mIRN21

MicroRNA 21
Identifiers
Symbols MIR21 ; MIRN21; hsa-mir-21; miR-21; miRNA21
External IDs OMIM: 611020 GeneCards: MIR21 Gene
Orthologs
Species Human Mouse
Entrez 406991 387140
Ensembl ENSG00000199004 ENSMUSG00000065455
UniProt n/a n/a
RefSeq (mRNA) n/a n/a
RefSeq (protein) n/a n/a
Location (UCSC) Chr 17:
59.84 – 59.84 Mb		 n/a
PubMed search

microRNA 21 also known as hsa-mir-21 or miRNA21 is a mammalian microRNA that is encoded by the MIR21 gene.[1]

MIRN21 was one of the first mammalian microRNAs identified. The mature miR-21 sequence is strongly conserved throughout evolution. The human microRNA-21 gene is located on plus strand of chromosome 17q23.2 (55273409–55273480) within a coding gene TMEM49 (also called vacuole membrane protein). Despite being located in intronic regions of a coding gene in the direction of transcription, it has its own promoter regions and forms a ~3433-nt long primary transcript of miR-21 (known as pri-miR-21) which is independently transcribed. The stem–loop precursor of miR-21(pre-miR-21) resides between nucleotides 2445 and 2516 of pri-miR-21.

Mature miR-21

Pri-miR-21 is cut by the endonuclease Drosha in the nucleus to produce pre-miR-21, which is exported into the cytosol. This pre-miR-21 is then cut into a short RNA duplex by Dicer in the cytosol. Although abundance of both strands is equal by transcription, only one strand (miR-21) is selected for processing as mature microRNA based on the thermodynamic stability of each end of the duplex, while the other strand (designated with an asterisk; miR-21*) is generally degraded. Mature microRNA is then loaded into microRNA ribonucleoprotein complex RISC (RNA-induced silencing complex) and guided to target mRNAs with near perfect complimentarily at 3’UTR.

Targets

A number of targets for microRNA-21 have been experimentally validated and most of them are tumor suppressors, Notable targets include:

Clinical significance

Cancer

miR-21 is one of the most frequently upregulated miRNAs in solid tumours, and its high levels were first described in B cell lymphomas. Overall, miR-21 is considered to be a typical 'onco-miR', which acts by inhibiting the expression of phosphatases, which limit the activity of signalling pathways such as AKT and MAPK.[18] miR-21 can be transcriptionally activated by NF-κB and downregulate phosphatases PDCD4 and PTEN. A recent study also suggested that miR-21 could provide a link between inflammation and cancer.[18] As most of the targets of miR-21 are tumor suppressors, miR-21 is associated with a wide variety of cancers including that of breast,[19] ovaries,[20] cervix,[21] colon,[10] lung,[22] liver,[11] brain,[23] esophagus,[24] prostate,[22] pancreas,[22] and thyroid.[25] A 2014 meta-analysis of 36 studies evaluated circulating miR-21 as a biomarker of various carinomas, finding it has potential as a tool for early diagnosis.[26]

Cardiac disease

miR-21 has been shown to play important role in development of heart disease. It is one of the microRNAs whose expression is increased in failing murine and human hearts.[16][27] Further, inhibition of microRNAs in mice using chemically modified and cholesterol-conjugated miRNA inhibitors (antagomirs) was shown to inhibit interstitial fibrosis and improve cardiac function in a pressure- overload cardiac disease mice model.[16] Surprisingly, miR-21 global knock-out mice did not show any overt phenotype when compared with wild type mice with respect to cardiac stress response. Similarly, short (8-nt) oligonucleotides designed to inhibit miR-21 could not inhibit cardiac hypertrophy or fibrosis.[28] In another study with a mouse model of acute myocardial infarction, miR-21 expression was found to be significantly lower in infarcted areas and overexpression of miR-21 in those mice via adenovirus-mediated gene transfer decreased myocardial infarct size.[29] miR-21 has been hypothesized to be an intermediary in the effects of air pollution that lead to endothelial dysfunction and eventually to cardiac disease. Expression of miR-21 is negatively associated with exposure to PM10 air pollution and may mediate its effect on small blood vessels.[30]

