MIRN21 explained

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 complementarily 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.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,[18] ovaries,[19] cervix,[20] colon,[9] lung,[21] liver,[10] brain,[22] esophagus,[23] prostate,[21] pancreas,[21] and thyroid.[24] A 2014 meta-analysis of 36 studies evaluated circulating miR-21 as a biomarker of various carcinomas, finding it has potential as a tool for early diagnosis.[25] miR-21 expression was associated with survival in 53 triple negative breast cancer patients.[26] miR-21 can also be detected in human faeces from colorectal cancer patients.[27] Additionally, it has been demonstrated as an independent prognostic factor in patients with pancreatic neuroendocrine neoplasms.[28]

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.[15] [29] 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.[15] 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.[30] 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.[31] 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.[32]

Further reading

External links

Notes and References

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  2. Liu M, Wu H, Liu T, Li Y, Wang F, Wan H, Li X, Tang H . 6 . Regulation of the cell cycle gene, BTG2, by miR-21 in human laryngeal carcinoma . Cell Research . 19 . 7 . 828–37 . July 2009 . 19546886 . 10.1038/cr.2009.72 . free .
  3. Wickramasinghe NS, Manavalan TT, Dougherty SM, Riggs KA, Li Y, Klinge CM . 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 . May 2009 . 19264808 . 2677875 . 10.1093/nar/gkp117 .
  4. Zheng J, Xue H, Wang T, Jiang Y, Liu B, Li J, Liu Y, Wang W, Zhang B, Sun M . 6 . miR-21 downregulates the tumor suppressor P12 CDK2AP1 and stimulates cell proliferation and invasion . Journal of Cellular Biochemistry . 112 . 3 . 872–80 . March 2011 . 21328460 . 10.1002/jcb.22995 . 5201999 . free .
  5. Lu TX, Munitz A, Rothenberg ME . MicroRNA-21 is up-regulated in allergic airway inflammation and regulates IL-12p35 expression . Journal of Immunology . 182 . 8 . 4994–5002 . April 2009 . 19342679 . 4280862 . 10.4049/jimmunol.0803560 .
  6. Hashimi ST, Fulcher JA, Chang MH, Gov L, Wang S, Lee B . 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 . July 2009 . 19398721 . 2927176 . 10.1182/blood-2008-09-179150 .
  7. Yelamanchili SV, Chaudhuri AD, Chen LN, Xiong H, Fox HS . MicroRNA-21 dysregulates the expression of MEF2C in neurons in monkey and human SIV/HIV neurological disease . Cell Death & Disease . 1 . 9 . e77 . September 2010 . 21170291 . 3002786 . 10.1038/cddis.2010.56 .
  8. 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 . 6 . 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 . December 2010 . 21078976 . 3000294 . 10.1073/pnas.1015541107 . 2010PNAS..10721098V . free .
  9. Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S, Allgayer H . MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer . Oncogene . 27 . 15 . 2128–36 . April 2008 . 17968323 . 10.1038/sj.onc.1210856 . free .
  10. Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T . MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer . Gastroenterology . 133 . 2 . 647–58 . August 2007 . 17681183 . 4285346 . 10.1053/j.gastro.2007.05.022 .
  11. Gabriely G, Wurdinger T, Kesari S, Esau CC, Burchard J, Linsley PS, Krichevsky AM . MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators . Molecular and Cellular Biology . 28 . 17 . 5369–80 . September 2008 . 18591254 . 2519720 . 10.1128/MCB.00479-08 .
  12. Sabatel C, Malvaux L, Bovy N, Deroanne C, Lambert V, Gonzalez ML, Colige A, Rakic JM, Noël A, Martial JA, Struman I . 6 . MicroRNA-21 exhibits antiangiogenic function by targeting RhoB expression in endothelial cells . PLOS ONE . 6 . 2 . e16979 . February 2011 . 21347332 . 3037403 . 10.1371/journal.pone.0016979 . 2011PLoSO...616979S . free .
  13. Schramedei K, Mörbt N, Pfeifer G, Läuter J, Rosolowski M, Tomm JM, von Bergen M, Horn F, Brocke-Heidrich K . 6 . MicroRNA-21 targets tumor suppressor genes ANP32A and SMARCA4 . Oncogene . 30 . 26 . 2975–85 . June 2011 . 21317927 . 3134876 . 10.1038/onc.2011.15 .
  14. Kim YJ, Hwang SJ, Bae YC, Jung JS . 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 . December 2009 . 19816956 . 10.1002/stem.235 . 32454261 .
