Biology:mIRN21

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Short description: Non-coding RNA in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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,[10] lung,[21] liver,[11] 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.[16][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.[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.[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]

References

  1. ↑ "Identification of novel genes coding for small expressed RNAs". Science 294 (5543): 853–8. October 2001. doi:10.1126/science.1064921. PMID 11679670. Bibcode: 2001Sci...294..853L. 
  2. ↑ "Regulation of the cell cycle gene, BTG2, by miR-21 in human laryngeal carcinoma". Cell Research 19 (7): 828–37. July 2009. doi:10.1038/cr.2009.72. PMID 19546886. 
  3. ↑ "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. doi:10.1093/nar/gkp117. PMID 19264808. 
  4. ↑ "miR-21 downregulates the tumor suppressor P12 CDK2AP1 and stimulates cell proliferation and invasion". Journal of Cellular Biochemistry 112 (3): 872–80. March 2011. doi:10.1002/jcb.22995. PMID 21328460. 
  5. ↑ 5.0 5.1 5.2 "MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells". Cancer Research 68 (19): 8164–72. October 2008. doi:10.1158/0008-5472.CAN-08-1305. PMID 18829576. 
  6. ↑ "MicroRNA-21 is up-regulated in allergic airway inflammation and regulates IL-12p35 expression". Journal of Immunology 182 (8): 4994–5002. April 2009. doi:10.4049/jimmunol.0803560. PMID 19342679. 
  7. ↑ "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. doi:10.1182/blood-2008-09-179150. PMID 19398721. 
  8. ↑ "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. doi:10.1038/cddis.2010.56. PMID 21170291. 
  9. ↑ "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. doi:10.1073/pnas.1015541107. PMID 21078976. Bibcode: 2010PNAS..10721098V. 
  10. ↑ 10.0 10.1 "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. doi:10.1038/sj.onc.1210856. PMID 17968323. 
  11. ↑ 11.0 11.1 "MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer". Gastroenterology 133 (2): 647–58. August 2007. doi:10.1053/j.gastro.2007.05.022. PMID 17681183. 
  12. ↑ "MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators". Molecular and Cellular Biology 28 (17): 5369–80. September 2008. doi:10.1128/MCB.00479-08. PMID 18591254. 
  13. ↑ "MicroRNA-21 exhibits antiangiogenic function by targeting RhoB expression in endothelial cells". PLOS ONE 6 (2): e16979. February 2011. doi:10.1371/journal.pone.0016979. PMID 21347332. Bibcode: 2011PLoSO...616979S. 
  14. ↑ "MicroRNA-21 targets tumor suppressor genes ANP32A and SMARCA4". Oncogene 30 (26): 2975–85. June 2011. doi:10.1038/onc.2011.15. PMID 21317927. 
  15. ↑ "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. doi:10.1002/stem.235. PMID 19816956. 
  16. ↑ 16.0 16.1 16.2 "MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts". Nature 456 (7224): 980–4. December 2008. doi:10.1038/nature07511. PMID 19043405. Bibcode: 2008Natur.456..980T. 
  17. ↑ "MicroRNA-21 targets Sprouty2 and promotes cellular outgrowths". Molecular Biology of the Cell 19 (8): 3272–82. August 2008. doi:10.1091/mbc.E08-02-0159. PMID 18508928. 
  18. ↑ "MicroRNA gene expression deregulation in human breast cancer". Cancer Research 65 (16): 7065–70. August 2005. doi:10.1158/0008-5472.CAN-05-1783. PMID 16103053. 
  19. ↑ "MicroRNA signatures in human ovarian cancer". Cancer Research 67 (18): 8699–707. September 2007. doi:10.1158/0008-5472.CAN-07-1936. PMID 17875710. 
  20. ↑ "Patterns of known and novel small RNAs in human cervical cancer". Cancer Research 67 (13): 6031–43. July 2007. doi:10.1158/0008-5472.CAN-06-0561. PMID 17616659. 
  21. ↑ 21.0 21.1 21.2 "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. doi:10.1073/pnas.0510565103. PMID 16461460. Bibcode: 2006PNAS..103.2257V. 
  22. ↑ "MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells". Cancer Research 65 (14): 6029–33. July 2005. doi:10.1158/0008-5472.CAN-05-0137. PMID 16024602. 
  23. ↑ "Prognostic significance of differentially expressed miRNAs in esophageal cancer". International Journal of Cancer 128 (1): 132–43. January 2011. doi:10.1002/ijc.25330. PMID 20309880. 
  24. ↑ "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. doi:10.1007/s12022-007-0023-7. PMID 18058265. 
  25. ↑ "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. doi:10.1007/s13277-014-2803-2. PMID 25527152. 
  26. ↑ "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. doi:10.1007/s10549-016-4013-7. PMID 27744485. 
  27. ↑ "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. doi:10.1038/s41598-019-45570-9. PMID 31263200. Bibcode: 2019NatSR...9.9491Y. 
  28. ↑ "Prognostic relevance of proliferation-related miRNAs in pancreatic neuroendocrine neoplasms". European Journal of Endocrinology 179 (4): EJE–18–0305. July 2018. doi:10.1530/EJE-18-0305. PMID 30006373. http://www.eje-online.org/content/early/2018/07/13/EJE-18-0305. 
  29. ↑ "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. doi:10.1093/cvr/cvp015. PMID 19147652. 
  30. ↑ "Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice". The Journal of Clinical Investigation 120 (11): 3912–6. November 2010. doi:10.1172/JCI43604. PMID 20978354. 
  31. ↑ "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. doi:10.1074/jbc.M109.027896. PMID 19706597. 
  32. ↑ "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. doi:10.1016/j.envres.2016.01.027. PMID 26836502. Bibcode: 2016ER....147...24L. 

Further reading

  • "Role for MicroRNA-21 in atrial profibrillatory fibrotic remodeling associated with experimental postinfarction heart failure". Circulation: Arrhythmia and Electrophysiology 5 (5): 1027–35. October 2012. doi:10.1161/CIRCEP.112.973214. PMID 22923342. 
  • "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. October 2012. doi:10.1007/s00432-012-1287-y. PMID 22806311. 

External links



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