References

  1. ↑ Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T (Oct 2001). "Identification of novel genes coding for small expressed RNAs". Science 294 (5543): 853–8. doi:10.1126/science.1064921. PMID 11679670.
  2. ↑ Liu M, Wu H, Liu T, Li Y, Wang F, Wan H, Li X, Tang H (Jul 2009). "Regulation of the cell cycle gene, BTG2, by miR-21 in human laryngeal carcinoma". Cell Research 19 (7): 828–37. doi:10.1038/cr.2009.72. PMID 19546886.
  3. ↑ Wickramasinghe NS, Manavalan TT, Dougherty SM, Riggs KA, Li Y, Klinge CM (May 2009). "Estradiol downregulates miR-21 expression and increases miR-21 target gene expression in MCF-7 breast cancer cells". Nucleic Acids Research 37 (8): 2584–95. doi:10.1093/nar/gkp117. PMC 2677875. PMID 19264808.
  4. ↑ Zheng J, Xue H, Wang T, Jiang Y, Liu B, Li J, Liu Y, Wang W, Zhang B, Sun M (Mar 2011). "miR-21 downregulates the tumor suppressor P12 CDK2AP1 and stimulates cell proliferation and invasion". Journal of Cellular Biochemistry 112 (3): 872–80. doi:10.1002/jcb.22995. PMID 21328460.
  5. 1 2 3 Papagiannakopoulos T, Shapiro A, Kosik KS (Oct 2008). "MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells". Cancer Research 68 (19): 8164–72. doi:10.1158/0008-5472.CAN-08-1305. PMID 18829576.
  6. ↑ Lu TX, Munitz A, Rothenberg ME (Apr 2009). "MicroRNA-21 is up-regulated in allergic airway inflammation and regulates IL-12p35 expression". Journal of Immunology 182 (8): 4994–5002. doi:10.4049/jimmunol.0803560. PMC 4280862. PMID 19342679.
  7. ↑ Hashimi ST, Fulcher JA, Chang MH, Gov L, Wang S, Lee B (Jul 2009). "MicroRNA profiling identifies miR-34a and miR-21 and their target genes JAG1 and WNT1 in the coordinate regulation of dendritic cell differentiation". Blood 114 (2): 404–14. doi:10.1182/blood-2008-09-179150. PMC 2927176. PMID 19398721.
  8. ↑ Yelamanchili SV, Chaudhuri AD, Chen LN, Xiong H, Fox HS (September 2010). "MicroRNA-21 dysregulates the expression of MEF2C in neurons in monkey and human SIV/HIV neurological disease". Cell Death & Disease 1: e77. doi:10.1038/cddis.2010.56. PMC 3002786. PMID 21170291.
  9. ↑ Valeri N, Gasparini P, Braconi C, Paone A, Lovat F, Fabbri M, Sumani KM, Alder H, Amadori D, Patel T, Nuovo GJ, Fishel R, Croce CM (Dec 2010). "MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2)". Proceedings of the National Academy of Sciences of the United States of America 107 (49): 21098–103. doi:10.1073/pnas.1015541107. PMC 3000294. PMID 21078976.
  10. 1 2 Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S, Allgayer H (Apr 2008). "MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer". Oncogene 27 (15): 2128–36. doi:10.1038/sj.onc.1210856. PMID 17968323.
  11. 1 2 Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T (Aug 2007). "MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer". Gastroenterology 133 (2): 647–58. doi:10.1053/j.gastro.2007.05.022. PMC 4285346. PMID 17681183.
  12. ↑ Gabriely G, Wurdinger T, Kesari S, Esau CC, Burchard J, Linsley PS, Krichevsky AM (Sep 2008). "MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators". Molecular and Cellular Biology 28 (17): 5369–80. doi:10.1128/MCB.00479-08. PMC 2519720. PMID 18591254.
  13. ↑ Sabatel C, Malvaux L, Bovy N, Deroanne C, Lambert V, Gonzalez ML, Colige A, Rakic JM, Noël A, Martial JA, Struman I. "MicroRNA-21 exhibits antiangiogenic function by targeting RhoB expression in endothelial cells". PLOS ONE 6 (2): e16979. doi:10.1371/journal.pone.0016979. PMC 3037403. PMID 21347332.
  14. ↑ Schramedei K, Mörbt N, Pfeifer G, Läuter J, Rosolowski M, Tomm JM, von Bergen M, Horn F, Brocke-Heidrich K (Jun 2011). "MicroRNA-21 targets tumor suppressor genes ANP32A and SMARCA4". Oncogene 30 (26): 2975–85. doi:10.1038/onc.2011.15. PMC 3134876. PMID 21317927.
  15. ↑ Kim YJ, Hwang SJ, Bae YC, Jung JS (Dec 2009). "MiR-21 regulates adipogenic differentiation through the modulation of TGF-beta signaling in mesenchymal stem cells derived from human adipose tissue". Stem Cells 27 (12): 3093–102. doi:10.1002/stem.235. PMID 19816956.
  16. 1 2 3 Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M, Galuppo P, Just S, Rottbauer W, Frantz S, Castoldi M, Soutschek J, Koteliansky V, Rosenwald A, Basson MA, Licht JD, Pena JT, Rouhanifard SH, Muckenthaler MU, Tuschl T, Martin GR, Bauersachs J, Engelhardt S (Dec 2008). "MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts". Nature 456 (7224): 980–4. doi:10.1038/nature07511. PMID 19043405.
