocarditis. Circulation Res, 111, 415-25.
  7. Croce CM (2008). Oncogenes and cancer. N Engl J Med, 358, 502-11.
  8. Darty K, Denise A, Ponty Y (2009). VARNA: Interactive drawing and editing of the RNA secondary structure. Bioinformatics, 25, 1974.
  9. Das R, Xu S, Quan X, et al (2014). Upregulation of mitochondrial Nox4 mediates TGF-$\beta$-induced apoptosis in cultured mouse podocytes. Am J Physiol Renal Physio, 306, 155-67.
  10. de Wit E, Linsen SE, Cuppen E, Berezikov E (2009). Repertoire and evolution of miRNA genes in four divergent nematode species. Genome Res, 19, 2064-74.
  11. Elton TS, Selemon H, Elton SM, Parinandi NL (2013). Regulation of the MIR155 host gene in physiological and pathological processes. Gene, 532, 1-12.
  12. Farooqi AA, Qureshi MZ, Coskunpinar E, et al (2014). miR-421, miR-155 and miR-650: emerging trends of regulation of cancer and apoptosis. Asian Pac J Cancer Prev, 15, 1909-12.
  13. Griffiths-Jones S, Hui JH, Marco A, Ronshaugen M (2011). MicroRNA evolution by arm switching. EMBO Rep, 12, 172-7.
  14. Hsu SD, Lin FM, Wu WY, et al (2011). miRTarBase: a database curates experimentally validated microRNA-target interactions. Nucleic Acids Res, 39, 163-9.
  15. Grimson A, Srivastava M, Fahey B, et al (2008). Early origins and evolution of microRNAs and Piwi-interacting RNAs in animals. Nature, 455, 1193-7.
  16. Guddeti S, De Chun ZHANG ALL, LESEBERG C H, et al (2005). Molecular evolution of the rice miR395 gene family. Cell Res, 15, 631-8.
  17. Hertel J, Bartschat S, Wintsche A, et al (2012). Evolution of the let-7 microRNA Family. RNA biology, 9, 231-41.
  18. Hu H Y, He L, Fominykh K, et al (2012). Evolution of the humanspecific microRNA miR-941. Nature Communications, 3, 1145.
  19. Kinsella RJ, Kähäri A, Haider S, et al (2011). Ensembl BioMarts:a hub for data retrieval across taxonomic space. Database, 2011, 30.
  20. Kozomara A, Griffiths-Jones S (2011). miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res, 39, 152-7.
  21. Landthaler M, Yalcin A, Tuschl T (2004). The human DiGeorge syndrome critical region gene 8 and its D. melanogaster homolog are required for miRNA biogenesis. Curr Biol, 14, 2162-7.
  22. Larkin M, Blackshields G, Brown N, et al (2007). Clustal W and Clustal X version 2.0. Bioinformatics, 23, 2947-8.
  23. Lewis BP, Shih IH, Jones-Rhoades MW, et al (2003). Prediction of mammalian microRNA targets. Cell, 115, 787-98.
  24. Liang T, Guo L, Liu C (2012). Genome-wide analysis of mir-548 gene family reveals evolutionary and functional implications. J Biomed Biotechnol, 2012, 679563
  25. Marco A, Hooks K, Griffiths-Jones S (2012a). Evolution and function of the extended miR-2 microRNA family. RNA biology, 9, 242-8.
  26. Louafi F, Martinez-Nunez RT, Sanchez-Elsner T (2010). MicroRNA-155 targets SMAD2 and modulates the response of macrophages to transforming growth factor-$\beta$. J Biol Chem, 285, 41328-36.
  27. MacRae IJ, Zhou K, Li F, et al (2006). Structural basis for doublestranded RNA processing by Dicer. Science, 311, 195-8.
  28. Maher C, Stein L, Ware D (2006). Evolution of Arabidopsis microRNA families through duplication events. Genome research, 16, 510-9.
  29. Marco A, Hui JH, Ronshaugen M, Griffiths-Jones S (2010). Functional shifts in insect microRNA evolution. Genome Biol Evol, 2, 686.
  30. Marco A, MacPherson JI, Ronshaugen M, Griffiths-Jones S (2012b). MicroRNAs from the same precursor have different targeting properties. Silence, 3, 8-.