  15. 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 . 6 . MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts . Nature . 456 . 7224 . 980–4 . December 2008 . 19043405 . 10.1038/nature07511 . 2008Natur.456..980T . 4333547 .
  16. Sayed D, Rane S, Lypowy J, He M, Chen IY, Vashistha H, Yan L, Malhotra A, Vatner D, Abdellatif M . 6 . MicroRNA-21 targets Sprouty2 and promotes cellular outgrowths . Molecular Biology of the Cell . 19 . 8 . 3272–82 . August 2008 . 18508928 . 2488276 . 10.1091/mbc.E08-02-0159 .
  17. Papagiannakopoulos T, Shapiro A, Kosik KS . MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells . Cancer Research . 68 . 19 . 8164–72 . October 2008 . 18829576 . 10.1158/0008-5472.CAN-08-1305 . free .
  18. 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 . 6 . MicroRNA gene expression deregulation in human breast cancer . Cancer Research . 65 . 16 . 7065–70 . August 2005 . 16103053 . 10.1158/0008-5472.CAN-05-1783 . free .
  19. 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 . 6 . MicroRNA signatures in human ovarian cancer . Cancer Research . 67 . 18 . 8699–707 . September 2007 . 17875710 . 10.1158/0008-5472.CAN-07-1936 . free .
  20. Lui WO, Pourmand N, Patterson BK, Fire A . Patterns of known and novel small RNAs in human cervical cancer . Cancer Research . 67 . 13 . 6031–43 . July 2007 . 17616659 . 10.1158/0008-5472.CAN-06-0561 . free .
  21. 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 . 6 . 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 . February 2006 . 16461460 . 1413718 . 10.1073/pnas.0510565103 . 2006PNAS..103.2257V . free .
  22. Chan JA, Krichevsky AM, Kosik KS . MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells . Cancer Research . 65 . 14 . 6029–33 . July 2005 . 16024602 . 10.1158/0008-5472.CAN-05-0137 . free .
  23. Hu Y, Correa AM, Hoque A, Guan B, Ye F, Huang J, Swisher SG, Wu TT, Ajani JA, Xu XC . 6 . Prognostic significance of differentially expressed miRNAs in esophageal cancer . International Journal of Cancer . 128 . 1 . 132–43 . January 2011 . 20309880 . 2937084 . 10.1002/ijc.25330 .
  24. Tetzlaff MT, Liu A, Xu X, Master SR, Baldwin DA, Tobias JW, Livolsi VA, Baloch ZW . 6 . Differential expression of miRNAs in papillary thyroid carcinoma compared to multinodular goiter using formalin fixed paraffin embedded tissues . Endocrine Pathology . 18 . 3 . 163–73 . 2007 . 18058265 . 10.1007/s12022-007-0023-7 . 40279671 .
  25. Wu K, Li L, Li S . 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 . March 2015 . 25527152 . 10.1007/s13277-014-2803-2 . 26060312 .
  26. Lánczky A, Nagy Á, Bottai G, Munkácsy G, Szabó A, Santarpia L, Győrffy B . miRpower: a web-tool to validate survival-associated miRNAs utilizing expression data from 2178 breast cancer patients . Breast Cancer Research and Treatment . 160 . 3 . 439–446 . December 2016 . 27744485 . 10.1007/s10549-016-4013-7 . 11165696 .
  27. Yau TO, Tang CM, Harriss EK, Dickins B, Polytarchou C . Faecal microRNAs as a non-invasive tool in the diagnosis of colonic adenomas and colorectal cancer: A meta-analysis . Scientific Reports . 9 . 1 . 9491 . July 2019 . 31263200 . 6603164 . 10.1038/s41598-019-45570-9 . 2019NatSR...9.9491Y .
  28. Grolmusz VK, Kövesdi A, Borka K, Igaz P, Patocs A . Prognostic relevance of proliferation-related miRNAs in pancreatic neuroendocrine neoplasms . European Journal of Endocrinology . 179 . 4 . EJE–18–0305 . July 2018 . 30006373 . 10.1530/EJE-18-0305 . free .
  29. Roy S, Khanna S, Hussain SR, Biswas S, Azad A, Rink C, Gnyawali S, Shilo S, Nuovo GJ, Sen CK . 6 . 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 . April 2009 . 19147652 . 2652741 . 10.1093/cvr/cvp015 .
  30. Patrick DM, Montgomery RL, Qi X, Obad S, Kauppinen S, Hill JA, van Rooij E, Olson EN . 6 . Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice . The Journal of Clinical Investigation . 120 . 11 . 3912–6 . November 2010 . 20978354 . 2964990 . 10.1172/JCI43604 .
  31. Dong S, Cheng Y, Yang J, Li J, Liu X, Wang X, Wang D, Krall TJ, Delphin ES, Zhang C . 6 . 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 . October 2009 . 19706597 . 2785585 . 10.1074/jbc.M109.027896 . free .
  32. Louwies T, Vuegen C, Panis LI, Cox B, Vrijens K, Nawrot TS, De Boever P . miRNA expression profiles and retinal blood vessel calibers are associated with short-term particulate matter air pollution exposure . Environmental Research . 147 . 24–31 . May 2016 . 26836502 . 10.1016/j.envres.2016.01.027 . 2016ER....147...24L .

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