  17. ↑ Sayed D, Rane S, Lypowy J, He M, Chen IY, Vashistha H, Yan L, Malhotra A, Vatner D, Abdellatif M (Aug 2008). "MicroRNA-21 targets Sprouty2 and promotes cellular outgrowths". Molecular Biology of the Cell 19 (8): 3272–82. doi:10.1091/mbc.E08-02-0159. PMC 2488276. PMID 18508928.
  18. 1 2 Musilova K, Mraz M (May 2015). "MicroRNAs in B-cell lymphomas: how a complex biology gets more complex". Leukemia 29 (5): 1004–17. doi:10.1038/leu.2014.351. PMID 25541152.
  19. ↑ Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, Ménard S, Palazzo JP, Rosenberg A, Musiani P, Volinia S, Nenci I, Calin GA, Querzoli P, Negrini M, Croce CM (Aug 2005). "MicroRNA gene expression deregulation in human breast cancer". Cancer Research 65 (16): 7065–70. doi:10.1158/0008-5472.CAN-05-1783. PMID 16103053.
  20. ↑ Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P, Taccioli C, Volinia S, Liu CG, Alder H, Calin GA, Ménard S, Croce CM (Sep 2007). "MicroRNA signatures in human ovarian cancer". Cancer Research 67 (18): 8699–707. doi:10.1158/0008-5472.CAN-07-1936. PMID 17875710.
  21. ↑ Lui WO, Pourmand N, Patterson BK, Fire A (Jul 2007). "Patterns of known and novel small RNAs in human cervical cancer". Cancer Research 67 (13): 6031–43. doi:10.1158/0008-5472.CAN-06-0561. PMID 17616659.
  22. 1 2 3 Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, Prueitt RL, Yanaihara N, Lanza G, Scarpa A, Vecchione A, Negrini M, Harris CC, Croce CM (Feb 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): 2257–61. doi:10.1073/pnas.0510565103. PMC 1413718. PMID 16461460.
  23. ↑ Chan JA, Krichevsky AM, Kosik KS (Jul 2005). "MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells". Cancer Research 65 (14): 6029–33. doi:10.1158/0008-5472.CAN-05-0137. PMID 16024602.
  24. ↑ Hu Y, Correa AM, Hoque A, Guan B, Ye F, Huang J, Swisher SG, Wu TT, Ajani JA, Xu XC (Jan 2011). "Prognostic significance of differentially expressed miRNAs in esophageal cancer". International Journal of Cancer. Journal International Du Cancer 128 (1): 132–43. doi:10.1002/ijc.25330. PMC 2937084. PMID 20309880.
  25. ↑ Tetzlaff MT, Liu A, Xu X, Master SR, Baldwin DA, Tobias JW, Livolsi VA, Baloch ZW (2007). "Differential expression of miRNAs in papillary thyroid carcinoma compared to multinodular goiter using formalin fixed paraffin embedded tissues". Endocrine Pathology 18 (3): 163–73. doi:10.1007/s12022-007-0023-7. PMID 18058265.
  26. ↑ Wu K, Li L, Li S (Mar 2015). "Circulating microRNA-21 as a biomarker for the detection of various carcinomas: an updated meta-analysis based on 36 studies". Tumour Biology 36 (3): 1973–81. doi:10.1007/s13277-014-2803-2. PMID 25527152.
  27. ↑ Roy S, Khanna S, Hussain SR, Biswas S, Azad A, Rink C, Gnyawali S, Shilo S, Nuovo GJ, Sen CK (Apr 2009). "MicroRNA expression in response to murine myocardial infarction: miR-21 regulates fibroblast metalloprotease-2 via phosphatase and tensin homologue". Cardiovascular Research 82 (1): 21–9. doi:10.1093/cvr/cvp015. PMC 2652741. PMID 19147652.
  28. ↑ Patrick DM, Montgomery RL, Qi X, Obad S, Kauppinen S, Hill JA, van Rooij E, Olson EN (Nov 2010). "Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice". The Journal of Clinical Investigation 120 (11): 3912–6. doi:10.1172/JCI43604. PMC 2964990. PMID 20978354.
  29. ↑ Dong S, Cheng Y, Yang J, Li J, Liu X, Wang X, Wang D, Krall TJ, Delphin ES, Zhang C (Oct 2009). "MicroRNA expression signature and the role of microRNA-21 in the early phase of acute myocardial infarction". The Journal of Biological Chemistry 284 (43): 29514–25. doi:10.1074/jbc.M109.027896. PMC 2785585. PMID 19706597.
  30. ↑ Louwies T, Vuegen C, Panis LI, Cox B, Vrijens K, Nawrot TS, De Boever P (2016). "miRNA expression profiles and retinal blood vessel calibers are associated with short-term particulate matter air pollution exposure". Environmental Research 147: 24–31. doi:10.1016/j.envres.2016.01.027. PMID 26836502.

Further reading

  • Cardin S, Guasch E, Luo X, Naud P, Le Quang K, Shi Y, Tardif JC, Comtois P, Nattel S (Oct 2012). "Role for MicroRNA-21 in atrial profibrillatory fibrotic remodeling associated with experimental postinfarction heart failure". Circulation. Arrhythmia and Electrophysiology 5 (5): 1027–35. doi:10.1161/CIRCEP.112.973214. PMID 22923342. 
  • Zhong Z, Dong Z, Yang L, Gong Z (Oct 2012). "miR-21 induces cell cycle at S phase and modulates cell proliferation by down-regulating hMSH2 in lung cancer". Journal of Cancer Research and Clinical Oncology 138 (10): 1781–8. doi:10.1007/s00432-012-1287-y. PMID 22806311. 

External links

miRNA precursor families
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