  31. Marco A, Ninova M, Ronshaugen M, Griffiths-Jones S (2013). Clusters of microRNAs emerge by new hairpins in existing transcripts. Nucleic Acids Res, 41, 7745-52.
  32. Mattiske S, Suetani RJ, Neilsen PM, Callen DF (2012). The oncogenic role of miR-155 in breast cancer. Cancer Epidemiol Biomarkers Prev, 21, 1236-43.
  33. Nahvi A, Shoemaker CJ, Green R (2009). An expanded seed sequence definition accounts for full regulation of the hid 3' UTR by bantam miRNA. RNA, 15, 814-22.
  34. O'Connell RM, Chaudhuri AA, Rao D S, Baltimore D (2009). Inositol phosphatase SHIP1 is a primary target of miR-155. Proc Natl Acad Sci USA, 106, 7113-8.
  35. O'Connell RM, Rao DS, Baltimore D (2012). microRNA regulation of inflammatory responses. Annu Rev Immuno 30, 295-312.
  36. Schwarz D S, Hutvagner G, Du T, et al (2003). Asymmetry in the assembly of the RNAi enzyme complex. Cell, 115, 199-208.
  37. Prasad TK, Goel R, Kandasamy K, et al (2009). Human protein reference database-2009 update. Nucleic Acids res, 37, 767-72.
  38. Price N, Cartwright RA, Sabath N, et al (2011). Neutral evolution of robustness in Drosophila microRNA precursors. Mol Biol Evol, 28, 2115-23.
  39. Pritchard CC, Cheng HH, Tewari M (2012). MicroRNA profiling: approaches and considerations. Nat Rev Gene, 13, 358-69.
  40. Smoot ME, Ono K, Ruscheinski J, et al (2011). Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics, 27, 431-2.
  41. Tamura K, Dudley J, Nei M, Kumar S (2007). MEGA4: molecular evolutionary genetics analysis (MEGA) software version 4.0. Mol Biol Evol, 24, 1596-9.
  42. Vargova K, Curik N, Burda P, et al (2011). MYB transcriptionally regulates the miR-155 host gene in chronic lymphocytic leukemia. Blood, 117, 3816-25.
  43. Vigorito E, Kohlhaas S, Lu D, Leyland R (2013). miR-155: an ancient regulator of the immune system. Immunological reviews, 253, 146-57.
  44. Wang L, Toomey N L, Diaz L A, et al (2011). Oncogenic IRFs provide a survival advantage for Epstein-Barr virus-or human T-cell leukemia virus type 1-transformed cells through induction of BIC expression. J Virol, 85, 8328-37.
  45. Wang X (2008). miRDB: a microRNA target prediction and functional annotation database with a wiki interface. Rna, 14, 1012-7.
  46. Wheeler BM, Heimberg AM, Moy VN, et al (2009). The deep evolution of metazoan microRNAs. Evol Dev, 11, 50-68.
  47. Yi R, Qin Y, Macara I G, Cullen B R (2003). Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev, 17, 3011-6.
  48. Wienholds E, Kloosterman WP, Miska E, et al (2005). MicroRNA expression in zebrafish embryonic development. Science, 309, 310-1.
  49. Xiao F, Zuo Z, Cai G, et al (2009). miRecords: an integrated resource for microRNA–target interactions. Nucleic Acids Res, 37, 105-10.
  50. Xu L, Dai WQ, Xu XF, et al (2012). Effects of multiple-target antimicroRNA antisense oligodeoxyribonucleotides on proliferation and migration of gastric cancer cells. Asian Pac J Cancer Prev, 13, 3203-7.
  51. Zhang H, Kolb F A, Jaskiewicz L, et al (2004). Single processing center models for human Dicer and bacterial RNase III. Cell, 118, 57-68.
  52. Zhang J, Haider S, Baran J, et al (2011). BioMart: a data federation framework for large collaborative projects. Database, 2011, 38.
  53. Zheng SR, Guo GL, Zhai Q, et al (2013). Effects of miR-155 antisense oligonucleotide on breast carcinoma cell line MDA-MB-157 and implanted tumors. Asian Pac J Cancer Prev, 14, 2361-6.
  54. Liu ZY, Zhang GL, Wang MM, Xiong YN, Cui HQ (2011). MicroRNA-663 targets TGFB1 and regulates lung cancer proliferation. Asian Pac J Cancer Pre, 12, 2819-23.
  55. Zuker M (2003). Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res, 31, 3406-15.

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